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Tardiv dyskinesi

Tilstand med ufrivillige tungebevægelser, urolig krop og mere træge cognitive evner end da personen var rask

Akathisia = urolighed i kroppen, har svært ved at sidde stille, skal helst bevæge sig eller gå småture. Meget vanskelig form for TD at behandle.

Tardiv dyskinesi (Tardive dyskinesia) (TD), dvs. forsinket udvikling (tardiv = langsom) af fejlfunktion af kroppens bevægelser, med udvikling af ufrivillige bevægelser af tungen, evt. læber og ansigt, samt ben og arme og evt. uro i kroppen.

MENNESKER DER HAR HAFT TD SKAL ADVARES MOD AT FÅ DOPAMIN-RECEPTOR BLOKERENDE LÆGEMIDLER I FREMTIDEN!  Advise the patient to avoid receiving dopamine-receptor blocking drugs. Advise the patient to obtain a medical alert bracelet to warn against the administration of dopamine-receptor blocking drugs

Vigtigt: Undgå store doser af antipsykotisk medicin, og brug medicinen i kortest mulig tid. Undgå det evt. helt om muligt. Vær opmærksom på tidligere tegn på TD.

Trap ikke hurtigt, men derimod langsomt ud af behandlingen med antipsykotisk medicin (da hurtig stop kan fremkalde TD). It is preferable to taper the dose slowly (by 10% increments of the original dose) while closely observing the patient for exacerbation of psychotic symptoms. Tilstanden kan optræde efter at man stopper med at tage lægemidlet. TD may worsen initially after neuroleptics are discontinued. Unlike TDs, withdrawal dyskinesias remit [dvs. lindres] within a month after discontinuance of neuroleptics.

Prevention-based focus of TD treatment starts with a clinical consideration of pharmacologic choices related to each individual patient's history.

TD ses hos 20%-50% af patienter der tager antipsykotisk medicin (men optræder også med andre medicinformer).

En person med TD har mindre fleksible cognitive evner, husker dårligere, forstår dårligere, og har svært ved at koncentrere sig om at læse en bog.

Især ældre mænd kan få Tardive dyskinesi af Pregabalin: https://www.ehealthme.com/ds/pregabalin/tardive-dyskinesia/

BEHANDLING AF TD:

QUETIAPINE: Amelioration [dvs. lindring] of TD resulting from the administration of quetiapine (dvs. at stoffet lindrer TD). Quetiapine er en dopamine antagonist: Increased dopamine transport (DAT) uptake after treatment with quetiapine has been reported with the amelioration of TD. Quetiapine er en second-generation antipsychotics

  • GINKGO BILOBA: Ginkgo Biloba (f.eks. 240 mg 1x dagligt) lindrer TD. Der kan bruges 240 mg/dag af  EGb-761, som er et standardiseret ekstrakt i kapselform.  Anbefalet daglig dosis til mennesker uden sygdom er er 120-240 mg/dag, men dosis i præparaterne varierer fra 100 mg dosis til 5.000 mg dosis. Ginkgo biloba indholder syren ginkgolic, som kan forårsage allergi. Ginkgo er blodfortyndende (stop en uge før operation).

(I en forsøg med mus gav man musene 100 mg pr. kg, svarende til 8000 mg. pr. 80 kg). The evidenced-based guidelines of the American Academy of Neurology recommend the use of Ginkgo biloba for TD. [The American Academy of Neurology suggest that ginkgo biloba extract may also help relieve tardive dyskinesia symptoms in some people. It is worth noting, however, that its effects were only studied in people hospitalized with schizophrenia. Ginkgo biloba extract is a potent antioxidant possessing free radical-scavenging properties. Ginkgo biloba øger koncentrationen af BDNF (brain-derived neurotrophic factor)

Frie radikaler kan medføre lav koncentration af BDNF (brain-derived neurotrophic factor)

Until recently, there were no FDA-approved treatments for tardive dyskinesia. In 2017, two medications were approved to treat this condition:

Valbenazin (VALBENAZINE (INGREZZA)): Er endnu ikke godkendt i Europa . Har vedvarende effekt i op til et års behandling, men 1 måned efter behandlingsophør oplever patienterne en forværring af symptomerne til samme sværhedsgrad som før behandlingen. 40 mg/dag i første uge, derefter 80 mg dagligt. FDA-approved to treat tardive dyskinesia (APPROVED AS FIRST DRUG AGAINST TD). FDA has approved valbenazine(Ingrezza), the first drug to treat tardive dyskinesia. Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor. These drugs modulate the presynaptic packaging and release of dopamine into the synapse, and may offset the movement-related effects of antipsychotics and other dopaminergic blockers. 40% af patienterne gavnedes af behandlingen hvis de fik 80 mg dagligt. Valbenazine (VBZ) = kapsler med 40 mg eller 80 mg. Start med 40 mg dagligt. Efter en uge tages 80 mg dagligt (forbliv på 40 mg/dag hvis leveren er moderat eller svært dårlig, eller hvis der også tages stærke CYP3A4-inducers eller dårlig CYP3A4-metabolisme)  (en kapsel der sluges, behøver ikke at være sammen med mad men kan tages sammen med mad). Bruges ikke til patienter med "Medfødt Langt Qt syndrom" (tjekkes med en EKG-test; nogle lægemidler forlænger QTc). FDA-godkendt mod TD d. 11. april 2017. Highly‐selective reversible VMAT2 inhibitor . Orally active agent with two active metabolites also highly selective for VMAT2: NBI‐98782 [(+)α‐dihydrotetrabenazine] and NBI‐136110 • Unique pharmacokinetic profile results in reduced peak plasma concentrations and variability that may improve safety/tolerability • Once daily dosing (T1/2=20 hours). I et studie brugtes 100 mg. I et andet studie brugtes 25-75 mg. I et tredie studie brugtes 40 eller 80 mg (bedre virkning end ved 40 mg ved 2 måneders behandling). Der anvendtes 40 mg den første måned. Efter ½ år var der ikke forskel på 40 mg og 80 mg grupperne. (Tåles godt. Bivirkninger: døsighed; i et studie: 9% urinvejsinfektion, 5% hovedpine). Valbenazine is not contraindicated in hepatic dysfunction

https://www.psykiatri-regionh.dk/presse-og-nyt/pressemeddelelser-og-nyheder/Forskningsresumeer/Sider/Nyt-pr%C3%A6parat-behandler-tardiv-dyskinesi.aspx?rhKeywords=tardiv+dyskinesi

DEUTETRABENAZINE (AUSTEDO) 24 mg/day –  36 mg/day is FDA-approved to treat tardive dyskinesia. Deutetrabenazine (Austedo) is a novel, highly selective vesicular monoamine transporter type 2 (VMAT2) inhibitor. FDA has approved deutetrabenazine tablets for the treatment of adults with tardive dyskinesia (TD). 24 mg/day and 36 mg/day—were associated with statistically significant improvement in patients’

Følgende (VMAT2 inhibitors) kan lindre akathisia-TD (uro i kroppen):

propranolol

clonazepam

anticholinergics

mirtazapine

 

PROPRANOLOL (VMAT2 inhibitor) is useful for tardive akathisia. Lav dosis af propranolol lindrer TD.

CLONAZEPAM 2 mg/dag (VMAT2 inhibitor) Lindrer TD. 1-4.5 mg/day showed a decrease of TD symptoms by 35%. The evidenced-based guidelines of the American Academy of Neurology recommend the use of clonazepam for TD. [There is some evidence that an anti-anxiety drug known as clonazepam can help treat tardive dyskinesia, but this drug can be habit-forming.

CLOZAPINE: Clozapine has treated tardive tremor successfully. In particular, clozapine has been recommended as treatment for patients with TD who require antipsychotics. Although clozapine has been associated with TD, [64] the incidence of TD with this and other atypical agents appears markedly less than that of traditional neuroleptics. The benefits of clozapine may result from its affinity for the D4 receptor. Clozapine er en second-generation antipsychotics. Treatment with CLOZAPINE requires regular hematologic evaluation to avoid fatal agranulocytosis.

Clozapine er en serotonin-  og dopamin-receptor antagonist [hvordan virker det forskelligt fra Risperidon, for Risperidon er også en dopamin-receptor antagonist?]. Clozapine er det bedste valg når en patient skal have antipsykotisk medicin og vil undgå TD.  Det kan også stoppe TD-bivirkningerne.

Ondansetron, a selective 5-hydroxytryptamine-3 antagonist, has helped some individuals with TD.

Other therapeutic agents for which there is some anecdotal support include  benzodiazepines, botulinum toxinreserpinetetrabenazine, , [66] and dopamine-depleting agents.

olanzapine også kaldt  zyprexa (2,5-30mg/dag), er en dopamine og  serotonin receptor antagonist, kan lindre TD-symptomer

Donepezil, en reversibel acetylcholinesterase-hæmmer, nedsætter TD-bivirkningerne.

Apomorphine, en dopamine receptor antagonist, kan lindre TD-symptomer når det gives sammen med L-DOPA

En tetrabenazine-analog såsom valbenazine, (og tetrabenazine selv har samme virkning, men det nedbrydes for hurtigt i kroppen til at virke godt) kan lindre TD,  og synes at være særlig velegnet til at lindre TD.

Amantadine lindrer TD når det gives til Parkinsonpatienter som får L-DOPA (og som får TD af L-DOPA)

Branched-chain amino acids (BCAAs) lindrer TD. De nedsætter blodets indhold af phenylalanin ved at stimulere proteinsyntesen og insulin-frigivelsen.  De nedsætter også ophobningen af tyrosin som er forstadie til dopamin. Derved nedsættes dopamin-syntesen i hjernen.  BCAA kan købes i helsekostforretninger, såsom forretningen "The Touch" på 2. sal th i Frederiksbergcenteret. 

Da oxidativt stress medvirker til TD (formentlig) kan antioxidanter gives som tilskud og derved lindre TD, f.eks.  zonisamide, yi gan san (en kinesisk urt, herb), levetiracetam, melatonin, omega-3 fedtsyrer, piracetam, resveratrol, vitamin B6 og vitamin E.

Curcumin, an antioxidant, may prevent the development of dyskinesia.

There is not enough evidence to show whether other natural remedies, such as vitamin E and melatonin, work for tardive dyskinesia.

Andre midler mod TD:

  • Ginkgo biloba • Amantadine • Clonazepam • Tetrabenazine • Pyridoxine • Melatonin Additional Treatment Interventions for Tardive Dyskinesia Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther. 2013. • Vitamin E • Botulinum toxin • Zonisamide • Levetiracetam • Branched chain amino acids • Omega‐3 fatty acids

Discontinuance of anticholinergic therapy may relieve TD. A controversial strategy for treating TD is to continue or increase the dose of the dopamine antagonist. Anecdotal support also include levodopa (synes at være ulogisk, der henvises til carbidopa/levodopa). Antiparkinsonism agents usually do not improve neuroleptic-induced dyskinesias.

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ÅRSAG TIL TD:

Skyldes medicin-bivirkning, såkaldt "dopaminergic antagonist medications", typisk antipsykotiske lægemidler (antipsychotic drugs [APD] – men også en række andre lægemidler, se nedenfor og se artiklens kilde ovenfor).

Tilstanden kan optræde efter kort tids brug eller længere tids brug af lægemidlet. TD kan udløses af blot 2 uger på medicinen.  (kilde 3: https://www.jns-journal.com/article/S0022-510X(18)30063-7/pdf)

Hvis det varer mindst 1 måned efter at man er ophørt med at tage lægemidlet har man en TD-diagnose.

I mange patienter er TD irreversibel.  Det er meget generende for patientens dagligdag og sociale liv og kan hæmme evnen til at læse mv.

Årsagen tænkes at være blokering af de postsynaptiske dopamin-receptorer, hvilket kroppen søger at kompensere for ved at gøre dopamin-receptorerne alt for meget følsomme (dopamine receptor supersensitivity) samt nedsætte mængden af GABA (gamma-aminobutyric acid (GABA) depletion) samt fremkalde mangel på acetylcholin (cholinergic deficiency) samt medføre noget som kræver antioxidanter (tilstanden oxidative stress) og ved at ændre synapsernes forandringsparathed (altered synaptic plasticity) og ved at dræbe visse hjerneceller (neurotoxicity) og ved at give fejl i hjernecellernes signalkommunikation når de påvirkes (defective neuroadaptive signaling)..

Med hensyn til den forklaring, som går ud på at lægemidlets bivirkning, altså TD-tilstanden, skyldes at lægemidlet har blokeret for dopamin, hvorved kroppen har reageret ved at opregulere følsomheden hos dopamin-receptorerne, så vil resultatet altså være, at der kommer et for stort respons på dopamin, når dette dopamin rammer receptorerne (efter synapsekløften mellem to hjernenerveceller, dvs. postsynaptisk).

Man kan tænke sig, at kroppen (måske som kompensation) danner for meget dopamin.  Denne øgede "dopamin-metabolisme" medfører øget dannelse af frie radikaler. 

Enzymet Monoaminoxidase metaboliserer dopamin. Og dette kan fremkalde skadelig iltning af fedtmolekyler ((dvs. fremkalde lipid peroxidation og ændring af antioxidant-enzymer, hvilket kan dræbe celler i hjernen. Dopamin i sig selv kan også give disse virkninger. 

De såkaldte basalganglier (basal ganglia), og bestemte hjerneområder inde i hjernen, som kaldes "subcortical nuclei" og som bl.a. er områderne "striatum" og "substantia nigra" har mange nerveceller, som bruger dopamin som signalstof. Disse steder i hjernen er derfor særlig følsomme og udsatte for oxidativt stress og hvis det sker, opstår TD (de ufrivillige bevægelser).

 

Nedbrydningsprodukterne af psykofarm-lægemidler kan i sig selv være giftige for disse hjernenerveceller, igen formentlig fordi de fremkalder oxidativt stress. 

Proton magnetic resonance spectroscopy has demonstrated neural damages in the left lenticular nucleus in a group of patients with TD.

Der kan også være genetiske varianter, idet nogle mennesker har særlige varianter af dopamine D3 receptor Ser9Gly og i øvrigt er der også særlige varianter af serotonin 2A receptoren og serotonin 2C receptoren.

Der kan også være nogle mennesker med særlige varianter af neurotrophic factor Val66Met

Disse personer kan være særlig følsomme for disse typer af oxidativt stress.

TD opstår hos hver tredje som får såkaldt "typisk antipsykotisk medicin" (typical APD) får TD, dvs. ufrivillige bevægelser.

TD opstår hos hver 7. af dem, som får "atypisk antipsykotisk medicin (atypical APD). Årsagen er at de atypiske (!) antipsykotiske lægemidler bindes svagere til dopamin-D2 receptor i "dorsal striatum"

OBS: Et studie viste, at de gamle præparater måske ikke er så tossede: Ifølge forfatterne skyldes den hyppigere ordination af antikolinerg medicin (bivirkningsmedicin) hos de patienter, der fik de ældre antipsykotika, sikkert ”den kliniske forventning om hyppigere bivirkninger”. Forskerne konkluderer, at ordinationen af antikolinerg medicin mod bivirkninger, kan betyde, at behandling med ældre antipsykotika kan have en lige så lav risiko for ekstrapyramidale bivirkninger som de nyere antipsykotika – men uden de livsforkortende metaboliske bivirkninger (som de nyere midler kan være for nogle patienter, må man forstå! Der var hele 30 gange større chance for at lægerne gav medicin mod bivirkningerne, når patienten fik de gamle første-generations lægemidler. Nutidens psykiatere har ikke erfaring med de gamle lægemidler). Kilde: https://www.psykiatri-regionh.dk/presse-og-nyt/pressemeddelelser-og-nyheder/Forskningsresumeer/Sider/Nyere-antipsykotika-har-flere-ekstrapyramidale-bivirkninger-end-antaget.aspx?rhKeywords=tardiv+dyskinesi

risperidone, aripiprazole og amisulpride er såkaldt "atypiske" antipsykotiske lægemidler som kan give TD.

Nogle mennesker er mere følsomme herfor, det gælder f.eks.  ældre kvinder. Østrogen har en antioxidant virkning, som måske beskytter mod TD (derfor er ældre kvinder, der er ældre og altså lever efter den tid hvor kroppen danner meget østrogen, mere udsat for TD).

Blokering af dopamin-receptorer skyldes lægemidler, som virker som "dopamin antagonister", måske især "dopamin-D2 receptor antagonister, så basal-ganglierne bliver for supersensitive for dopamin-D2.

D3 og D5 receptorer, og ikke kun D2 dopaminreceptorer er også forbundet med TD på denne måde.

Ubalance mellem dopamin og acetylcholin kan sandsynligvis også give TD. 

Ubalance mellem dopamin og serotonin kan sandsynligvis også give TD. (idet for meget serotonin, fremkaldt af SSRI-lægemidler, hæmmer dannelsen af dopamin, og så bliver dopaminreceptorerne også supersensitive af denne grund). 

Ubalance mellem dopamin og GABA: GABA-nerveceller kan hæmme dopamin-nerveceller i visse hjerneområder.

Personer som tager lithium har større risiko for at et antipsykotisk lægemiddel vil fremkalde TD. 

SSRI-lægemidler, såsom fluoxetine, kan medføre TD.  Det samme gælder sertraline, et andet SSRI.

Monoamine oxidase inhibitors (MAOI) bruges mod depression og Parkinson. Det hæmmer metabolismen af monoaminer. Derved kan niveauet af monoaminer øges. Der findes to typer af monoamine oxidase (MAO) Type A og type B. De laves i hypothalamus, hippocampus og cingulate cortex og striatum samt globus pallidus (de sidste to er især type B). Hjernebarken har kun høje niveauer af type A. Dette forklarer at det er lægemidler som virker på type B som kan fremkalde TD (da type B laves i hjerneområder hvor der er meget dopamin, såsom striatum-hjerneområdet).

Selegiline bindes f.eks. kun til MAO-type B hvorved enzymet inaktiveres så dets aktivitet hæmmes altså.

Rasagiline, har samme historie, men giver TD i mildere grad.

Phenelzine, bindes både til type A og til type B. Den giver også TD.

TD kan også opstå fra lægemidler mod kvalme, mod malaria, mod allergi, og mod Parkinson og mod frygt mv. se artiklen ifølge kilden ovenfor.

Følgende er ikke godt, når man har TD: histamine, serotonin, norepinephrine, dopamine, and epinephrine. Tyramin  i gammel ost, kød, fermenterede madvarer, alkohol, chokolade.

Lav dosis (100 mg) caffein nedsætter TD (men høj dosis caffein (over 1000 mg) er dårligt og øger TD). Haloperidol induced vacuous chewing movements, orofacial movements, and facial stereotypies in rats. These changes were reversed after treatment with adenosine or caffeine;

The prevalence of TD is higher in cigarette smokers

Tungemusklen bliver større på grund af den stadige aktivering (macroglossia).

Når tungen bevæges ud af munden kaldes dette for fly-catchers tongue.

Kun 2% bliver helt raske af TD.

Symptoms typically begin with an insidious [snigende] onset, evolving to a full syndrome over days to weeks following onset. This is followed by a stabilization of symptoms in a chronic, but
sometimes waxing and waning [= øge og falde, komme og gå, variere over tid] course [11].

Tungebevægelserne kan mindskes under tale og spisning eller når man sætter en finger på læben. TS can persist for years after discontinuation of the offending agent, although some patients can experience partial or complete remission [= bedring] of symptoms a few years after discontinuation of the causative agent.

The prevalence of TD is 29% in elderly patients receiving dopamine antagonist treatment for 3 months and 26-67% in patients undergoing long-term treatment.

Diagnosis of neuroleptic-induced TD generally requires exposure to neuroleptics for at least 3 months. At least 1 month of exposure is typically required if the patient is aged 60 years or older.

Neuroleptic-induced TDs are absent during sleep.

Test for TD:

Have the patient sit in a chair with hands on knees, legs slightly apart, and feet flat on the floor. Examine the entire body for movements while the patient is in this position, then ask the patient to count backwards from 30.

Ask the patient to sit with hands hanging unsupported (between the legs if male, or hanging over the knees if female and wearing a dress). Observe the hands and other body areas, then request that the patient describe in detail the path traveled that day. Ask the patient where the trip started, what streets were traveled, where turns were made, where the trip terminated, and what floor and room were entered. These procedures stimulate the patient and may provoke the appearance of movement disorders.

If asked to hold the tongue in a protruded position, the person may be unable to maintain protrusion for longer than 1 second. Although the individual may attempt to disguise the movements by placing the hand to the mouth, in time, the movements become constant during waking hours and cannot be suppressed by the patient.

Ask the individual to remove shoes and socks so that the movements of the toes and feet can be observed fully. Movements typically become constant during waking hours. Often, the individual cannot suppress them for longer than 1 second.

Neuroleptic-induced TD is present at rest and diminishes or subsides when the affected body part is activated. For example, squeezing the hand of another person often eliminates finger dyskinesias, tongue protrusion commonly reduces tongue dyskinesias, and mouth opening diminishes orofacial dyskinesias. Simply pointing out these movements and asking the patient to stop can reduce the movements. For example, orofacial movements may be stopped by placing the patient’s fingers on his or her lips.

Asking the patient to repeatedly touch the thumb to each finger sequentially in both hands may amplify TD in the tongue and the face. Provocative distracting movements may be necessary to induce movement in mild TD

Tardive akathisia includes the presence of subjective symptoms of restlessness and the urge to move. It refers to the inability to sit down or remain still. People with tardive akathisia exhibit constant pacing and moving of the hands and feet. They typically shift their weight from one foot to the other when standing and swing their legs when sitting.

Examine the patient with his or her feet bare and hands exposed so that movements of the extremities can be observed. Ask the patient to sit, stand, and lie still for 2 minutes in each position.

After the patient has maintained the designated position for a full minute, ask, “Do you feel restless inside? Do you have the urge to move? Are you able to keep your feet still?” If the patient responds that these sensations are present, ask him or her to quantify the magnitude of the urge to move as mild, moderate, or severe.

Kilder:

Posted on October 9, 2018 | By adminNo comments

Ochsner J. 2017 Summer; 17(2): 162–174.

Medication-Induced Tardive Dyskinesia: A Review and Update

Elyse M. Cornett, PhD,1 Matthew Novitch, BS,2 Alan David Kaye, MD, PhD,3 Vijay Kata, MS,3 and Adam M. Kaye, PharmD4

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https://emedicine.medscape.com/article/1151826-overview#a2

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https://www.medicalnewstoday.com/articles/320175.php

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https://emedicine.medscape.com/article/1151826-overview#a1

og

https://emedicine.medscape.com/article/1151826-questions-and-answers

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Man kan læse om emnet ved at lave en søgning på "medication-induced TD" eller "tardive dyskinesia".

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https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD000208.pub2/full

Kilden konkluderede at ingen midler var klinisk egnede mod TD, men at der måske var en lille virkning af VALBENAZINE (INGREZZA) og måske af Ginkgo biloba.

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https://www.ceconcepts.com/assets/425/CPNP%20TD%20Participant%20Handout.pdf

The risk of relapse of TD without antipsychotics for patients diagnosed with psychosis is greater than 50%

  • Annual incidence of TD with SGAs (second-generation antipsychotica) is 3.9% vs. 5.5% with FGAs (first-generation antipsychotica)

Global TD prevalence = 25.3% • Current: SGA 20.7%  vs. FGA 30.0% (P=0.002) • Lower TD prevalence in FGA‐naive patients vs. SGA treated with FGA history

  • Four hypotheses 1) D2 receptor upregulation in nigrostriatal pathway resulting in hypersensitivity to dopamine 2) Loss of cholinergic interneurons in the basal ganglia 3) Disruption of GABA/glutamate axis resulting in hyperstimulation 4) Oxidative stress underlying all three of the above

Increased age (higher incidence and lower remissions over age 50) • Female gender • Postmenopausal • Head injury • Substance abuse (including tobacco) • Primary mood disorder • Concurrent medical disease (diabetes) • Use of antipsychotics in high doses • Exposure to antipsychotics over time • History of acute EPS with antipsychotics (Parkinsonism, dystonia, akathisia) • Exposure to anticholinergics [dvs. anticholinergika, som hæmmer den fysiologiske virkning af acetylsholin på receptoren. Atropin har antikolinerg virkning. Antikolinerge stoffer bruges til behandling af lidelser i bevægeapparatet eller tarmkramper, mavekramper, køresyge, Parkinsons sygdom]

  • Drug‐induced Parkinsonism

Midler mod TD: • Ginkgo biloba • Amantadine • Clonazepam • Tetrabenazine • Pyridoxine • Melatonin Additional Treatment Interventions for Tardive Dyskinesia Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther. 2013. • Vitamin E • Botulinum toxin • Zonisamide • Levetiracetam • Branched chain amino acids • Omega‐3 fatty acids

Tetrabenazine (TBZ) = • VMAT2 reversible inhibitor • Treatment used for schizophrenia in the 1970s; obtained FDA approval in 2009 for Huntington’s disease • May have therapeutic application in wide variety of hyperkinetic movement disorders • Requires dosing titration and TID dosing • Numerous adverse effects limit its clinical use; some serious and potentially fatal: • Sedation, parkinsonism, EPS, dysphagia, hypotension, neuroleptic malignant syndrome • Depression, suicidality (BOXED WARNING)

Deutetrabenazine (12, 24 eller 36 mg/dag i forsøg; virkning indtræder først efter 1-2 måneder; bivirkninger hos 10%: døsighed (eller svært ved at falde i søvn), snue, angst, hovedpine, depression; 5% parkinsonisme, 8% diarre. FDA-godkendt 30.aug.2017 mod TD, var FDA-godkendt mod Huntingtons chorea 4.apr.2017, tabletter i 6 mg, 9 mg, 12 mg. Mod TD startes (indtages samtidig med mad) med 6 mg 2x dagligt med yderligere 6 mg pr. dag dosis stigning hver uge indtil op til 24 mg 2x dagligt eller mindre så snart TD lindres; Maximum dose in poor CYP2D6 metabolizers (or concomitant use of strong CYP2D6 inhibitors) is 36 mg per day)= (bliver længere tid i kroppen og har derfor mindre udsving i giftig koncentration end Tetrabenazine) • VMAT2 reversible inhibitor • Deutetrabenazine is a novel molecule structurally related to tetrabenazine • Incorporates deuterium (dvs. hydrogen med en ekstra neutron) in lieu of hydrogen at first metabolism sites • Deuteration of TBZ results in a more than 2‐fold increase in systemic exposure to total (α+β)‐HTBZ, a near doubling of half‐life • The increased half‐life of total (α+β)‐HTBZ allows for administration of lower doses of deutetrabenazine compared with TBZ, thus permitting comparable plasma exposure with lower peak and higher trough concentrations • FDA‐approved for both Tardive Dyskinesia (8/30/17) and Huntington’s disease (4/4/17) • BID dosing (dvs. to-gange-om-dagen doser) for TD: doses ≥12 mg/day should be divided)

Valbenazine (VBZ) = kapsler med 40 mg eller 80 mg. Start med 40 mg dagligt. Efter en uge tages 80 mg dagligt (forbliv på 40 mg/dag hvis leveren er moderat eller svært dårlig, eller hvis der også tages stærke CYP3A4-inducers eller dårlig CYP3A4-metabolisme)  (en kapsel der sluges, behøver ikke at være sammen med mad men kan tages sammen med mad). Bruges ikke til patienter med "Medfødt Langt Qt syndrom" (tjekkes med en EKG-test; nogle lægemidler forlænger QTc). FDA-godkendt mod TD d. 11. april 2017. Highly‐selective reversible VMAT2 inhibitor . Orally active agent with two active metabolites also highly selective for VMAT2: NBI‐98782 [(+)α‐dihydrotetrabenazine] and NBI‐136110 • Unique pharmacokinetic profile results in reduced peak plasma concentrations and variability that may improve safety/tolerability • Once daily dosing (T1/2=20 hours). I et studie brugtes 100 mg. I et andet studie brugtes 25-75 mg. I et tredie studie brugtes 40 eller 80 mg (bedre virkning end ved 40 mg ved 2 måneders behandling). Der anvendtes 40 mg den første måned. Efter ½ år var der ikke forskel på 40 mg og 80 mg grupperne. (Tåles godt. Bivirkninger: døsighed; i et studie: 9% urinvejsinfektion, 5% hovedpine). Valbenazine is not contraindicated in hepatic dysfunction

En 40-årig med bipolær lidelse fik TD efter i  5 år at have fået Risperidone 0.5 mg po TID (samtidig med 600 mg lithiumcarbonat). (Patienten fik Valbenazine-behandling; resultat ikke oplyst).

All antipsychotics, including second generation drugs, have the potential to induce parkinsonism.

Drug-induced parkinsonism can develop in patients days or weeks after initiating antipsychotic use or increasing a dose, but symptom may not appear for months or more.

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Int J Clin Pract. 2003 Mar;57(2):147-9.

Successful therapy of tardive dyskinesia in a 71-year-old woman with a combination of tetrabenazine, olanzapine and tiapride.

Koch HJ1, Szecsey AVogel MFischer-Barnicol D.

There is no generally accepted treatment for tardive dyskinesia following intake of neuroleptics. Many compounds with effects on serotonine, GABA, cholinergic or dopamine receptors have been clinically useful. We report on a 71-year-old female patient suffering from orofacial tardive dyskinesia after treatment with haloperidol, which did not respond to monotherapy with antidyskinetic drugs. The syndrome disappeared almost completely within two weeks after a multidrug approach consisting of tetrabenazine, olanzapine and tiapride. A combination of antidyskinetic drugs should be considered in patients with severe tardive dyskinesia.

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https://www.ncbi.nlm.nih.gov/pubmed/29795977With

Valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal.

Deutetrabenazine 12-48 mg/day; Starting dose of deutetrabenazine for TD is 6 mg BID (dvs. 6 mg to gange dagligt, i alt12 mg/dag),

Valbenazine 12.5-100 mg/day

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472076/

Evidence also indicates that individuals with bipolar disorder who are takig APDs are more sensitive to developing TD compared to other individuals taking APDs. These individuals tend to take low doses of APDs, and yet TD symptoms emerge much sooner than in patients with other conditions such as schizophrenia and depression.1

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https://www.ncbi.nlm.nih.gov/books/NBK448207/

Post-menopausal women have incidence rates as high as 30% after almost a year of exposure to antipsychotic medications suggesting estrogen may have an antioxidant effect protecting against tardive dyskinesia. Elderly patients are more likely to develop tardive dyskinesia due to age-related changes in the brain and body.

In addition to dopamine, the other neurotransmitter receptors that may be involved in causing tardive dyskinesia include 5-hydroxytryptophan receptors that are found in the striatum. These receptors interact with dopaminergic neurons and considered to be involved in regulating motor activity.

Tardive dyskinesia remains for many years after the offending drug has been discontinued

Brain CT and MRI are normal in patients with tardive dyskinesia

Clozapine is recommended in patients with tardive dyskinesia who continue to require antipsychotics as the incidence of tardive dyskinesia with clozapine is significantly less than other antipsychotics

In susceptible patients (schizophrenics and those with developmental disabilities who may develop the movement disorder when administered a dopamine blocking agent. ), even a single dose of an anti-dopaminergic drug can lead to the instant development of disabling movement disorders.

Long-term studies suggest that in at least 10-30% of patients, TD persist.

Recently the FDA approved the drug Valbenazine to treat TDs. Early data from the clinical trial reveals that the drug is effective in abolishing TDs and is safe. 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.

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https://www.ncbi.nlm.nih.gov/pubmed/26979525

Frie radikaler kan medføre lav koncentration af BDNF (brain-derived neurotrophic factor)

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https://www.psychiatrist.com/jcp/article/Pages/2011/v72n05/v72n0508.aspx

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https://onlinelibrary.wiley.com/doi/full/10.1111/ijcp.12964

valbenazine is not recommended in patients with severe renal impairment.

Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to increased risk of adverse reactions such as serotonin syndrome, or attenuated treatment effect of valbenazine. It is recommended that concomitant use of valbenazine with MAOIs be avoided.

Presently (forår 2017), the cost of a 30‐count bottle of valbenazine 40 mg capsules is $5 275, resulting in an expense of $126 600 for a year's treatment at the recommended dose of 80 mg/d

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https://www.psykiatri-regionh.dk/presse-og-nyt/pressemeddelelser-og-nyheder/Forskningsresumeer/Sider/Valbenazin-behandler-tardiv-dyskinesi-og-har-en-gunstig-sikkerhedsprofil-i-op-til-et-%C3%A5r.aspx?rhKeywords=tardiv+dyskinesi

Valbenazin  er associeret med vedvarende effekt i op til et års behandling. Efter behandlingsophør oplever patienterne en forværring af symptomerne til samme sværhedsgrad som før behandlingen.

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Nedenstående er blot et forsøg med mus, der gives kæmpedosis af Ginkgo biloba gink

og beskyttes mod skader efter slagtilfælde i hjernen.

https://www.sciencedaily.com/releases/2008/10/081009162739.htm?utm_medium=cpc&utm_campaign=ScienceDaily_TMD_1&utm_source=TMD

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https://www.ncbi.nlm.nih.gov/pubmed/29609698

Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine.

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FORKORTELSER:

VBZ = Valbenazine

FGA = first-generation antipsychotics (første generations antipsykotikum såsom sulpirid, trifluoperazin og chlorpromazin)

SGA = second-generation antipsychotics (første generations antipsykotikum såsom amisulprid, olanzapin, quetiapin eller risperidon).

TD = tardive dyskinesia (dansk: tardiv dyskinesi)

DRB = dopamine receptor blocking

DRBA = dopamine receptor blocking agent.

DIP = drug-induced parkinsonism

O-B-L betyder , oral-buccal-lingual (dvs. mund, mundhule og tunge

VMAT2 = Vesicular monoamine transporter 2 (VMAT2)  responsible for monoamine transport from cellular cytosol into synaptic vesicles

VMAT2 inhibitors = Vesicular monoamine transporter 2 (VMAT2) inhibitors – bind to distinct sites on the protein and inhibit its activity, thereby reducing monoamine concentrations in the synaptic cleft

HTBZ = (+)-alpha-dihydrotetrabenaxine (HTBZ), som er det aktive stof i tetrabenazine (TBZ, handelsnavn Xenazine) der er FDA-godkendt til behandling af ufrivillige bevægelser hos patienter med Huntington's chorea.

TBZ = tetrabenaxine (handelsnavn Xenazine) der er FDA-godkendt til behandling af ufrivillige bevægelser hos patienter med Huntington's chorea. Det aktive stof i TBZ er (+)-alpha-dihydrotetrabenaxine (HTBZ)

DBRPC study = Double-Blind, Randomized, Placebo-Controlled (study)

AIMS = Abnormal Involuntary Movement Scale [en måde at vurdere patientens tilstand på]

Schooler and Kane's criteria for persistent TD. [en måde at vurdere patientens tilstand på]

WSCT = Wisconsin Card Sorting Test [en måde at vurdere patientens tilstand på]

CPT = Continuous Performance test [en måde at vurdere patientens tilstand på]

CGIC = Clinical Global Impression of Change [en måde at vurdere patientens ændrede tilstand på efter medicinindgivelse]

PGIC = Patient Global Impression of Change [en måde at vurdere patientens ændrede tilstand på efter medicinindgivelse]

mCDQ‐24 = modified Craniocervical Dystonia Questionnaire [en måde at vurdere patientens tilstand på]

ARM‐TD =           Aim to Reduce Movements in Tardive Dyskinesia [betegnelse for et studie] https://clinicaltrials.gov/ct2/results?cond=&term=AIM%E2%80%90TD+&cntry=&state=&city=&dist=]

AIM‐TD =  Addressing Involuntary Movements in Tardive Dyskinesia [betegnelse for et studie, https://clinicaltrials.gov/ct2/results?cond=&term=AIM%E2%80%90TD+&cntry=&state=&city=&dist=]

RIM‐TD = Reducing Involuntary Movements in Tardive Dyskinesia (RIM-TD) [betegnelse for et studie]

KINECT = (vist nok et navn på et specifikt klinisk studie)

PET = positron emission tomography

SD-809 = Deutetrabenazine

BPRS = Brief psychiatric Rating Scale [protokol for patientvurdering, dvs. en måde at vurdere patientens tilstand på]

SAS = Simpson-Angus Rating Scale [protokol for patientvurdering, dvs. en måde at vurdere patientens tilstand på]

UKU = Udvalg for Kliniske Undersogelser side effect ratings [protokol for patientvurdering, dvs. en måde at vurdere patientens tilstand på]

BAS = Barnes akathesia scale [protokol for patientvurdering, dvs. en måde at vurdere patientens tilstand på]

NNT = number needed to treat

NNH = number needed to harm

GEE = generalized estimating equation models [til vurdering af mulige fejlkilder ved et klinisk studie]

FDA = Den amerikanske sundhedsstyrelse, som godkender brug af lægemidler.

TEAE = Treatment‐Emergent Adverse Events

AE = Adverse effects

MeSH terms = søgeord (såsom:

Dyskinesias
Tardive Dyskinesia
Movement Disorders
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Dyskinesia, Drug-Induced

BID = 2x dagligt; twice a day / twice daily / 2 times daily, fra latin: "bis in die"

TID = betyder tre gange om dagen (TID er en forkortelse for latin "ter in die" hvilket netop betyder "tre gange om dagen". (f.eks. "Tetrabenazine 25 mg po TID", po = per oral, dvs. via munden; eller "Lithium Carbonate 600 mg po TID")

APD = antipsychotic drugs

AST = et leverenzym, f.eks. er 65 U/L en let forhøjet (dvs. uønsket) værdi af AST

ALT = et leverenzym, f.eks. er 72 U/L en let forhøjet (dvs. uønsket) værdi af ALT

APs = antipsychotics

AP = antipsychotic

DSM-IV = [Amerikansk system til katalogisering af sygdomme] f.eks. "diagnosis under the DSM-IV"

BDNF = brain-derived neurotrophic factor

WMD = Weighted mean difference

RR = Risk ratio

CI  = ±95% confidence intervals

"n=299" betyder at der er 299 forsøgspersoner

ac before meals ante cibum
bid twice a day bis in die
 cap capsule capsula
 gt drop gutta
 hs at bedtime hora somni
 od right eye oculus dexter
 os left eye oculus sinister
 po by mouth per os
 pc after meals post cibum
 pil pill pilula
 prn as needed pro re nata
 q2h every 2 hours quaque 2 hora
 qd every day quaque die
 qh every hour quaque hora
 qid 4 times a day quater in die
 tab tablet tabella
 tid 3 times a day ter in die

OTC = Over-the-counter medications

EGb  = extract of Ginkgo biloba

RCT = randomized controlled trial data

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Andre forkortelser:

FES = first episode schizophrenia-spectrum disorders

RCT = randomized controlled trials

G24.01 = I USA er dette noteringen for diagnosen "Tardive Dyskinesia".

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Keywords: Anti-dyskinesia agentsdyskinesia–drug-induceddyskinesiasmovement disorderstardive dyskinesia

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