TARDIVE DYSKINESIA BULLETS
ü TD hyperkinetic movement disorder from prolonged dopamine block
o Caused by antipsychotics and metoclopramide
o “Tardive” latin tardus –slow (delayed onset) history of >3months don’t confuse w/acute and EPS (although associated)
o Involuntary movements –
§ Choreiform (greek khoreia: to dance– rapid, jerky, nonrepetitive
§ Athetoid (greek athetos: without position)– slow, sinuous
§ Rhythmic (stereotypies)
ü TD manifestations
o Oral, facial, lingual dyskinesia (3/4 of patients, typical in older patients)– protruding/twisting tongue, pouting, puckering, smacking, bulging of cheeks, chewing, blepharospasm
o Limb dyskinesia (~1/2 of patients, more typical in younger patients) – “piano playing” finger movements, foot tapping, toe extension, akathisia (subjective motor restlessness; occur both early and late in AP tx)
§ Tardive akathisia – inability to sit still, crossing/uncrossing, marching in place, rubbing hair or face w/hand
o Neck/trunk dyskinesia (Tardive dystonia) (~1/4 of patients)– torticollis, shoulder shrugging, rocking/swaying, arching
o Respiratory dyskinesia – cause tachypnea, grunting
o Tremor/tics/myoclonus – uncommon
ü SUBTYPES
o Transient TD – brief, limited only during treatment
o Withdrawal Emergent TD – described in pediatrics following discontinuation! Common for TD to appear after a reduction in dose or switch to less potent AP. Called “unmasking”. Withdrawal TD normally resolves within several weeks.
o Persistent TD – permanent. Most feared!
§ Classic tardive – “fly-catcher tongue”, trunk flexion/extension, “piano playing” (prevalence increases with age, elderly women)
§ Manifested by reducing dose or coming off drug which unmask the disorders (in fact last resort treatment to resume AP)
ü Pathophysiology
o Unknown – working theories include
§ Dopamine receptor supersensitivity (evidence of striatal dopamine receptor upregulation)
§ Decreased GABA inhibitory interneuron firing in basal ganglia leads to excitotoxicity (ev -chronic AP treatment in primates leads to reduced GABA/glutamic decarboxylase)
· D2 block (inhibitory) increase glutamate firing in striatum and subthalamic nucleus
o Leading theory – imbalance between D1/D2 firing b/c of preferential block of D2 (supported by increased atypical EPS threshold)
ü Prevalance – AIMS (12 item inventory) difficult to assess accurately b/c AP both cause and mask the clinical manifest, fluctuates based on emotional arousal, orofacial dyskinesia common in age 65
o Thus, current point prevalence has range from 3-77%
o DSM-IV – 20-30%
ü 1st Generation -1982 analysis of 35K cases put prevalence @ 20%
o controls had prevalence of spont dyskinesias @5%
§ therefore – estimated prevalence at 15%
ü 2nd Generation – less D2 block, more 5-HT2A block
o Case reports -Clozapine – almost no risk of EPS
o Case reports – risp/olanz have greater risk for TD than other atypical
o associated w/akathisia and NMS
o still better than 1st gen, but not as safe as previously thought
§ short term studies
§ very few patients are AP naïve, this is a risk factor for TD
§ In reviews earlier patients had schizo later had dementia
ü Risk factors -
o Older age, length of exposure, female, brain damage, affective disorder, history of ECT, use of anti-cholinergics, African American ethnicity
ü PREVENTION – early detection!
o >3months treatment should be limited
o metoclopramide should not be used >12months
o should inform patient of risk, possibly obtain consent given medicolegal implications
ü Treatment guidelines – only give when absolutely necessary, if the psychosis is controlled, attempt to reduce dosage or eliminate
o Long term use is discouraged in neurosis, anxiety, Axis II, chronic pain
o Monitor patient using AIMS scale (abnormal involuntary movement)
ü TREATING TD – few therapies (lower, change, stop)
o Discontinue drug – within 3 months ~1/3 remit, 12-18months 50%, as late as 3 years
o switch to atypical antipsychotic – may just be masking, or gradual improvement w/weaker drug
§ clozapine - @least 8 studies since 1991, all uncontrolled, effective at reducing tardive dystonia
o Benzodiazepine- mixed results in trials: DBRCT 19 patients: clonazepam- start 0.5mg and titrate max 3-4mg/day
o Botulinum: multicenter 29/34 shown to help cervical dystonia/blepharospasm
§ Contraindicated in Myasthenia Gravis
o Tetrabenazine (approved Aug08 for HD)/mirtazapine – deplete dopamine storage used for Huntington’s chorea and debilitating TD
o Anticholinergics - benztropine (*anticholinergics exacerbate choreiform disorders but good for acute/tardive dystonias/EPS)
§ Contraindicated: narrow angle glaucoma, confusion, dementia.
§ Use with caution: >60yrs, BPH, obstructive GI,
o Last resort: resumption of anti-psychotics! Usually SGA.
o Misc treatments: bblock, calcium block, 5-HT antagonist, buspirone, B6, amantadine, lithium, levetiracetam
o Deep brain stim: bilateral internal globus pallidus
§ 10 patient prospectus – all ten had result – mean decrease in EPS rating scale of 50% when stimulation was on
o Vitamin E (via anti-oxidant) – not found to be beneficial in 6 placebo controlled clinical trials
ü CLINICAL TRIALS – HAND OUT PAPERS w/STUDIES STARTING
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