With the approval of chlorpromazine (Thorazine®) in 1952 came the clinician's quandry of medications that significantly improved psychotic symptoms at the mercy of movement disorders that are both disturbing and disfiguring to the client (Stanilla & Simpson, 2017). Blocking dopamine release in some parts of the brain diminishes symptoms, such as hallucinations, delusions, and aggression, but in other parts of the brain contributes to movement disorders similar to Parkinson's disease and choreoathetosis. Initially, these side effects were also seen as the indication that the medication would be effective in treating schizophrenia.
The incidence of tardive dyskinesia (TD) with any dopamine antagonist is 1%, with atypical serotonin dopamine antagonist having approximately one half the incidence and prevalence of up to 30% (Uhlyar & Rey, 2018). The exception is clozapine (Clozaril®), which seems to reverse the effects of TD (Woods et al., 2010). Individuals taking dopamine-blocking agents for prolonged periods of time, being of older age, and African American are at greatest risk for TD (Stegmayer, Walther, & van Harten, 2018). The current article differentiates TD and its associated movement disorders, explains the putative neurophysiological mechanisms contributing to the behaviors, and describes two new medications recently approved by the U.S. Food and Drug Administration (FDA) to treat TD.
Idiopathic Movement Disorders
Movement disorders is a broad term used to describe disorders associated with the extrapyramidal tract innervating the basal ganglia. More specific than the extrapyramidal tract is the nigrostriatal dopamine pathway, which affects the substantia nigra and projects to the caudate and putamen (striatum) and largely regulates movement. Some medications affect this pathway as adverse effects; therefore, these disorders are medication-induced or idiopathic as opposed to disease states such as Parkinson's disease or Huntington's chorea, and are characterized by hyperkinetic movement.
There are four types of hyperkinetic disorders: acute dystonic reactions, akathisia, Parkinsonian syndrome, and TD. Acute dystonic reactions are sudden, usually within the first 4 to 10 days of initiation of medication and are characterized by intense muscle spasms, such as oculogyric crisis, involuntary tongue protrusion, torticollis, and opisthotonos. These dystonic reactions may cause laryngeal spasms that obstruct breathing but are otherwise not life threatening, albeit highly distressing. Akathisia is objective motor restlessness that the client describes as the inability to stay still and the need to move. Akathisia is often confused with anxiety even in the absence of subjective distress. Parkinsonian syndrome or pseudoparkinsonism ostensibly mimics Parkinson's disease, including slowed movement and gait (bradykinesia), frozen facies, rigidity of the arms with cogwheeling movements, a resting tremor, and hypersalivation. TD has stereotypical irregular movements of the mouth, face, and tongue, as well as choreoathetoid movements (i.e., twisting, writhing contractions) that the client is unaware of but that contribute to social stigma. The distinguishing feature of TD from the other movements is that it is more resistant to treatment and persists over time, sometimes even after discontinuation of the causative medication (Stanilla & Simpson, 2017).
Several rating scales are available to assess for movement disorders, including the Barnes Akathisia Rating Scale, Simpson-Angus Rating Scale, and Abnormal Involuntary Movement Scale (AIMS). It is important for psychiatric nurses to distinguish between the different movement disorders, document clearly in the medical record, and reassess at appropriate intervals. The AIMS requires some prior training to be accurate and consistent in interpretation; training videos are available through YouTube (access https://www.youtube.com/playlist?list=PL5D905F2FF006EB9D). AIMS testing should be conducted within the first 6 months of initiating any dopamine antagonist and repeated annually (Sadock & Kaplan, 2015).
Neurophysiology of Tardive Dyskinesia
Although it is not completely understood, the prevailing theory to explain the causes of hyperkinetic adverse effects is a supersensitivity dysregulation of the dopamine 2 (D2) receptor in the striatum. Three mechanisms occur with the long-term D2 receptor blockade by antipsychotic agents: increase in D2 receptor density in the striatum, increase in D2 receptor synthesis, and/or a decrease in D2 receptor degradation. Ultimately, there is a supersensitivity to dopamine stimulation resulting in increased psychomotor activity (Chouinard et al., 2017). Chronic administration of dopamine antagonists activates upregulation of D2 receptors in the striatum in response to the blockade with increased dopamine-mediated signaling. However, the supersensitivity theory does not completely explain the phenomenon and it is likely that gamma-aminobutyric acid and glutamate in the substantia nigra also play a role that is not yet fully established (Nakata, Kanahara, & Iyo, 2017; Oda et al., 2017). Because serotonin-dopamine antagonists have briefer occupancy of the D2 receptors, the assumption was that this upregulation would be less likely. In fact, although second-generation antipsychotic agents (i.e., serotonin-dopamine antagonists) have a lower incidence of medication-induced movement disorders, TD and other movement disorders are still possible. The behavioral consequence of dopamine upregulation in the basal ganglia is erratic muscle stimulation and spasmodic responses.
Treatments for the hyperkinetic adverse effects of dopamine antagonists have been symptomatic and tend to mask, rather than alleviate, the effects of TD. These treatments include anticholinergic agents to counterbalance dopamine and acetylcholine in the basal ganglia, benzodiazepine agents for muscle spasms, antihista-mines to inhibit muscle constriction, dopaminergics (e.g., amantadine) to reduce Parkinsonian symptoms, and beta-adrenergic antagonists for tremors (Stanilla & Simpson, 2017). Prevention is the primary treatment target, which is achieved by prescribing the lowest dosage possible for the necessary time for effective treatment, switching to less dopamine receptor occupancy, or switching to clozapine. Decreasing the dosage of the dopamine antagonist may be helpful at the risk of increased psychotic symptoms. No drug or dosage change, however, could address the underlying upregulation mechanism until recently with the discovery of vesicle monamine transporter (VMAT) inhibition.
Role of Vesicle Monamine Transporter in Tardive Dyskinesia
Within the neuron are vesicles or sacs containing the presynaptic neurotransmitters that transport and recycle monamine neurotransmitters across the synapse. VMAT2 inhibitors increase the degradation of monamine neurotransmitters in the striatal nerve terminals, particularly dopamine, thereby inhibiting the buildup of dopamine and the compensatory upregulation (Tarakad & Jimenez-Shahed, 2018; Touma & Scarff, 2018). The first VMAT2 inhibitor on the market was tetrabenazine used in the treatment of Huntington's disease, but it is not approved for treatment of TD. However, two similar drugs have shown more promise specific to medication-induced TD: valbenazine and deutetrabenazine (Niemann & Jankovic, 2018; Stahl, 2018). These VMAT2 inhibitors are derivatives of tetrabenazine.
Valbenazine (Ingrezza®) is the alpha isomer of tetrabenazine and the most potent inhibitor of VMAT2 and antagonist of D2. It is highly selective of VMAT2 without occupying either 5HT7 or D2 and is metabolized by CYP2D6 and 3A4/5 (Stahl, 2018). There are two dosages, 40- and 80-mg capsules with a half-life of 15 to 22 hours, allowing single daily dosing. In randomized Kinect studies, valbenazine reduced AIMS scores significantly within 6 weeks (Hauser et al., 2017). Adverse effects include somnolence (10.9%), anticholinergic effects (5.4%), balance disorders and falls (4.1%), headache (3.4%), akathisia (2.7%), vomiting (2.6%), and nausea (2.6%) (Uhlyar & Rey, 2018). The FDA includes a warning for QT prolongation although incidence is clinically insignificant at recommended dosages (Uhlyar & Rey, 2018); therefore, it is prudent to have a baseline electrocardiogram with a 6-week follow up for comparison. The major drawback with valbenazine is the cost, with a wholesale price for 1 month between $5,750 and $6,225 (Uhlyar & Rey, 2018).
Deutetrabenazine (Austedo®) is a deuterated form of tetrabenazine, which slows the metabolism and decreases the half-life, necessitating twice daily dosing. Similar to valbenazine, deutetrabenazine is metabolized by CYP2D6 and 3A4. Deutetrabenazine acts in the same manner as valbenazine but has four active metabolites, one of which has moderate occupancy of 5HT7 and D2. The extent of clinical significance of 5HT7 and D2 involvement is not clear but may have some added benefits by enhancing antipsychotic effects, improving circadian rhythm, activating motivation, and improving mood and cognition (Stahl, 2018). Deutetrabenazine was equally efficacious in the KINECT studies with statistically and clinically significant improvement in AIMS scores within 6 weeks of initiation (Touma & Scarff, 2018). Deutetrabenazine is available in 6-, 9-, and 12-mg tablets with the starting dose of 6 mg twice daily for 2 weeks and titrated to a maximum of 24 mg twice daily. Because it has a half-life of 9 to 10 hours, deutetrabenazine must be given twice daily. The most common side effects are somnolence, fatigue, insomnia, headache, diarrhea, and akathisia with no apparent changes in QT intervals (Touma & Scarff, 2018; Uhlyar & Rey, 2018). Cost is prohibitive without insurance coverage, and it is likely to require prior authorization.
Summary and Recommendations
TD is a serious and disfiguring consequence of long-term use of dopamine antagonists and serotonin-dopamine antagonists. The effects of TD contribute to the experience of stigma, which motivates clients to stop taking medications that have been effective in managing their symptoms. The VMAT2 inhibitors show promise in managing TD as an adjunct to the treatment regimen. Unfortunately, individuals most likely to be affected by TD are those who are chronically disabled by their psychiatric condition with third-party coverage that will not cover such an expensive medication. Both medications are equally efficacious; however, deutetrabenazine requires twice daily dosing that may jeopardize consistency, and daytime drowsiness may interfere with functioning. It then becomes the clinician's burden in seeking third-party authorization for medication and negotiating with the client in achieving a full trial of 6 weeks to determine effectiveness. The advanced practice psychiatric nurse must balance improvement in TD symptoms with sedation and expense in providing optimal care for clients with severe mental illness.
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