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University of California, San Diego
La Jolla, California
California Department of State Hospitals
Jonathan M. Meyer, MD, has disclosed that he has received consulting fees from Acadia, Alkermes, Intra-Cellular Therapeutics, and Neurocrine and fees for non-CME/CE services from Acadia, Alkermes, Intra-Cellular Therapeutics, Neurocrine, Noven, Otsuka, and Sunovion.
Why Do We Use Anticholinergics?
Because of the cognitive and functional impairment induced by anticholinergics in patients with schizophrenia and the increased risk for cognitive impairment and delirium in older individuals, anticholinergics are being increasingly avoided.1 Yet they clearly have therapeutic benefit. Long before Arvid Carlsson discovered that dopamine loss in the nigrostriatal pathway caused the motor symptoms of Parkinson disease, anticholinergics were known to reduce tremor and rigidity in these patients. Traditional Ayurvedic healers prescribed hemp smoking for this purpose, and subsequent research defined muscarinic antagonism as the mechanism. This realization spurred the synthesis of anticholinergic antiparkinsonian medications (eg, benztropine, trihexyphenidyl) more than a decade before Carlsson’s Nobel Prize–winning insight.
Associative striatum D2 antagonism is central to antipsychotic activity for most agents, but the cost of this is nigrostriatal dopamine blockade. Of interest, the ability of anticholinergics to reverse antipsychotic-induced parkinsonism does not involve interference with antipsychotic actions at D2 receptors. Instead, anticholinergics balance out the disinhibiting effects of D2 antagonism on nigrostriatal neurons by blocking muscarinic M1 receptors on those neurons and adjacent interneurons.2 The net effect is like applying dopamine to nigrostriatal neurons without directly manipulating dopamine. And it is for this reason that the anticholinergic “pro-dopaminergic” effects on nigrostriatal neurons do not result in loss of antipsychotic efficacy from D2 antagonism as might be seen with use of a D2 agonist.
How Anticholinergics Make Tardive Dyskinesia Worse
Life is not simple in the world of psychopharmacology. Although anticholinergics improve antipsychotic-induced parkinsonism, there is the burden of unwanted peripheral and central adverse events, and, sadly, the realization that what makes parkinsonism better makes tardive dyskinesia (TD) worse. Parkinsonism occurs when the nigrostriatal neuron is deprived of an adequate dopamine signal, but TD represents the opposite situation. Long-term exposure of nigrostriatal neurons to D2 antagonism causes upregulation of supersensitive dopamine D2 receptors.3 Any dopamine binding to these supersensitive receptors causes an exaggerated response, and this overreaction to dopamine is manifested clinically as TD. Not surprisingly, the indirect “pro-dopaminergic” effect of anticholinergics makes TD symptoms worse. It is for this reason that healthcare professionals are encouraged not to lump all antipsychotic-related movement disorders under the label of extrapyramidal side effects (EPS)—the antiparkinsonian medications that improve certain forms of EPS (eg, parkinsonism, dystonia) typically exacerbate TD. This differential response to anticholinergics between TD and parkinsonism/dystonia can be clinically useful when there is doubt whether a movement represents TD. If it is TD, an anticholinergic trial will tend to worsen symptoms.
In an ideal world, stopping the D2 antagonist would allow TD to remit, but reversibility is often quite low.4 Unfortunately, numerous studies have also shown that dose reduction or (with the exception of clozapine) switching to weaker D2 antagonists is not useful for improving TD.5 The approach with the strongest evidence base for managing TD, especially when antipsychotic therapy is necessary, is use of vesicular monoamine type 2 (VMAT2) inhibitors. VMAT2 inhibitors dial down the presynaptic dopamine signal by decreasing how much dopamine is packaged into presynaptic vesicles. The resulting reduction in synaptic dopamine is enough to significantly decrease TD symptoms.5 Clinical trials of the 2 FDA-approved VMAT2 inhibitors for TD, valbenazine and deutetrabenazine, show that they are effective for TD and well tolerated even in patients who continue on antipsychotic treatment.6
What About the Patient With Parkinsonism or Acute/Subacute Dystonia and TD?
Life is not simple in the world of psychopharmacology, and the same is true in the nigrostriatal pathway. It is indeed possible to manifest symptoms of parkinsonism and TD at the same time, reflecting different processes acting at different neurons. This situation is most likely to occur in older patients with schizophrenia, given their 5-fold higher TD risk and the ongoing need for D2 antagonism.7 So, what’s a healthcare professional to do, especially if the patient is not a clozapine candidate and attempts at dose reduction or switching to weaker D2 antagonists to reduce parkinsonism worsens psychosis? Moreover, the anticholinergic that improves parkinsonism exacerbates TD, and VMAT2 inhibitors improve TD but do not treat parkinsonism and may occasionally worsen it. This is a clinical bind for which there is no perfect answer, with recommendations generally focusing on managing the more disabling movement disorder with full recognition there may be a price to pay by exacerbating the other problem.
I would like to hear your opinion about the response of your patients to the FDA-approved VMAT2 inhibitors for TD, including those patients who continue on antipsychotics. I am also interested to learn about your experience with anticholinergics exacerbating TD symptoms, and if you have used anticholinergics to differentiate TD from other movement disorders. And finally, I would like to hear how you have approached the conundrum of those patients with coexisting parkinsonism and TD. A detailed discussion of clinical trials and dosage considerations for VMAT2 inhibitors in TD management is covered here.References
Tell us about your thought process when you see a patient with suspected TD. What techniques have you used to differentiate medication-related movement disorders? Which TD clinical cases have been most challenging to recognize and diagnose? Please share your experiences and thoughts in the comments box.