Welcome to Psydactic - Residency Edition. Today is… I am Dr. O’Leary, and in 6 weeks I will be a 4th year psychiatry resident in our National Capital Region. This is a podcast about psychiatry and neuroscience and if you haven’t been here before, I welcome you. Today I am continuing an intermittent series called, “In a Word,” and the word that I chose for today is akathisia. I have heard it pronounced AKAHTHEESHA and AKAHTHISSEEA, but mostly I have seen it written, so if I switch back and forth between pronunciations, please forgive me. This podcast is just me trying to make sense of things that I struggle to understand. What I say here is my own opinion. As informed or uniformed as it might be, it is not the opinion of anyone else, and that includes the Federal Government, the Department of Defence, the Defense Health Agency, or the Universities of California. If you keep listening to the end of the episode, you’ll understand why I included them in the disclaimer this time.
According to Stat Pearls in the National Library of Medicine online database: “Akathisia is defined as an inability to remain still.” Psychiatrists are most aware of this condition because it sometimes is associated with antipsychotics and we think that it has something to do with D2 receptor blockade, because it is a common side effect of antipsychotics that tend to have an affinity for D2 receptors. However, it appears much more complex than that. If you remember back to an episode that I did about the cortico-striatal-thalamo-cortical tract in the brain, D2 expressing neurons help us to coordinate movements in the striatum. But these neurons are also modulated by glutamatergic, serotonergic, cholinergic, and noradrenergic pathways. Somehow messing around with striatal neurons results in constant movement that is different from the large choreiform movements of Huntington’s disease or the tremors of parkinsonism. If you ask someone with Akathisia to stop moving, they will likely become very uncomfortable, but while they are moving, they experience at least some relief. It is curious that constant fidgeting and movement is also a common symptom in individuals with hyperactive ADHD. We may ask candidates if they often feel restless, like they are “driven by a motor.” They may fidget or squirm constantly, and sometimes occupational therapists will recommend that kids with this disorder be given fidget-toys like spinners in school in order to help them to focus their need to move onto an object that is not as distracting as getting up and moving around the classroom. They may also be very uncomfortable when asked to sit still. However, the treatments for ADHD and akathisia are very different, and I don’t want anyone to confuse the two things. There is little evidence to my knowledge that they share more than this superficial resemblance.
Akathisia can be obvious to an observer or to a sufferer, but it might also be more subtle. If you notice a large change in the amount of activity of the lower extremities of a patient who is taking antipsychotics, like they sitting and dancing to non-existent music while tapping their fingers, then that is suspicious for akathisia. But what if they are just wandering around the ward or pacing their room, how sensitive is that for akathisia?
Heather Thompson, when she was a doctoral candidate at the University of Southern Mississippi in 2021 published a Doctor Project titled IMPLEMENTATION OF AN AKATHISIA SCALE INTO THE MENTAL HEALTH ASSESSMENT TO SCREEN FOR EARLY-ONSET AKATHISIA. She points out that the AIMS or Abnormal Involuntary Movement Scale is less sensitive for akathisia than for dystonias or tardive dyskinesia in part because this scale is really designed to look for tardive dyskinesia. The items that might indicate akathisia instead are grouped together with the rest into a global score that does not indicate akathisia by itself. While akathisia and tardive dyskinesia are both movement disorders that are caused by the use of psychotropics, they are different entities and are treated differently. Tardive dyskinesia or dystonias are often obvious in facial movements, or in the tongue or the mouth, but can also be present in the extremities. Akathisia is generally isolated to the extremities, especially the legs. It is important, then, to use appropriate scales separately for early detection of each. She recommends the BARS scale or Barnes Akathisia Rating Scale. She promotes this scale because akathisia is more than just annoying. It can result in the patient stopping the offending medication on their own and relapsing into psychosis. It might also increase a patient’s risk of suicide, which I will get to later.
When patients who take antipsychotics develop akathisia one of the most effective ways to treat it is to discontinue the offending medication and try another. For example a second generation antipsychotic may be tried in lieu of a first generation. But what if the patient has tried many medications and the one that they are on is the first one to actually improve their psychosis? One of the traditional methods to try to manage this side effect is to give anticholinergic medications, but these are not very effective. Given benadryl or benztropine will likely do little to treat the akathisia, but might sedate your patient a little. A more effective strategy is to give beta-blockers like propranolol, because there may also be some noradrenergic systems at play. When this is not effective, giving benzodiazepines can have an overall dampening effect on the motor system and be helpful. However, long term use of benzodiazepines is not generally a good strategy. There is also evidence that giving low dose mirtazapine or trazodone can help. When so many different kinds of drugs are given to help with one side effect or condition, this suggests that there is more than one mechanism at play in various individuals and we don’t really understand the condition that well. Akathisia can be seen rarely with serotonergic and noradrenergic agents as well. Prozac and Zoloft were noticed to contribute to akathisia in some patients early in their use.
It is important to note that akathisia may or may not also be associated with severe or moderate anxiety in an individual. Rarely individuals do not have any insight into what is happening until you ask them to try to stop moving and then they become extremely uncomfortable. Acute and tardive akathisia may also have different mechanisms. Acute akathisia usually responds to reduction of the offending agent, but tardive akathisia (or akathisia that arises late in the course of antipsychotic treatment) might worsen or suddenly appear when a dose is reduced or a medication stopped. There is even an entity called pseudo-akathisia when a patient has symptoms of akathisia, but is not at all bothered by them. This term is controversial. What appears obvious is that there is something different going on in the striatum for those who have been on antipsychotics for a long time and those who have recently started them. The adaptations of striatal neurons are not well understood, but this difference suggests that D2 receptor blockade is only part of the story. There is some balance between the signals induced by D2 receptors and the density and relative responsiveness of other receptors that also play roles.
Now it is my pleasure to talk about a study that was published on the first of July 2023. Given that it is only May of 2023, I am grateful to have this glimpse into the future. What this means of course is that this study has been released online, but has not yet made it to print. It is called “Antipsychotic-induced akathisia in adults with acute schizophrenia: A systematic review and dose-response meta-analysis,” and it is (or will be) in the journal European Neuropsychopharmacology. This study included only one first generation antipsychotic (haloperidol) and 16 second generation antipsychotics. It also reported only on the acute phase of treatment of schizophrenia and not on tardive akathisia. In general this study showed that there is a dose response for most antipsychotics with regards to the odds of reporting acute akathisia, but the odds of akathisia tended to increase at moderate doses and then level out, which means for most drugs, if they are at a high dose, then simply lowering to a moderate dose is not necessarily expected to resolve the akathisia. Also, there were only three drugs that had high quality evidence available and these were haloperidol, risperidone, and quetiapine. Of these, quetiapine had the lowest odds of akathisia and risperidone had lower odds that haloperidol.
Quetiapine and its metabolite norquetiapine at different concentrations together antagonize just about every kind of receptor including histaminic receptors, serotonergic receptors, muscarinic receptors, adrenergic receptors, NMDA receptors, and all of the dopamine receptors. It has particular affinities for different receptors at different doses. The only receptor that it partially agonizes is the 5HT1A receptor. Given quetiapine’s broad scope in the brain, it is less likely to cause akathisia than other antipsychotics.
There was one antipsychotic that curiously appeared not to plateau, which means that higher doses appear to always increase the risk of akathisia. This was lurasidone (aka Latuda). Lurasidone is an full antagonist for dopamine type 2, serotonin 5HT2A, and 5HT7 receptors, and a partial agonist for 5HT1A.
This study supports the idea that drugs that prefer D2 receptors have higher risk of causing akathisia than those that preferentially block 5HT2A.
Another paper I will recommend is by Salem et al in Current Neuropharmacology in 2017 titled “Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges.” It provides a well researched and easily read review of this subject. I especially recommend this paper to readers who would like a gateway into exploring the various neurobiological hypotheses of akathisia along with treatment strategies. You can find my references at the end of the show transcript at psydactic.buzzsprout.com.
Now let me get back to the risk of other bad things associated with akathisia like suicide. It may seem obvious that akathisia which can increase anxiety and result in shame or stigma, may also increase risk of suicide or aggression in a patient. I explored the suicide claim in particular by following the citations in the papers I have already mentioned as well as trying a literature search myself. What I found were merely case studies. This is not to say that suicide risk is not associated with akathisia, but that I could not find high quality evidence of this. Regardless of whether akathisia increases the risk of violence or suicide, it is certainly unpleasant and we should be aware of it, and prevent or treat it in our patients. It is not confined to patients using antipsychotics. Serotonin and norepinephrine reuptake inhibitors are also associated with akathisia, though more rarely than antipsychotics, possibly because increased serotonergic transmission can under certain circumstances also reduce dopamine transmission in the striatum.
BELLS
Before I leave you today, I want to give you an update on my journey using AI. I wondered if ChatGPT or Google Bard had anything to say about this podcast. ChatGPT disappointingly had never heard of the podcast PsyDactic, which isn’t surprising, because it is trained on static data sets that either did not include me or did not find me interesting enough to make a neural note of. Bard on the other hand, which can search the internet, was more than willing to comment and the results were amusing. It identified me as Dr. Patrick O'Leary, which is not true, though undoubtedly Irish. My name is Thomas Ryan O’Leary, or T. Ryan as I am known by my signature line. It also said that I am a psychiatrist and assistant professor of psychiatry at the University of California, San Francisco, which I am not. I am a psychiatry resident who has no official connection whatsoever with the Universities of California.
Bard went on to say, quote, “the podcast covers a wide range of topics, including the latest research in psychiatry, clinical practice, and public policy. PsyDactic is a valuable resource for anyone interested in learning more about psychiatry and mental health.” I have covered those topics, but whether PsyDactic is a valuable resource is a bit more subjective. Bard continued, quote, “In each episode, Dr. O'Leary interviews experts in the field of psychiatry to discuss a variety of topics,” which is not true. I have only ever been able to convince a single other resident from my program to come on the show and only for one episode. Finally, Bard reported, “Dr. O'Leary also hosts a Q&A segment at the end of each episode, where he answers questions from listeners about psychiatry and mental health.” I have never had a Q&A segment. Maybe Bard is predicting the future.
When AI makes up facts, this has been called hallucination, but I don’t like that term. I think the term confabulation is more appropriate. Confabulation is when a person appears to be making up facts, like that they are in hospital for a surgery when they really were brought here because they were lost and disoriented in the local mall. Their explanation seem true, reasonable, and clear to them, but it is not at all true. Hallucinations, on the other hand, are sensory experiences that may or may not be experienced as true or real by the person experiencing them. The term confabulation would make a good “In a word,” but that is for a future episode.
Today, we have explored the term akathisia for better or for worse. This has been an episode of PsyDactic - Resident Edition. ***Make a outro like in advertisements***
https://www.ncbi.nlm.nih.gov/books/NBK519543/#:~:text=Akathisia%20is%20defined%20as%20an,usually%20involves%20the%20lower%20extremities.
Barnes TR: A Rating Scale for Drug-Induced Akathisia. British Journal of Psychiatry 154:672-676, 1989.
https://aquila.usm.edu/cgi/viewcontent.cgi?article=1180&context=dnp_capstone
Hui Wu, Spyridon Siafis, Dongfang Wang, Angelika Burschinski, Johannes Schneider-Thoma, Josef Priller, John M. Davis and Stefan Leucht. Antipsychotic-induced akathisia in adults with acute schizophrenia: A systematic review and dose-response meta-analysis. European Neuropsychopharmacology, 2023-07-01, Volume 72, Pages 40-49, Copyright © 2023 Elsevier B.V. and ECNP
Salem H, Nagpal C, Pigott T, Teixeira AL. Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges. Curr Neuropharmacol. 2017;15(5):789-798. doi: 10.2174/1570159X14666161208153644. PMID: 27928948; PMCID: PMC5771055.
Pondé, M.P.; Freire, A.C. Increased anxiety, akathisia, and suicidal thoughts in patients with mood disorder on aripiprazole and lamotrigine. Case Report. Psychiatry, 2015, 2015, 419746. [http:// dx.doi.org/10.1155/2015/419746] [PMID: 26509095]
Lipinski, J.F., Jr; Mallya, G.; Zimmerman, P.; Pope, H.G., Jr Fluoxetine-induced akathisia: clinical and theoretical implications. J. Clin. Psychiatry, 1989, 50(9), 339-342. [PMID: 2549018]
