Overprescription of Benzodiazepines in the Autism Population
Hari Srinivasan
Psych C19 Drugs and The Brain, UC Berkeley, Prof David Presti. Nov 2017
Abstract
Benzodiazepines belong to the powerful sedative-hypnotic family and are some of the most widely prescribed class of drugs today. There is, however, a serious overprescription of benzodiazepines in the developmentally disabled populations like Autism Spectrum Disorder without regard to the long-term health consequences. Studies have shown that adult autistics have significantly fewer GABAA receptors and that benzodiazepines work by binding to the GABAA receptors, thereby potentiating the GABA neurotransmitter and producing its anxiolytic effects. Benzodiazepines are very effective in the short term so there is resistance to reducing medication as there is often a reversal of symptoms or other side effects. Long-term usage even at moderate doses can impair cognition and memory and bring about tolerance and dependence. As the growing autism population ages, they may also be subject to the reported effects of benzodiazepines on the elderly, such as increased risk of hip fracture, Alzheimer’s, and dementia. In addition, studies have suggested that benzodiazepines themselves may contribute to behavioral symptoms which could be mistaken for other psychiatric behaviors which need to be further treated. This is ironic as benzodiazepines are given to mitigate these very symptoms. This paper suggests that more research is needed into understanding the underlying physiological underpinnings rather than just medicating based on observable symptoms or observable side effects. For instance, further investigation is needed into better and reliable ways to measure neurotransmitter levels so that dosages can be tailored more specifically for the individual and monitored, thus minimizing long-term effects.
Keywords: Benzodiazepine, Autism, GABA, Neurotransmitters, benzodiazepine side effects
Overprescription of Benzodiazepines in the Autism Population
The use of medications like benzodiazepines is a growing problem in the developmentally disabled such as Autism Spectrum Disorder, who practically speaking often have less say on what medications are administered to them. From a young age, there is often pressure to medicate such individuals from schools, teachers, support staff, and therapists who often have to manage multiple students simultaneously. Medication is often seen as a quick fix to mitigate disruptive or maladaptive social behaviors. Families too turn to medication in the hopes that it will improve the quality of life for the affected family member.
Benzodiazepines have been around since the 1960s with the introduction of chlordiazepoxide (Librium) in 1960, diazepam (Valium) in 1964 and a slew of other benzodiazepines since. Though they belong to the powerful sedative-hypnotic family, they are one of the most widely prescribed classes of drugs today. Prescriptions have, for instance, increased from 4.1% in 1996 to 5.6% in 2013 (Bachhuber, Hennessy, Cunningham, & Starrels, 2016). There is a serious overprescription of benzodiazepines in the vulnerable population of the intellectually disabled like Autism Spectrum Disorder, without regard to the long-term health consequences for these individuals.
Neural Mechanism of Benzodiazepines
Benzodiazepines are believed to work by potentiating GABA receptors at the chemical synapses in the brain. The neurotransmitter GABA inhibits the action of neurons by binding to GABAA receptors, thus producing its calming, sedating, anxiolytic, anticonvulsant, and vasodilation effects. Benzodiazepines are not GABA agonists, rather they act as positive allosteric modulators (PAMs) since they can only act when GABA is bound at the receptor. Benzodiazepines actually bind to a subset of the GABAA receptor complex called BzR (benzodiazepine receptors). This serves to increase the inflow of chlorine ions at the ion channel, hyperpolarize the membrane potential of the neuron and reduce the chances of action potential. In effect, it makes the GABA receptor less sensitive. Since there are benzodiazepine receptors all over the brain connected to different neural circuits, there is bound to be variation in individual physiological responses to the drug. Besides GABA, benzodiazepines also potentiate other neurotransmitters. For instance, clonazepam also acts as a serotonin agonist. In addition, benzodiazepines also stimulate the peripheral nervous system (PNS) as benzodiazepine receptors are found in the PNS tissues and glial cells. This could well account for its muscle relaxant effects (Griffin, Kaye, Bueno & Kaye, 2013).
Benzodiazepines are classified according to their elimination half-life action in the body. Shorter-acting ones (less than 12 hours) include midazolam (just 10 minutes duration of action) and alprazolam. Intermediate-acting ones (12-40 hours) include clonazepam and lorazepam, and longer-acting ones (40-250 hours) include diazepam. Benzodiazepines are further metabolized which extends their duration of action. For instance, diazepam metabolizes into nordiazepam, oxazepam, and temazepam. The speed of onset also differs for each. Midazolam (Versed) takes just 5 minutes to work while clonazepam (Klonopin) takes a few hours, though the latter also stays longer in the body (Griffin et al., 2013).
What makes benzodiazepines attractive to use is their relatively high therapeutic index when compared to barbiturates. This is believed to be due to the fact that benzodiazepines can open chloride ion channels only in the presence of GABA, unlike Barbiturates or propofol which can open the chloride ion channel independently. When barbiturates are combined with alcohol it can cause respiratory depression to a degree that a person can stop breathing. The therapeutic index runs in the 100’s for benzodiazepines with diazepam at exactly 100. A high therapeutic index implies that it is difficult to overdose on benzodiazepines. The rare cases of overdoses are treated with Flumazenil, which acts as an antagonist at the benzodiazepine binding sites (Tulane University School of Medicine, 2017).
It is not surprising therefore that benzodiazepines are often used to address symptoms associated with learning disabilities like Autism Spectrum Disorder. In fact, a study by Oblack, Gibbs and Blatt (2009) found that the adult autistics had significantly fewer GABAA receptors and benzodiazepine sites when compared to the neuro-typical adults. Tomography results (Mendez et al., 2013) further indicate that there are reduced levels of GABA (specifically GABAA α5 subtype) in the nucleus accumbens and amygdala. There is a delicate balance in the brain between neuron excitation and neuron inhibition and their outputs to different regions of the brain. This balance, in turn, requires just the right amount of energy to the nerves. Disturbances in this mechanism could well be the underpinnings of the socio-emotional behaviors seen in Autism.
Effects of Benzodiazepines
Indeed, benzodiazepines are very effective in the short term. They are so effective that their use is continued to prolong the feel-good effects, especially on mood and anxiety. In the meantime, tolerance builds up as does dependence. It is like being caught between Scylla and Charybdis, can’t live with them, can’t do without them either as other medications are less effective. It is ironic indeed that benzodiazepines are powerful enough to be classified as Schedule II drugs (“high potential for abuse”), yet are classified as Schedule IV (“low potential for abuse”) due to their prevalent use (Donaldson, Gizzarelli & Chanpong, 2007).
The study by Oswald and Sonenklar (2007) draws attention to the fact that almost 70% of children over age 8, with the Autism Spectrum diagnosis, were prescribed some form of psychoactive medication including benzodiazepines. Benzodiazepines are often given to this population for co-morbid conditions such as bipolar disorder, severe anxiety, obsessive compulsive behaviors and mood swings that can cause disruptive, aggressive or even self-injurious behaviors.
What is even more troubling is a study by Kalachnik, Hanzel, Sevenich and Harder (2002) which suggests that many of these behavioral symptoms could be caused by the benzodiazepines themselves and then be mistaken for other psychiatric behaviors which need to be further treated. Another study by Albrecht et al. (2014) had suggested a link between benzodiazepines and aggression, especially diazepam and alprazolam (Xanax). The effect is to synergistically disinhibit, especially if the diazepam were combined with other medications or substances such as alcohol, causing any bottled-up anger to come out. The irony is that benzodiazepines are often given to this population in the first place to mitigate these very behavioral symptoms.
This population is often also highly susceptible to dependence and addiction. There is resistance to stopping or reducing medication as there could be a resurgence of symptoms which are hard for the individual, their families or support staff in their social settings to cope with. Withdrawal symptoms can include increased panic and anxiety, sweating, headache, palpitations and muscle stiffness (Pétursson, 1994). Withdrawal from higher doses could even result in seizures and psychosis. As a result, low to therapeutic doses are often continued long term to alleviate withdrawal symptoms which increases the risk of physical dependence (Busto & Sellers, 1991). Inevitably, powerful drugs are also often accompanied by side effects and the benzodiazepines are no exception. The toxicology list by the Tulane University’s School of Medicine include some worrying effects such as, “drowsiness, confusion, ataxia (loss of voluntary body movement), nystagmus (uncontrolled eye movements), slurring of speech, amnesia, hypotension and respiratory depression,” (2017). In addition, long term usage has shown to have negative effects on memory and cognition.
One in eighty-eight children are diagnosed with autism spectrum disorder today and the number just continues to increase (Center for Disease Control, 2016). Much of the current therapeutic interventions and research focus on the early years to take advantage of the neuroplasticity of a young brain. However, not every child benefits from the current array of therapies. This means that the main recourse for most adult autistics who did not benefit from early therapy is medication to control symptoms. Recent research has however shown that neuroplasticity continues well into the adult years (Garrett, 2013). What is often overlooked is that all these growing thousands of young children with autism will age into adults with autism and then eventually the elderly with autism. Aging will bring about its own set of health issues with decreased immunity and reduced disease fighting ability. Wang, Bohn, Glynn, and Robert (2001) report that the use of even modest doses of benzodiazepines for over a month increased the risk of hip fracture by 50% in the elderly. Other studies have found links between continued use of benzodiazepines and increased risk of Alzheimer's and dementia (deGage et al., 2014). All this does not bode well for the Autism population who are already prone to a myriad of health issues, often due to a compromised immune system, such as seizures, allergies, respiratory issues, endocrine issues, digestive problems, sleep disorders, sensory dysregulation and bacterial or viral infections.
Conclusions and Future Study
There is clearly an overuse of medications such as benzodiazepines in the Autism population, without regard to consequences of long-term health effects. This is especially significant in light of the fact that the line between benzodiazepines alleviating symptoms and causing additional symptoms seem to be blurred in the Autism population. Currently, medication is based on observable outward behavioral symptoms and observable side effects. It is a shot in the dark as to whether they work or not, so various permutations, combinations, and substitutions are tried by medical specialists in an effort to mitigate maladaptive symptoms. The need of the hour is more research into understanding the underlying physiological underpinnings rather than just symptom-based medication. For instance, further investigation is needed into better and reliable ways to measure neurotransmitter levels so that dosages can be tailored more specifically for the individual and monitored, thus minimizing long-term effects.
References
Albrecht, B., Staiger, P. K., Hall, K., Miller, P., Best, D., & Lubman, D. I. (2014). Benzodiazepine use and aggressive behaviour: A systematic review. Australian & New Zealand Journal Of Psychiatry, 48(12), 1096. doi:10.1177/0004867414548902
Bachhuber, M. A., Hennessy, S., Cunningham, C. O., & Starrels, J. L., (2016). Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. AJPH. 106(4), 686-688. doi:10.2105/AJPH.2016.303061
Busto, U., & Sellers, E. M. (1991). Pharmacologic aspects of benzodiazepine tolerance and dependence. Pubmed. Retrieved November 10, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/1675689
Centers for Disease Control. (2016). Autism spectrum disorder (ASD). Retrieved November 10, 2017, from https://www.cdc.gov/ncbddd/autism/data.html
de Gage S.B., Moride, Y., Ducruet, T., Kurth, T., Veroux, H., Tournier, M., Pariente, A., & Begaud, B. (2014). Benzodiazepine use and risk of alzheimer’s disease: case-control study. British Medical Journal. 349:5205 https://doi.org/10.1136/bmj.g5205
Donaldson, M., Gizzarelli, G., & Chanpong, B. (2007). Oral sedation: A Primer on anxiolysis for the adult patient. Retrieved November 07, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1993866/
Garrett, M. (2013, April 27). Brain plasticity in older adults. Psychology Today. Retrieved November 10, 2017, from https://www.psychologytoday.com/blog/iage/201304/brain-plasticity-in-older-adults
Griffin, C. E., Kaye, A. M., Bueno, F. R., & Kaye, A. D. (2013). Benzodiazepine Pharmacology and central nervous system–mediated effects. Retrieved November 07, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/
Kalachnik, J. E., Hanzel, T. E., Sevenich, R. & Harder H. R., (2003) Brief Report: Clonazepam Behavioral Side Effects with an Individual with Mental Retardation. Development of Autism and Developmental Disorders. 33(3), 349-354 https://doi.org/10.1023/A:1024466819989
Mendez, M. A., Horder, J., Myers, J., Coghlan, S., Stokes, P., Erritzoe, D., Howes, O., … Nutt, D. (2013). The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study. Neuropharmacology, 68, 195-201. https://doi.org/10.1016/j.neuropharm.2012.04.008
Oblak, A., Gibbs, T. T., & Blatt, G.J. (2009), Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Autism Res, 2: 205–219. doi:10.1002/aur.88
Oswald, D. P., & Sonenklar, Neil. A.. (2007). Medication use among children with autism spectrum disorders. Journal of Child and Adolescent Psychopharmacology, V 17(3), 348-355. https://doi.org/10.1089/cap.2006.17303
Owen, R.T. & Tyrer, P. (1983). Benzodiazepine dependence. Drugs 25 (4): 385-398. https://doi.org/10.2165/00003495-1983
Pétursson, H. (1994). The benzodiazepine withdrawal syndrome. Pubmed. Retrieved November 10, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/7841856
Tulane University School of Medicine. (2017). Benzodiazepine Toxicology. Retrieved November 06, 2017, from http://tmedweb.tulane.edu/pharmwiki/doku.php/benzodiazepine_toxicology
Wang, P. S., Bohn, R. L., & Glynn. Robert. J. (2001). Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture, The American Journal of Psychiatry, V 158 (6),892-898. https://doi.org/10.1176/appi.ajp.158.6.892
