Pharmaceutical Alternatives: Considering Invasive Treatments to Avoid Side Effects

by Andrea Cumpelik

Illustration: “Still” by Tiffany Chaey

In a 2016 case study, David Maltête describes a 50-year-old man with Restless Leg Syndrome (RLS) and a resting tremor due to Parkinson’s disease. 1 Both of these diseases are associated with dopamine deficiency: Parkinson’s is characterized by death of dopamine producing neurons, and RLS is associated with deficient dopamine neurotransmission in certain brain regions. 2 Both of these diseases are often treated with dopamine agonists, or drugs that share a similar structure with dopamine, which enables them to interact with all or some dopamine receptors. Maltête prescribed Pramipexole, a commonly prescribed dopamine agonist that has a high affinity for D3 dopamine receptors. 3 Both the tremor and RLS symptoms disappeared, but within a few weeks, the patient developed a strong interest in gambling and tattoos. “He would spend hours on the Internet to find new models for future tattoos. He got tattooed 7 times in 6 months and he planned to make 5 others.” 1 He had no previous history of addictions, did not smoke cigarettes, take drugs, or ever have any interest in gambling or tattoos. After Dr. Maltête decreased the Pramipexole dose and replaced it with a different medication with a different mechanism of action, the patient’s pathological gambling disappeared along with his interest in tattoos, and he had no more since the treatment was discontinued.

This case is somewhat of a rarity in its specificity for tattoos, but Impulse Control Disorders (ICDs), such as pathological gambling, compulsive shopping, or hypersexuality are a common side effect of dopamine agonists. Several case studies have described an emergence of these behaviors weeks or months after the patients were prescribed dopamine agonists, usually disappearing when the medication was interrupted. 4 One elderly woman became addicted to buying rabbits, buying a new one every day “like an addiction.” Another woman in her sixties began spending $6,000 a month on slot machines, and a wealthy man around the same age spent $50,000 on cars for his two young girlfriends and $1.25 million on a penthouse for his third girlfriend. 5

In 2005, Klos et al. 6 reviewed fifteen case studies of hypersexual behaviors that began after dopamine agonist treatment. These behaviors ranged from excessive pornography consumption to compulsive masturbation to increased sex drive, which led some of the patients to ask their partners for sex up to every few hours when their norm was a few times a year, while others had extramarital affairs or began propositioning family friends for sex. One man compulsively attended nightclubs every evening until he found a sexual partner, describing an overpowering feeling of “being on the hunt.” Another patient propositioned his friend’s daughter for sex in return for money to relieve her financial difficulties, while another suggested a threesome between his son and daughter-in-law. None of these patients had shown any hypersexual behavior prior to the study.

Examples of less extreme side effects exist for many pharmaceuticals, such as for selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant prescribed today under brand names such as Zoloft, Prozac, or Lexapro. SSRIs work by blocking serotonin breakdown, allowing it to remain in the synapse (the junction between two neurons) longer. Unlike agonists, they do not directly increase serotonin levels, but they allow it to remain in the synapse longer, so the same amount of serotonin packs a bigger punch. SSRIs can affect appetite, sleep patterns, or ability to orgasm. Compared to Pramipexole, these side effects are minimal, and to many patients, they are a small price to pay for alleviating depression. However, minimal or not, a more general takeaway from these side effects is that the pharmaceuticals that we currently use are “messy,” or not specific for the problem we are trying to treat.

Parkinson’s and RLS are caused by dopamine-related pathologies, but so is addiction, ADHD, or depression. This is because neurotransmitters like dopamine are often implicated in a very broad range of functions— such as dopamine’s function in regulating movement, as shown by tremors in Parkinson’s, but also in evaluating reward and regulating impulsive behavior. All drugs of abuse act on the dopaminergic pathway in the brain, as well as natural rewards such as food or sex. So, taking a dopamine agonist will affect Parkinson’s-related tremors, but because the drug is administered systemically, it will act on all of the brain regions that respond to dopamine. Similarly to dopamine, serotonin acts almost everywhere in the brain and affects everything from mood to sleep patterns to appetite—there are cells that respond to serotonin even in the gut. Many of these side effects do not appear until years later, as changes that are initially subtle accumulate over time.

The two possible solutions to this problem are to look for alternate treatments besides pharmaceuticals, or create more selective drugs that target specific areas of the brain. Electroconvulsive therapy (ECT) is used to treat cases of disorders such as major depressive disorder 7 , and deep brain stimulation (DBS) is used frequently and successfully to prevent seizures 8 . Both of these treatments take advantage of the fact that electrical impulses are the brain’s currency; all neurons communicate via electrical signals called action potentials. ECT uses small currents to induce seizures in the brain, while DBS involves implanting electrodes at specific sites into the brain that inject current. They are currently only used if pharmaceuticals do not work or have unmanageable side effects, because of how invasive they are compared to pharmaceuticals.

Some of this stigma is unwarranted, and in some cases myths are perpetrated due to pop culture. Those who have seen the movie “One Flew Over a Cuckoo’s Nest” may remember a particularly powerful scene in which Randle McMurphy, a subversive patient in a mental asylum, was forced to undergo induced seizures as part of electroconvulsive therapy. McMurphy, played by Jack Nicholson, walks into the procedure room in his characteristically jovial and flippant manner. There, he is made to lie down onto a chair, has a mouthpiece put into his mouth and a headset with electrodes placed onto his head. He starts to hum while he waits for the procedure to begin, and as soon as it does, his relaxed expression turns to one of terror and pain. His muscles convulse violently due to the induced seizures, and he has to be held down by a group of doctors and nurses, his screams muffled by the mouthpiece.

The scene conjures up nightmarish images of what the field of neuroscience and psychiatry used to be, such as lobotomies with disastrous consequences and compulsory “treatment” of mental illness; inducing seizures seems like a procedure from this medieval period of neuroscience. However, ECT is far from the crude, painful torture that this scene depicts; a spokeswoman for the British The Royal College of Psychiatrists said, “One Flew Over The Cuckoo’s Nest did for ECT what Jaws did for sharks.” 9 ECT is only ever conducted with voluntary consent, never as a punishment or disciplinary action, and rarely has complications. It is conducted under general anesthesia, and muscle relaxants are to inhibit convulsions.

Even so, it does not sound particularly desirable, and taking a pill every day sounds much safer. However, perhaps we need to change how we think about the mode of administration of a treatment versus the magnitude of its effect on our body. When we take a pill, it is flooding our entire brain, and even though the drug will only have an effect on areas that have the corresponding receptor (the lock for its key), drugs that affect serotonin or dopamine will involve most of the brain. In the case of SSRIs, their efficacy does not even have to do with serotonin, but rather is due to some unknown effect that is the result of a chain reaction that occurs in the brain. 10

SSRIs were originally introduced as a treatment because of a flawed belief that depression is due to an imbalance in serotonin levels. The so-called “serotonin hypothesis” was first formulated in the late sixties 11,12 and has been consistently debunked several times since then. Depleting serotonin in humans was not enough to induce depression 13 , and huge increases of serotonin were not found to relieve it 14 . The serotonin hypothesis is further challenged by the fact that SSRIs do not take effect until six weeks after treatment onset, and even mice that lack the gene that produces serotonin respond to SSRIs. 15

In his 2005 review “Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature,” Jeffrey Lacasse and Jonathan Leo aptly summarize the conclusions of the last few decades of research on the role of serotonin in depression and other neuropsychiatric disorders: “Contemporary neuroscience research has failed to confirm any serotonergic lesion in any mental disorder, and has in fact provided significant counterevidence to the explanation of a simple neurotransmitter deficiency. Modern neuroscience has instead shown that the brain is vastly complex and poorly understood.” 8

Why, then, are SSRIs the most widely used treatment for depression? The answer is: because they have been consistently shown to work 16 , and because we currently have no better alternative. The contemporary view is that rather than being the result of a chemical imbalance, depression is the result of large-scale neural circuit dysfunctions. 17 This brings us to ECT; its proposed mechanism of action is that circuits that are pathologically suppressed during depression are “reset”, allowing the brain to reorganize in a different way. However, its specific mechanism of action is not known. In many ways, it is reminiscent of the serotonin hypothesis of our time: we have a treatment that works very well—it is much effective than SSRIs and takes effect within hours instead of weeks—and there is no consensus on how it works.

Does the fact that we do not understand how it works mean that we should not use it? The primary benefits of ECT compared to pharmaceuticals are its efficacy and rapid remission. It is often used for catatonic patients who are suicidal or refuse to eat, taking effect as soon as the anesthesia wears off. It has consistently been shown to work in 80–90% of patients 18,19,20 , and taking into account that it is mainly used on treatment-resistant patients, these statistics are astonishing. Another benefit of ECT is that the brain is not constantly exposed to the treatment as with pharmaceuticals, but rather in bouts. This is a significant advantage compared to antidepressant medications, which take weeks to have an effect, suggesting that large-scale circuit changes must first occur—changes that we currently do not understand.

Nevertheless, ECT produces a generalized seizure, which is hardly selective, and comes with side effects such as cognitive decline, which may or may not be temporary; some studies show that this effect wears off after six weeks, while others are inconclusive. 21 Therefore, it is hardly an ideal treatment. It turns out that there is a way to selectively target brain circuits that is widely used in neuroscience on mammals: DREADDs, or “designer receptors exclusively activated by designer drugs.” The receptors are “designer” in that they are a class of G-protein coupled receptors (GPCRs) modified to interact with clozapine-N-oxide (CNO), a compound that is otherwise inert but bioavailable. With the help of viral vectors generated to only affect neurons that express a specified gene, they have very high specificity. 22,23 The use of DREADDs falls under gene therapy, a promising type of treatment that is still in its infancy when it comes to humans, currently only run in clinical trials. 24 Combining genetic tools with pharmaceuticals gives us the precision that we currently lack, and would allow us to target one brain region, a certain subtype of neurons within that brain region, or one type of receptor throughout the entire brain. Potential problems with gene therapy include delivery to the correct location on the genome, avoiding turning on the correct cells/processes, and avoiding the immune response that can sometimes kill cells that show abnormal activity. These are only the technical issues in getting the technique to work, and there will surely be a whole array of new issues concerning how to figure out which cells or receptors to target, as well as possible side effects that result from altering the genome and targeting even a select population of cells. For many of the diseases we intend to treat, we have not conclusively localized the affected circuit or the main cause of the problem. Even when we do figure out which area to target and how, there is still no such thing as total selectivity; the brain is a dense web of connections, and it is not possible to isolate an area without affecting the rest of it. Hopefully by minimizing the area we target, we can ameliorate unnecessary downstream effects. Although we have a long way to go in pharmaceutical reform with many potential roadblocks, hopefully the benefits will outweigh the risks.

Works Cited:
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2) Liu GJ, Wu L, Lin Wang S, Xu LL, Ying Chang L, Fu Wang Y. Efficacy of Pramipexole for the Treatment of Primary Restless Leg Syndrome: A Systematic Review and Meta-analysis of Randomized Clinical Trials. Clin Ther. 2016;38(1):162-179.e6. doi: 10.1016/j.clinthera.2015.10.010.

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6) Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord. 2005;11(6):381-6. DOI: 10.1016/j.parkreldis.2005.06.005

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9) Estridge B. Jack Nicholson did for shock therapy what Jaws did for sharks: An expert argues that ECT is really more effective than antidepressants. Daily Mail. July 9, 2011. Retrieved October 29, 2016.

10) Lacasse JR, Leo J. Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature. PLoS Med. 2005; 2(12): e392. doi: 10.1371/journal.pmed.0020392

11) Schildkraut JJ, Gordon EK, Durell J. (1965). Catecholamine metabolism in affective disorders. I. Normetanephrine and VMA excretion in depressed patients treated with imipramine. J Psychiatr Res. 1965;3(4):213-28.

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14) Mendels J, Stinnett JL, Burns D, Frazer A. Amine precursors and depression. Arch Gen Psychiatry. 1975;32(1):22-30.

15) Angoa-Pérez M, Kane MJ, Briggs DI, Herrera-Mundo N, Sykes CE, Francescutti DM, Kuhn DM. Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype. ACS Chemical Neuroscience. 2014; 5(10): 908-919. doi:10.1021/cn500096g

16) Hieronymus F, Emilsson JF, Nilsson S, Eriksson E. Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Mol Psychiatry. 2016;21(4):523-30. doi: 10.1038/mp.2015.53.

17) Hurley D. The Return of Electroshock Therapy. The Atlantic. n.d. Retrieved October 29, 2016.

18) Prudic J, Sackeim HA, Devanand DP. Medication resistance and clinical response to electroconvulsive therapy. Psychiatry Res. 1990;31(3):287-96.

19) Prudic J, Haskett RF, Mulsant B, Malone KM, Pettinati HM, Stephens S, Greenberg R, Rifas SL, Sackeim HA. (1996). Resistance to antidepressant medications and short-term clinical response to ECT. Am J Psychiatry. 1996;153(8):985-92. DOI: 10.1176/ajp.153.8.985

20) Rose D, Fleischmann P, Wykes T, Leese M, Bindman J. Patients’ perspectives on electroconvulsive therapy: systematic review. BMJ. 2003;326(7403):1363. DOI: 10.1136/bmj.326.7403.1363.

21) Oudega ML, van Exel E, Wattjes MP, Comijs HC, Scheltens P, Barkhof F, Eikelenboom P, de Craen AJ, Beekman AT, Stek ML. White matter hyperintensities and cognitive impairment during electroconvulsive therapy in severely depressed elderly patients. Am J Geriatr Psychiatry. 2014;22(2):157-66. doi: 10.1016/j.jagp.2012.08.002.

22) Urban DJ, Roth BL. DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility. Annu Rev Pharmacol Toxicol. 2015;55:399-417. doi: 10.1146/annurev-pharmtox-010814-124803.

23) Roth BL. DREADDs for Neuroscientists. Neuron. 2016;89(4): 683-694. doi:10.1016/j.neuron.2016.01.040

24) Mayo Clinic Staff. Gene therapy. Mayo Clinic. Published September 13, 2016. Retrieved October 29, 2016.

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