Pharmacology and the Future for Schizophrenia

by Olivia Lanza, Biology

In recent years, researchers have expressed growing interest in the prospect of modern schizophrenia treatments. Currently accepted treatments largely consist of prescribed antipsychotics that aim to reduce dopamine signaling and relieve patients of their persistent symptoms. However, it has been revealed that the scope of these prescription drugs is rather limited in their medicinal reach, leaving many patients with continued symptoms following their use. Consequently, recent studies have drawn researchers’ attention to the cholinergic system with hopes of uncovering a novel source of hope for patients diagnosed with schizophrenia. More specifically, scientists have focused their efforts on understanding the role of acetylcholine, a neurotransmitter known to elicit responses pertaining to memory, learning, and attention—all of which can be affected by schizophrenia. By uncovering a pathway linked to cognitive function, researchers may be pioneering the discovery of an alternative pharmacological target and a transformative treatment for countless patients. In support of these efforts, clinical trials and experimental studies have explored potential treatment sources, such as betel nut, as well as pharmacological approaches, such as fixed-dose combination. While many patients desperately await the introduction of a new treatment, the barriers to clinical entry remain high in the field of pharmacology. Unsurprisingly, engineering a new drug comes with challenges pertaining to side-effects, dosage, and approval for human use. Though the obstacles confronting researchers are all but scarce, the prospect of new pharmacological practices offers hope for patients who fall outside of the scope of current treatments.

Schizophrenia, pharmacology, symptoms, dopamine, neurotransmitters

“When would a parent hope for a diagnosis of drug abuse? If the alternative is schizophrenia, you wish the problem was ‘only’ drugs,” writes Marjorie Baldwin, mother of the then 21 year-old David Baldwin (Baldwin, 2016, p. 4). David, a young and previously healthy male, had been admitted to a psychiatric unit following the outbreak of alarmingly bizarre behaviors. After going away to college at the University of North Carolina earlier that year, David had begun to display symptoms of what his mother initially thought to be drug abuse—emotional outbursts, incoherent rambling, and behavior that simply didn’t make sense. Despite Mrs. Baldwin’s efforts to make sense of these tendencies, she had hardly ever considered mental illness to be the explanation. David’s unusual behaviors, however, would ultimately result in a life-changing diagnosis of schizophrenia—a single word that was able to turn the Baldwins’ world on its head. ­

The term “schizophrenia,” or “split mind,” was first coined by psychiatrist Eugen Bleuler in 1911 after witnessing in his patients what he described as the dissociation of psychic functions (Baldwin, 2016). Today, this term refers to a mental illness characterized by irregular thoughts, perceptions, and behaviors, which ultimately impede the affected individual’s school, work, and personal life. Symptoms can be further categorized into three groups: positive symptoms, such as hallucinations, delusions, and racing thoughts; negative symptoms, such as apathy, lack of emotion, and poor or non-existent social functioning; and lastly cognitive deficits, such as disorganized thoughts, difficulty concentrating or following instructions, difficulty completing tasks, and memory problems (Scarr & Dean, 2008). The severity of such symptoms can span a spectrum with some patients displaying more mild cases than others; however, they almost always lower the individual’s quality of life and pose challenges to daily tasks.

According to recent reports, schizophrenia is witnessed in roughly one out of every 300 people, resulting in grievous diagnoses around the world for patients like David and parents like Marjorie (World Health Organization, 2022). Though there are current remedies in place to ameliorate the effects of the illness, recent clinical trials suggest the growing prospect of other treatments that may accommodate a larger pool of patients suffering from the disorder, with acetylcholine (ACh) receptors at the forefront of this research. Receptors are essentially proteins within or on a cell’s membrane that can bind small molecules to elicit a cell response. This response, in turn, translates to physiological activity that can be observed in patients. Before understanding the promise of these receptors, it is first important to understand the current medications prescribed and their shortcomings as treatment.

While it is still under study, schizophrenia has long been explained using the dopamine model—a model that attributes symptoms to irregular dopamine release by neurons as they transmit a signal throughout the body. Dopamine plays a role in perception, memory, mood, and attention among other physiological roles. In agreement with this hypothesis, current antipsychotic drugs approved for clinical use all work to reduce dopamine signaling and are reported to reduce positive symptoms (Foster et al., 2021). With that being said, their failure to reduce negative and cognitive symptoms remains a limitation of these drugs, not to mention their long list of side-effects that take an additional toll on affected individuals. In fact, studies suggest that up to 30% of schizophrenia patients display treatment-resistant psychosis, meaning they failed to respond to one antipsychotic and still experienced symptoms after trying a second (Brannan et al., 2021). As research on schizophrenia and the physiology behind it continues to develop, the prospect of a more efficient treatment becomes of increasing interest.

One physiological system under extensive research for schizophrenia—as well as Alzheimer’s disease, Parkinson’s disease, and depression—is the cholinergic system. This system, which belongs to the larger nervous system, plays a key role in cognitive processing, memory, attention, sleep, and psychosis, making its relevance to schizophrenia readily apparent (Raedler, 2008). Historically, the cholinergic system was the target of coma therapy, which was used to treat patients having psychotic episodes before the advent of antipsychotics. The cholinergic system was later considered in the creation of anticholinergic drugs, which worked to minimize the side effects of antipsychotics. Finally, it has recently been valued for its promising ability to regulate the activity of certain receptors (Scarr & Dean, 2008). Receptor sites generally act as locks to selectively fit neurotransmitters, or keys, with certain configurations. When considering schizophrenia, the neurotransmitter of particular interest is acetylcholine, as its activity elicits responses pertaining to memory, learning, and attention. The unique key configuration of acetylcholine is a perfect match with two particular locks: the nicotinic receptor and the muscarinic receptor. Seeing as cognitive deficits “are now recognized as being the most debilitating aspect of the disorder,” the ability for these receptors to regulate a neurotransmitter that affects cognitive function is key to discovering more efficient treatments (Scarr & Dean, 2008, p. 1189).

 While the nicotinic ACh receptors may hold future promise, current research emphasizes the role of muscarinic receptors in alleviating the negative and cognitive symptoms that persist with antipsychotic drugs. One of the reasons for this is nicotinic receptors seem to have more narrow implications, affecting only the cognitive aspect, while muscarinic receptors tend to have a broader scope of implications. “Give muscarinic agonists, get robust efficacy,” says Assistant Professor Daniel Foster who researches muscarinic targets at the University of South Carolina (D. Foster, personal communication, March 23, 2023). This efficacy has been supported by a number of studies that examine the different subtypes of muscarinic receptors. Subtypes include M1, M2, M3, M4, and M5, each setting off slightly different signal cascades to create their own unique responses within the nervous system. Interestingly, neuroimaging studies performed on schizophrenia patients have shown significantly decreased levels of the M1 and M4 subtypes, two types particularly associated with positive and cognitive effects (Raedler, 2008). Furthermore, studies exploring genetic irregularities in patients have revealed M1 and M5 polymorphism, meaning that the receptors in these individuals are encoded by slightly mutated DNA sequences. This ultimately results in altered structure and function at these sites (Berman et al., 2007).

Aside from genetic and neuroimaging evidence, other leading signs of muscarinic efficacy have been found in substances more familiar to the general public. One particular substance comes in the form of a seed, and upon consumption, resembles the warm flavors of cinnamon and nutmeg. Betel nut, as it is called, is an ingredient found in Asian and Pacific cultures that has developed a new importance amongst researchers and physicians. Though many people are familiar with the more commonly known drugs such as caffeine, nicotine, and alcohol, few people are aware of betel nut, which ranks fourth, after alcohol, as the most widely used drug (Sullivan et al., 2007). What is unique to this particular substance, however, is its leading component known as arecoline. Believed to reduce positive and negative symptoms of schizophrenia, arecoline has been classified as a muscarinic agonist, meaning it has the ability to increase the activity of muscarinic ACh receptors (Raedler, 2008).

One study performed by the Behavioral Health Division of the Belau National Hospital supported the hypothesis that if arecoline truly was a muscarinic agonist, then consumption of betel nut would result in fewer symptoms associated with schizophrenia (Sullivan et al., 2007). In this study, 69 outpatients who had previously been diagnosed with schizophrenia or schizoaffective disorder were advised to consume betel nut over a set period of time, with examinations at the start of the trial, after four months, and after eight months. The results were, to an extent, what was anticipated, with the higher-consuming males displaying fewer positive symptoms than the lower consuming males. However, the trial also revealed potentially significant disparities between the male and female populations, with negligible changes in symptoms across the different intensities of female chewing groups (Sullivan et al., 2007). With this in mind, future trials may call into question the potential gaps in betel nut efficacy across male and female patients, opening doors to broader studies exploring how gender influences muscarinic agonists in general. While future studies may be required to unveil the implications of muscarinic agonists, trials such as these seem to endorse the appeal of a muscarinic target.

In addition to the betel nut trials, other pharmacological trials have positioned a few key drugs at the forefront of schizophrenia breakthroughs. One of these drugs is known as Clozapine, which has a unique metabolite known as norclozapine that acts as both a dopaminergic and muscarinic agonist. Unlike the antipsychotics currently available, Clozapine has been effective in roughly 70% of patients who failed to respond to their initial drug treatment (Foster et al., 2021). Researchers believe that the agonist character of norclozapine may be responsible, as its ability to modulate dopamine and acetylcholine levels gives the drug a broader scope of efficacy (Raedler, 2008).

Xanomeline is another muscarinic agonist that has been shown to reduce positive, negative, and cognitive symptoms. Its drawbacks, however, pertain to reports of gastrointestinal side-effects with usage side-effects that were so bad in the 90s that the drug was discontinued in Alzheimer’s experimentation (Singh, 2022). In response to this, recent scientists have turned their attention to fixed-dose combination methods, in which another drug is introduced in combination with Xanomeline to reduce its side effects. The drug of interest, known as Trospium, has antimuscarinic character that essentially counters Xanomeline without interfering with its benefits. The combination has proven effective in both Phase I and Phase II trials and requires only one more phase before receiving clinical approval (Singh, 2022). With the success of this pharmacological approach could come simpler treatment plans, fewer prescribed pills, and less room for prescription errors.

Despite the seemingly abundant benefits, the combination has its limitations. “We’ve seen a lot of merit to a biological model of these disorders that’s resulted in medications that can be lifesaving, but they can also have undesirable, potent side effects,” states Ian Raugh, a graduate student in the Behavioral and Brain Sciences Program at UGA (I. Raugh, personal communication, April 6, 2023). While less severe than those of Xanomeline alone, side-effects of the combination drug still present in patients are nausea, vomiting, and dry mouth. The second drawback comes from the ratio of one drug to another in making the combination as efficacy requires each to be present in a very narrow range of proportions (Singh, 2022). While targeting the muscarinic receptors holds undeniable promise, it is clear across nearly all trials that further research on potential implications is necessary. The necessity of these studies, however, continues to grow as the potential applications of a muscarinic treatment expands beyond the treatment of schizophrenia.

Though muscarinic acetylcholine receptors hold profound opportunities for patients and families who live with the effects of schizophrenia, their ability to target certain negative and cognitive symptoms has opened doors for their use across other disorders as well. “It’s difficult to get a drug into a real patient for the first time, but once this drug has successfully reached the schizophrenia population, the barriers to trying this treatment in other patient populations are significantly reduced,” says Dr. Foster (D. Foster, personal communication, March 23, 2023). One disorder whose patient population is of particular interest to Dr. Foster is autism spectrum disorder. Surprisingly, autism spectrum disorder can be characterized by cognitive rigidity and repetitive behavior, leading researchers to believe that acetylcholine may ameliorate these cognitive deficits in a similar manner as with schizophrenia (Karvat & Kimchi, 2013). While studies on a muscarinic approach to autism spectrum disorder remain in the early stages, advances in schizophrenia research may hold an impact that is greater than originally thought.

Living with schizophrenia irrefutably comes with hardships and pain—not to mention the added obstacle that society presents as stereotypes and stigma surrounding mental illnesses. Though today’s treatments provide relief for many, even the most widely used antipsychotics fail to offer patients the quality of life they deserve. As a result, many patients, families, and caregivers such as Marjorie Baldwin are faced with unimaginable obstacles to their daily lives. Acetylcholine receptors, however, seem to hold promise for individuals like David Baldwin who feel defeated by a disorder that seems to control their lives. While it is unclear whether the solution may reside in newly formulated drugs, fixed-dose combination, or betel nut, continued investigation pertaining to the cholinergic system may uncover some answers. In time, the success of the targeted receptors and the application to patients could pave the way for the treatment of related disorders as well. With continued clinical studies, muscarinic acetylcholine receptors may have the perfect lock-and-key fit for the door to a new era of pharmacological treatment.


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Thank you to Dr. Holly Gallagher who supported me throughout the writing process and encouraged me to share my work with other readers.

Citation style: APA 7th