Schizophrenia:

Abstract

There are several structural and functional abnormalities associated with the development of schizophrenia. This paper offers an overview of recent research on the development of schizophrenia, identifying patients at risk as early as possible, and current treatments. This disease results in hallucinations, delusions, and can severely impact day-to-day function due to cognitive dysfunction. By developing more targeted therapies and implementing them as early as possible, physicians can prevent loss of brain volume and decline of cognitive skills in schizophrenic patients. Current research is rooted in the dopamine hypothesis, which suggests that positive symptoms (hallucinations, changes in behavior, etc.) of schizophrenia develop due to hyperactivity of the dopamine D2 receptor, resulting in increased dopamine production. In contrast, negative symptoms can be attributed to hypofunctionality of the dopamine D1 receptor in the prefrontal cortex (Liu et al., 2021). Recent studies focus on treatments beyond the dopamine hypothesis and attempt to investigate the causes of schizophrenia through animal models. While there has been progress with ideas such as self-medication and transcranial direct current stimulation, further research needs to be done on the origins of schizophrenia and how to suppress hallucinations. 

About half the population in the United States will be diagnosed with some form of a mental illness throughout their life. The World Health Organization states that schizophrenia is one of the less common mental health disorders, affecting 0.32% of people worldwide. (World Health Organization, 2022). It affects how a person thinks and behaves, which can make it difficult for them to participate in everyday activities. Schizophrenic individuals can experience loss of motivation, withdrawal from social life, and problems related to attention and concentration. Some of the more distressing symptoms are hallucinations (hearing or seeing things that aren’t there), delusions, and thought disorder (unable to follow a train of thought and hold a conversation).

Past research has associated the development of schizophrenia with dopamine dysfunction, and much of it focused on suppressing the symptoms of this disorder rather than investigating the cause of it (Liu et al., 2021). For more common mental health disorders, such as anxiety or PTSD, there are several forms of therapy that focus on investigating the root cause of an individual’s fears or trauma. Since schizophrenic individuals can experience symptoms that distort their perception of reality, past research heavily focused on suppressing the symptoms as much as possible so individuals could lead normal lives. 

Understanding the Causes of Schizophrenia

Schizophrenia is a distinctly human disorder, meaning that its symptoms vary considerably from patient to patient. A problem faced by health professionals is finding a common cause to this disorder. For example, one structural abnormality associated with the development of schizophrenia throughout most patients is gray matter decline. Yang and Tsai (2017) conducted an eight month study to investigate the link between gray matter decline and cognitive deficits in schizophrenic patients . Comparing the amount of gray matter volume initially to the final amount suggested that impairments in initial neuropsychological testing are associated with progressive gray matter degeneration. Neuropsychological testing includes the Wisconsin Card Sorting Test and the Controlled Oral Word Association Test. The Wisconsin Card Sorting Test measures an individual's strategic planning skills and how they utilize feedback to shift their cognitive skills. The Controlled Oral Word Association Test measures verbal fluency. Worse neuropsychological test performance initially can indicate that neurodegeneration was occurring for years prior to the onset of illness. It can take years for family or friends to notice schizophrenic behavior in someone. More often than not, patients have been hearing voices and experiencing hallucinations for several months before someone notices. This can lead to a slow but steady decline in cognitive skills which results in worse performance on the tests mentioned above.

Other researchers have attempted to understand the influence of sex in the onset of schizophrenia. Vasconcelos et al. (2021) hypothesized that male animals exposed to the two-hit model of schizophrenia would be more prone to present hippocampal inflammatory changes than females . The two-hit model suggests that a prenatal genetic/environmental “first hit” will disrupt brain development and establish increased vulnerability to a “second hit” later in life. Combined, these can induce schizophrenia. 360 mice were put through the two-hit model of schizophrenia (hit one was neonatal immune activation and hit two was pubertal stress exposure). Candesartan (a hypertension medication known as CAND) was administered to half the groups (equal numbers male and female groups) starting from five days before the stress protocol to a few days after the protocol ended. A combination of behavioral assessments and analysis of blood samples showed that CAND significantly prevented prepulse inhibition (PPI) deficits in both males and females. Prepulse inhibition is a reflex modification; in schizophrenic patients, deficits of prepulse modification manifest in an inability to filter out unnecessary information.  Dissection of the hippocampus revealed that males and females exhibited similar structural changes, meaning that there weren’t any sex influences observed. However, CAND effectively blocked the symptoms induced by the two-hit model. Further research into the small group of bioactive molecules that CAND belongs to could possibly show how to suppress many symptoms in schizophrenic patients.

Identifying Patients at Risk

Although significant research has been done on the symptoms of schizophrenia and how to suppress them, there is lots unknown about how this disorder occurs and how we can identify patients at risk. Arnedo et al. (2015) conducted a quantitative study that allowed them to create three distinct phenotypes of schizophrenic patients . This was done through a method called biclustering (a combination of two pre-existing methods: generalized factorization method and non-negative matrix factorization algorithms), which analyzed white matter abnormalities through a collection of fractional anisotropy (FA) images from schizophrenic patients who had pre-selected similar categories (Arnedo et al., 2015). The first phenotype of patients is more likely to display bizarre symptoms (social-sexual and aggressive behavior); the second phenotype is associated with delusions of persecution, grandeur, control, and through withdrawal; and the third phenotype is more likely to have poverty of speech and carelessness in their social/physical behavior (Arnedo et al., 2015). By categorizing schizophrenic patients into these phenotypes, researchers can develop more targeted treatments to suppress the symptoms for each group.

Liu et al. investigated whether schizophrenia is associated with expression profiles of the granule cell (GC) related genes in the human prefrontal cortex (PFC). Granule cells control the development of the cerebellum, which is involved in cognitive functions (memory and balancing). Samples from six donated brains were used to generate PFC samples and determine candidate GC-related genes. When the candidate genes were cross-examined between schizophrenic patients and healthy control, researchers found six genes more significantly expressed in schizophrenic patients. The results of this study can help identify patients at risk for developing schizophrenia. Treating this disorder as early as possible can help minimize loss of brain volume and keep symptoms at bay for a longer amount of time.

Treatment Methods

Treating Negative Symptoms

Negative symptoms are characteristics present in healthy individuals that seem to be lacking in schizophrenic patients. These include diminished expression, lack of interest in hobbies, and withdrawal from personal and social relationships. Many antipsychotic medications are effective at reducing positive symptoms (cause changes in behaviors and thoughts, including hallucinations) in schizophrenic patients, but are ineffective in terms of negative symptoms. Deroza et al. (2012) studied the effects of self-medication to alleviate negative symptoms of schizophrenia via an animal study. They exposed 100 schizophrenic rats (symptoms induced by ketamine) to cigarette smoke for either seven days or twenty-one days. The rats went through a locomotor activity evaluation (positive symptoms) and social interaction evaluation (negative symptoms) pre-trial and post-trial. While positive symptoms were not impacted by smoke exposure, it increased the number of social contacts the schizophrenic rats had (Deroza et al., 2012). However, it is important to keep in mind that self-medication via cigarettes can create other health issues, such as lung cancer. In contrast, Valiengo et al. (2020) have recently been studying transcranial direct current stimulation (tDCS) as a treatment for the negative symptoms of schizophrenia. This is a non-invasive and tolerable treatment with no known adverse side effects. When a quantitative, double-blind, placebo-controlled, randomized trial was conducted on this treatment, researchers found that five days of tDCS had lasting effects on schizophrenic patients (Valiengo et al., 2020). After six weeks, 40% of the experimental group presented an improvement on the PANSS (positive and negative scale for schizophrenia) scale as compared to 4% of the placebo group (Valiengo et al., 2020). These positive effects persisted for 38% of the experimental group after twelve weeks . 

Treating Positive Symptoms

While antipsychotic medications can reduce positive symptoms, they do not completely eliminate hallucinations and delusions schizophrenic patients experience. In a study conducted at Cambridge, one patient (Susan) was having trouble coping with her visual hallucinations of snakes (O’Brien & Johns, 2013). Since schizophrenic hallucinations often stem from real fears, Susan genuinely thought she could be physically harmed by the snakes. She decided to try exposure therapy to help reduce her fears. Throughout the course of therapy, her self reported anxiety associated with snakes decreased from 8 out of 10 to 2 out of 10 (O’Brien & Johns, 2013). Her score on the PSYRATS (psychotic symptom rating scale) was reduced from 32 (pre-therapy) to 7 (post-therapy) (O’Brien & Johns, 2013). Susan was able to tolerate the symptoms and she felt a greater sense of control (O’Brien & Johns, 2013).

Expanding Treatments

Liu et al. (2021) evaluated current treatment methods and commented on how they could be expanded . While current antipsychotics are effective at reducing symptoms, patients often relapse after release from the hospital (Liu et al., 2021). These researchers believed that targeting other groups of neurotransmitters would reduce these issues . Second generation antipsychotics do not have the same efficacy as other medications, but there has been renewed interest in the development of 5-HT3 antagonists (medications usually taken by cancer patients after chemotherapy to reduce nausea) for reducing negative/cognitive symptoms (Liu et al., 2021). While current research in schizophrenia is rooted in the dopamine hypothesis, Liu et al. (2021) suggest that neuropeptides could have potential efficacy across several schizophrenia symptoms and the incorporation of brain imaging markers into the treatment strategy can provide new opportunities for precisely treating schizophrenia . 

Conclusion

Cumulative findings from previous studies show that currently, health professionals know who is most at risk for schizophrenia and which antipsychotic medications will suppress their symptoms most effectively. However, the use of antipsychotic medication in schizophrenic patients is often discontinuous and leads to relapse, meaning that it is not a long-term solution (Liu et al., 2021). They can also tell which parts of the brain are affected, but it is unknown how to eliminate visual/auditory hallucinations, how the disorder can be identified early, and how to reduce the risk of relapse.

Recent studies have made more of an effort to understand where in the body schizophrenia originates and how the disorder can be identified as early as possible. High loss of brain volume and frequent hallucinations in schizophrenic patients call for more targeted therapies to be developed. New treatments such as transcranial direct current stimulation and exposure therapy show potential for treatments outside the dopamine hypothesis. Despite the fact that the high variability of symptoms makes it difficult to replicate schizophrenia in animals, certain studies have succeeded in inducing schizophrenia in rats to investigate how this disorder occurs. In the coming years, more research could focus on how to suppress visual and auditory hallucinations, which can happen multiple times a day for schizophrenic patients. 

References 

Arnedo, J., Mamah, D., Baranger, D. A., Harms, M. P., Barch, D. M., Svrakic, D. M., de Erausquin G. A., Cloninger, C. R., & Zwir, I. (2015). Decomposition of brain diffusion imaging data uncovers latent schizophrenias with distinct patterns of white matter anisotropy. NeuroImage, 120, 43–54.https://doi.org/10.1016/j.neuroimage.2015.06.083

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Deroza, P. F., Ghedim, F. V., Heylmann, A. S., de Luca, R. D., Budni, J., Souza, R. P., Quevedo, J., & Zugno, A. I. (2012). Effect of cigarette smoke exposure in the behavioral changes induced by ketamine. Schizophrenia research, 141(1), 104–105.https://doi.org/10.1016/j.schres.2012.07.004

Liu, H., Xu, L., Fu, J., Su, Q., Liu, N., Xu, J., Tang, J., Li, W., Zhao, F., Ding, H., Liu, F., Qin, W., & Yu, C. (2021). Prefrontal Granule Cell-Related Genes and Schizophrenia. Cerebral cortex, 31(4), 2268–2277.https://doi.org/10.1093/cercor/bhaa360

Valiengo, L. D. C. L., Goerigk, S., Gordon, P. C., Padberg, F., Serpa, M. H., Koebe, S., Santos, L. A. D., Lovera, R. A. M., Carvalho, J. B., van de Bilt, M., Lacera, A. L. T., Elkis, H., Gattaz, W. F., & Brunoni, A. R. (2020). Efficacy and Safety of Transcranial Direct Current Stimulation for Treating Negative Symptoms in Schizophrenia: A Randomized Clinical Trial. JAMA psychiatry, 77(2), 121–129.https://doi.org/10.1001/jamapsychiatry.2019.3199

Vasconcelos, G. S., Dos Santos Júnior, M. A., Monte, A. S., da Silva, F. E. R., Lima, C. N. C., Moreira Lima Neto, A. B., Medeiros, I. D. S., Teixeira, A. L., de Lucena, D. F., Vasconcelos, S. M. M., & Macedo, D. S. (2021). Low-dose candesartan prevents schizophrenia-like behavioral alterations in a neurodevelopmental two-hit model of schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry, 111, 110348. https://doi.org/10.1016/j.pnpbp.2021.110348

Yang, A. C., & Tsai, S. J. (2017). New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. International journal of molecular sciences, 18(8),1689.https://doi.org/10.3390/ijms18081689

https://www.who.int/news-room/fact-sheets/detail/schizophrenia