Treatment of Schizophrenia

Schizophrenia is a very consequential mental illness, its effects can alter how someone can think, feel, and act. Often it tends to go untreated. According to WHO only 31.3% of people with schizophrenia get treatment from specialists. You might ask yourself “if help is offered, why don’t people get the help?” Well, it isn’tthat easy.

Pathways Targeted by Anti-Psychotics.

There are four major pathways that anti-psychotics can target. The mesolimbic pathway is altered because people with schizophrenia have too much dopamine. This can cause satisfaction, emotions, and thoughts not be the same. Anti-psychotics lower dopamine transmission.  The mesocortical pathway controls cognition and reward processing. The nigrostriatal pathway controls movement can cause things like tics.  The tuberoinfundibular pathway gets effected by the high dopamine levels by causing too much prolactin. This causes the hysteria and hallucinations.

Most anti-psychotics target dopamine receptors in the brain. They block the receptors so that dopamine isn’t processed that cause the symptoms of schizophrenia. Which again you still might be asking yourself “why don’t they take the treatment?”

What Happens at These Receptors?

Antipsychotics cause D2 receptors to inhibit the enzyme Akt. Akt is responsible for the phosphorylation of GSK3β. Antipsychotics cause the GSK3β to be inhibited.

In medicated schizophrenia patients compared to ones not treated with an anti-psychotic, non- medicated had 5.8% more active D2 receptors.

The dopamine D2 receptor releases clozapine and quetiapine (both are commonly used to treat schizophrenia) more rapidly than it do any of the other antipsychotic drugs.

Perceived Effects of Anti-Psychotics

It inhibits dopamine transmission; it can cause people’s lives to become dull. Sadly, it seems to be a hit or miss acting. Yes, anti-psychotics can stop extreme symptoms, but it also inhibits dopamine transmission for typical everyday life. There are things in life that naturally produce dopamine you don’t even think of. Any sort of action or activity that gives you satisfaction gets dulled while on anti-psychotics. I am not sure about you, but simple things even like selfcare Sunday night to get ready for the upcoming week is something I look forward too. I get so much satisfaction from doing a facemask and crawling into a freshly washed and made bed. While on anti-psychotics, that wouldn’t be rewarding. It can cause people to be a lot less motivated.

Another factor that often gets mentioned is the stigmatism about taking “anti-psychotics.” Think of the word means, I personally think “undoing-the delusion.” As much as I don’t want to say it, but in society it is made to seem if you take anti-psychotics you are “crazy.” Which I can understand how that stigmatism happened due to some cases of symptoms. Yet, if we all had the same unbalance within ours brains we’d be “crazy” too. At the end of the day, we don’t and we can’t undo it for others that do. So truly tagging such negative ideals to something so impacting such a schizophrenia is unfair. Those that deal with it are already just trying to deal with impacts.

The Future of Treatment

As time goes on so does research, more suitable treatment plans are being investigated. A middle ground, not an all or nothing strategy is the goal. Recently an oral compound SEP-363856, has been studied as a medication for schizophrenia. A 2020 study posted to the New England Medical Journal has studied SEP-363856. It isn’t a D2 inhibitor, but an agonist at TAAR1. TAAR1 is a G-coupled protein receptor that has been shown to alter dopamine, serotonin, and glutamate activity. It is currently in phase 3 of clinical testing. Most studies were short, (around 4 months long) yet have shown positive results. The only one thing negative thing I can find so far on this drug is that it may be suitable for mild Schizophrenia cases. Another note on treatment plans I found is that majority of treatment is being done to treat Schizophrenia. There isn’t much being done or real definitive answers to help the physical brain matter of people with Schizophrenia. That not too much can be done for preventative care.

A Peak into Schizophrenia

I found this little youtube video that has a young boy with schizophrenia and his treatment team. I think it is worth the watch. You can read as much as you want to try to understand what symptoms may be like, this video helps me see what it is somewhat like going off of this real life story. It also mentions another treatment plan that is in clinical trial, this one focuses on the auditory system. Which personally blows my mind that so far it seems to be effective. It doesn’t effect dopamine pathways which cuts out the bad effects of anti-psychotics. Instead it helps with auditory hallucinations. It targets the processings within the brain.

Sources

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

https://pubmed.ncbi.nlm.nih.gov/32294346/

https://psychopharmacologyinstitute.com/publication/the-four-dopamine-pathways-relevant-to-antipsychotics-pharmacology-2096

https://www.nature.com/articles/s41398-021-01331-9#:~:text=SEP%2D363856%20is%20a%20trace,for%20the%20treatment%20of%20schizophrenia

Schizophrenia is hypothesized to be a brain developmental disorder that can be diagnosed or evident in late adolescence or early adulthood. This mental illness disorder can be characterized by hallucinations, delusions, social withdrawal, and cognitive disabilities. The main concern with this disorder is that the onset can be in adolescence childhood, which is a critical period for the brain’s neural development and growth. Therefore, the main question is how do we focus more on prevention along with treatment for Schizophrenia?

In a brain with Schizophrenia it is evident that there is cortical thinning in the superior temporal gyrus and patients with Schizophrenia have a smaller hippocampus, amygdala, thalamus. Suggesting a possible correlation to Alzheimer’s disease as the hippocampus is the first portion of the brain to be affected. Therefore, with a smaller brain volume there is greater lateral and ventricle volumes and as a result greater cerebrospinal fluid. In terms of genes, the protein C4 from a C4 gene on chromosome 6 puts an individual at greater risk for Schizophrenia.

As related to the article, An emerging role for Wnt and GSK3 signaling pathways in schizophrenia, the pathway related to Schizophrenia is the Wnt signaling pathway. This pathway is based in the role it plays in the neural development to adult neural circuit function as it relates to Schizophrenia. During developmental stages patients with schizophrenia may show delays in certain milestones such as problems with neuromotor development, poor performance on cognitive tests, problems with speech, and difficulties in social adjustment. As it relates to development, studies have suggested that there is a correlation between utero and early environmental factors like infection that could play a role during pregnancy in later development of Schizophrenia. Therefore, disrupting fetal brain development from unfortunate events during pregnancy and increasing the risk of child to develop Schizophrenia.

https://doi.org/10.1111/cge.12111

As briefly discussed in small break out groups, prenatal vitamins were suggested to possibly have part to increase the likelihood of developing schizophrenia in the child later on. However, from a nutrition standpoint prenatal vitamins contain important nutrients such as folic acid or folate that help to drastically decrease the risk of the fetus having spina bifida. On the argument that prenatal vitamins could increase the risk, I question the role folate plays with schizophrenia. As a result in vitro and in vivo studies suggest that folate deficiency increases risk of Schizophrenia in the developing fetus. Considering that with folate deficiency there is also higher levels of homocysteine that can build up in the blood. Homocysteine creates greater risk for not only cardiovascular disease but also negatively impacting brain development from neuronal dysfunction in a developing fetus. Higher homocysteine levels have also been seen in patients with Alzheimer’s disease or other forms of dementia.

Along with this, a prenatal supplement in the nutrition world is understood as a supplement; a supplement should go along with proper nutrition from food otherwise the effects and benefits could be impacted. Nutrition plays a key role in fetal development early on and as a more recently discovered mental illness there is still a lot to learn about Schizophrenia. More research is needed on the topic of when Schizophrenia develops and whether or not there are ways to prevent it or better treat this disorder.

Citations:

Schizophrenia’s strongest known genetic risk deconstructed. NIH, 2016. https://www.nih.gov/news-events/news-releases/schizophrenias-strongest-known-genetic-risk-deconstructed

An emerging role for Wnt and GSK3 signaling pathways in Schizophrenia. Singh, KK. Developmental Biology: Frontiers for clinical genetics, 2013. Wiley Online Library. https://doi.org/10.1111/cge.12111

Childhood developmental abnormalities in Schizophrenia: evidence from high-risk studies. Suvisaari, J., tuulio-Henriksson, A., Lonnqvist, J. Schizophrenia Research, 2003. Science Direct. https://www.sciencedirect.com/science/article/pii/S0920996402002347?via%3Dihub#BIB12

The Origins of Schizophrenia, edited by Alan Brown, and Paul Patterson, Columbia University Press, 2011. ProQuest Ebook Central, https://ebookcentral.proquest.com/lib/cord-ebooks/detail.action?docID=909358.

Bipolar disorder, major depression, and schizophrenia are psychiatric conditions that make daily life difficult for many in society. Whether it’s the person who suffers from the disease, their family and friends, or even their caretaker, schizophrenia can be especially difficult to handle. Characterised broadly as a condition where someone’s reality is viewed abnormally, those with schizophrenia can experience disorderly thinking that can lead all the way to having hallucinations and delusions. This can impair their daily life often leading to the need for full time care and oversight. Current schizophrenia treatments include the use of antipsychotic medications which often have multiple side effects to the patient, ultimately leading to a low patient compliance. Beyond the lack of current treatment, the factors that contribute to the diagnosis are still under scrutiny. At a basic level, schizophrenia can see its rise from interruption of proper neural development in adolescence. A review by Michaud and Pourquie dove into the molecular pathways that have shown potential contributing factors to this developmental dysfunction. 

Two Important Molecules

Michaud and Pourquie devoted their attention to a molecular pathway that involves two molecules, Wnt and GSK3β. Wnt is a molecule that binds outside of the cell and is responsible for maintaining the activation of GSK3β inside of the cell. GSKβ, when it is activated by Wnt receptors, will inhibit the action of another molecule called β-Catenin. β-Catenin is responsible for the transcription of genes in the cell nucleus that are pivotal for proper neurological development. Thus, schizophrenia at its simplest form may be linked to the inhibition of β-Catenin by Wnt and GSK3β signalling. 

Above is Figure 2 from the review placed next to a simplified depiction of the two factors that affect β-Catenin and subsequent development of schizophrenia.

Multiple different factors are being studied that affect Wnt-GSK3β signalling. One of the biggest molecules that contributes to this is dopamine. When there is a high amount of dopamine signalling, a cell will allow GSK3β to remain in its active state. When this occurs, β-Catenin will remain inhibited. This will lead to dysfunction of cell development. 

Genetics

Genetics are also being considered as a factor that contributes to the development of schizophrenia. Research has assessed specific genes that may contribute to the disease along with specific changes to the individual “codes” that make up a DNA message; these are called single nucleotide variants. There are also copy number variants, which are composed of multiple genes. These can contribute to the development of schizophrenia by affecting the proper development of neurons whether it be through its affect to signalling mechanisms or other factors. Animal models are currently being used to assess these genetic factors but more research is needed.

Looking Into The Future

Schizophrenia can appear in adolescence and can occur from both interruptions to normal cellular signalling along with other genetic factors. Seeing that it has a strong relation to neural development, monitoring of the conditions that lead to schizophrenia development may serve valuable. Developing monitoring systems for chemical signalling like Wnt and GSKbeta may help assess abnormality in neural development before it becomes a problem. This can also apply to assessing for genetic variation in an individual through genome sequencing. These two interventions, however, both come with costs and ethical considerations. However, as we build understanding, we may soon have ways of assessing the development of schizophrenia before it becomes too late to fix it. 

Jacques L. Michaud and Oliver Pourquie, “An emerging role for Wnt and GSK3 signaling pathways in schizophrenia.” Clinical Genetics 83, 511-517, (2013)