The Pathophysiology of Schizophrenia

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Schizophrenia is a life changing disease that is distinguished as a severe psychotic disorder. It has a diagnosis impacting about 1% of the worldwide population, changing the way these individuals live their daily lives. Characteristics of schizophrenia include positive symptoms and negative symptoms. Positive symptoms include hallucinations and delusions, while negative symptoms involve changes in behaviors such as diminished emotions, lack of motivation, and impaired social functioning (Maycox et al., 2009).

Positive symptoms of schizophrenia can be defined as those which are present when they should not be. In contrast, negative symptoms are defined as behaviors that are not present but should be. In relation to these symptoms, it is clear that schizophrenia has life altering impacts on the daily functioning and quality of life for those who are diagnosed. According to Veerman, Schulte, & De Haan, negative symptoms of schizophrenia often develop before the onset of positive symptoms. This demonstrates how schizophrenia is a progressive disorder with more incapacitating symptoms evolving later on (2014).  The onset of the disease often occurs in people who are in their late teens to early twenties (Wang, Aleksic, & Ozaki, 2015).  It is unclear as to the exact cause of the disease, and as a whole, the pathophysiology of the disease is not well understood. There are many unknown answers and vague evidence to support the biological basis of this disease. Schizophrenia is thought to be impacted by both a very strong genetic component, as well as environmental influences. In addition to this, it has been observed that these types of psychotic illnesses tend to run in families. Through various twin and adoption studies, support for the hypothesis that schizophrenia has a biological basis has increased (Dinan, Borre, & Cryan, 2014). Since schizophrenia does not have a clear pathophysiology, treatment methods are varied and can have limited effectiveness on some individuals. Treatment often includes the use of antipsychotic or neuroleptic drugs that target certain brain areas or chemicals. These medications are by no means a cure for the disease, but many studies have indicated that they can help reduce or remove some positive symptoms (Madras, 2013). It is clear that biology has a large influence on schizophrenia, but the extent of its role and the overall knowledge on this subject is unclear. Researchers push to discover the source of the psychosis as well as what is contributing to the onset of the disease. If a target can be found, determining what causes the disease, what treatment methods would work, and finally what we can do to prevent the disease from occurring would have an extreme impact on the prognosis of this disease. This paper will explore a variety of concepts that relate to the pathophysiology of schizophrenia. Included in this will be three hypotheses that aim to provide insight to the causes of schizophrenia as well as the impact of glial cells on the disease.

Hypotheses of Schizophrenia Pathophysiology

Over the last few decades, extensive research has been carried out on the subject of schizophrenia and its biological components. Through this research, multiple hypotheses have surfaced that have looked at various brain areas as well as the chemicals that contribute to the onset, symptoms, and treatment of schizophrenia. Included in this are three important hypotheses: the dopamine hypothesis, the glutamate hypothesis, and the reduced neuropil hypothesis. The dopamine hypothesis has been one of the leading theories accepted as a framework for understanding how schizophrenia develops (Madras, 2013), and its use has extended over decades of research.  The glutamate hypothesis elaborates on the dopamine hypothesis by describing the relationship between glutamatergic and dopaminergic systems (Steele, Moore, Swan, Grant, & Keltner, 2012). Finally, the reduced neuropil hypothesis considers the impact of brain matter and neuronal deterioration on schizophrenia (Smiley et al., 2011). These three key theories will be discussed in terms of the role each biological system plays on the pathophysiology of schizophrenia, highlighting the key features involved in each.

The Dopamine Hypothesis

The dopamine hypothesis has been one of the longest running theories regarding the pathophysiology of schizophrenia. The hypothesis can be summarized to state that a dysregulation of dopamine and its systems impacts the etiology of schizophrenia (Madras, 2013). According to Madras, this hypothesis states that neuroleptic/antipsychotic drugs can block dopamine receptors in the brain. It is also suggested that some dopamine pathways within the brain become overactive in patients with schizophrenia, altering the way their brain processes this compound. Research has alluded that the overactive dopaminergic systems found in patients with schizophrenia could be due to multiple factors, including: excess dopamine release, increased numbers of dopamine receptors, or an overly sensitive dopamine receptor (2013). These findings note the importance of dopamine and how there may be possible variations of the chemical and its systems that impact schizophrenia.

Furthermore, according to Howes, McCutcheon, Owen, & Murray, two lines of evidence have emerged to support the dopamine hypothesis of schizophrenia. The first line of evidence considers findings through clinical studies. In these studies, dopaminergic agonists have been shown to induce a psychosis in healthy individuals as well as make symptoms worse in patients who already have schizophrenia. This implies that dopamine has the ability to alter and influence the expression of psychosis or psychosis-like symptoms. The second line of evidence emphasizes how researchers have already discovered the impact that antipsychotic drugs have on dopamine systems. Many neuroleptic drugs target dopamine receptors and research has found that altering these systems within the brain have resulted in positive changes regarding some symptoms of schizophrenia (2017).

In addition to these findings, the dopamine hypothesis also provides an explanation for the causes of positive symptoms found in patients with schizophrenia. Steele et al., (2012) indicated that dopaminergic agents are not what causes the negative or cognitive symptoms of schizophrenia. Their findings concluded that the dopamine receptors are not able to reverse these negative symptoms, and even if the dopamine system was stabilized to a certain degree, these symptoms still seemed to persist. Supporting evidence has been found in terms of the influence dopamine has on positive symptoms, helping researchers understand what to target when using antipsychotic medications aimed at reducing positive symptoms. Additionally, many post mortem studies have been carried out, providing extensive evidence for the hypothesized dopamine dysfunction within various brain systems. Evidence of higher levels of dopamine have been found from these types of studies, as well as higher levels of metabolites related to dopamine within the brain (Howes et al., 2017).

Over the many decades this hypothesis has been around for, the supporting evidence has varied and still lacks some clarity as to the impact dopamine has on the overall pathophysiology of schizophrenia. Edwards, Bacanu, Bigdeli, Moscati, & Kendler, critiqued this hypothesis and expressed that there are two themes that have stemmed from research on this topic. The first theme implicated that the overall “track record” of this hypothesis has not been strong or clear. They stated that the dopamine hypothesis has been unable to prove many of its features and viewpoints and that research is lacking in terms of the role dopamine plays. The second theme relates to the fact that this hypothesis has been used for so many years. In this time, the hypothesis has been altered and revised to reflect the new and upcoming findings, suggesting that the original hypothesis is no longer existent. According to these thoughts, the current dopamine hypothesis is a completely new reinterpretation of a previous hypothesis created years ago (2016).

As a whole, the dopamine hypothesis provides extensive insight into what possible causes of schizophrenia exists from a biological perspective. Despite its lacking evidence in some areas, the dopamine hypothesis has sparked many discussions and studies as to what biological mechanisms could be impacting schizophrenia.

The Glutamate Hypothesis

A second hypothesis about the pathophysiology of schizophrenia is called the glutamate hypothesis. This hypothesis evaluates the biological disturbances that occur within the brain of schizophrenics, while also elaborating on the dopamine hypothesis (Veerman et al., 2014). The dopamine hypothesis explains how positive and negative symptoms can develop, but the glutamate hypothesis describes the synaptic relationship between glutamatergic and dopaminergic systems within the brain. According to Veerman et al., glutamate is one of the primary neurotransmitters with excitatory abilities in the brain. It plays a key role in communication between neurons and the glutamatergic receptors play a vital part in regulating neurons in terms of their migration, growth, and pruning. The glutamate hypothesis claims that a problem occurs because of impaired activity around glutamate synapses in the cortex. Schizophrenia is said to be related to a lower amount of glutamate that is being released in addition to a lower number of present glutamate receptors within the brain. Studies have shown that glutamatergic metabolites seem to increase between the ages of 20 to 30 years old in healthy subjects. This suggests that there is a relationship between age and changes that occur in neurons and glutamatergic metabolism (2014). These findings also indicated that patients with early schizophrenia showed a higher peak of increased metabolites, reflecting the death of neuron cells, as stated by Veerman et al.,.  Following this peak, which often occurs during the early onset of schizophrenia, it was clear that glutamate levels decreased very quickly when compared to normal individuals. The decrease of glutamate in these frontal areas of the brain suggest a loss of synaptic activity over time, as well as reduced brain volume (2014).

In addition to these findings regarding glutamate, further studies have shown that a higher level of glutamate in the synaptic cleft of neurons results in an overstimulation of N-methyl-D-aspartate (NMDA) receptors. The role of NMDA is crucial to the glutamate hypothesis, and many studies have found that a hypofunction of NMDA leads to dysregulation of the glutamate system (Steele et al., 2012). According to Veerman et al., (2014) this hypofunction contributes to the development of schizophrenia, and the diminished activation of these receptors is a key underling mechanism.

Similar to the dopamine hypothesis, the glutamate hypothesis still has many loose ends. It does, however, provide insight into an additional chemicals that can play a role in the biology of schizophrenia. Since dopamine and glutamate are closely related, it is possible that these two chemicals interact with each other and impact the pathophysiology of schizophrenia together. For example, Steele et al., provided information on the hyperdopamine-hypoglutamate hypothesis which indicates that changes in dopamine are caused by an effect of hypoglutamate. It further suggests that the glutamatergic neurons are able to influence dopaminergic neurons and their transmission between each other. The hypothesis suggests that the hypofunction of NMDA receptors is a possible cause for changes in dopamine activity. Furthermore, glutamate regulates certain dopamine pathways through a gamma-amino-butyric acid (GABA) interneuron which results in dopamine inhibition. The glutamate stimulates the release of GABA which then inhibits the release of dopamine (2012). These studies allow us to consider to the concurrent effects that dopamine and glutamate potentially have on the pathophysiology of schizophrenia. More evidence is needed to support the role that both of these compounds play, but a solid foundation has been laid in terms of what contribution is already known.

The Reduced Neuropil Hypothesis

The final hypothesis to be considered is the reduced neuropil hypothesis. The research and evidence surrounding this hypothesis is limited, especially in terms of current advances. However, it is important to acknowledge this additional source of insight into the pathophysiology of schizophrenia. According to Smiley et al., the reduced neuropil hypothesis suggests that a reduction of neuropil in the prefrontal cortex can impact the pathophysiology of schizophrenia (2011).  It suggests that over time, neuropil in the brain decreases due to changes in various mechanisms such as dendrites or axons. The decrease in neuropil impacts the brain by increasing neural density (Bakhshi & Chance, 2015). Post mortem studies have acknowledged finding a reduced cortex volume in patients with schizophrenia which interacts with the increase in neurons. Smiley et al., stated that the volume loss is caused by a reduction of neuropil in the cortical area, without a simultaneous reduction in the number of neurons. Additionally, this study found that in those with schizophrenia, the cortical volume decreased about 5-10% in various brain regions, suggesting that neuropil related systems impact the biology of schizophrenia (2011).

Similar results have previously been found by Selemon & Goldman-Rakic, proposing that the reduction of neuropil in the prefrontal cortex can impact the pathophysiology of schizophrenia. There have been cases where an increase in neurons paired with a small brain volume has had an impact on cognitive dysfunction in schizophrenics (1999). Another key aspect of the reduced neuropil hypothesis is concerning decreased brain volume in the hippocampus and cortex (Bellon, 2007). Bellon claimed that a decrease in brain volume, in addition to ventricular enlargement, can result from less dendrites and axons. This impacts the amount of white matter in the brain as well fluids that impact cellular volume. Studies that have considered this hypothesis have found evidence that supports an increased density of neurons in schizophrenics. This increased density is often found alongside reduced neuronal space, but there are no changes in the actual number of neurons. This decreased space can imply that there is decreased neuropil in the brain (2007).

The reduced neuropil hypothesis is unable to provide clear insight into the effects neuropil has on schizophrenia, and many investigations have produced results that do not match up to this hypothesis (Bakhshi & Chance, 2015). However, some of the research that has been conducted seems to indicate an importance in this area. Since white matter alterations and changes in brain volume are considered in many other studies of schizophrenia, it is reasonable to consider looking more extensively into this hypothesis in the future.

The Effects of Glial Cells on Schizophrenia

Glial cells are found in the brain and they play a large role in providing support for neurons as well as insulating them. The brain has several types of glial cells, three of which are related to schizophrenia: oligodendrocytes, astrocytes, and microglia (Wang et al., 2015). As advances in research arise, confirming evidence seems to suggest that schizophrenia can occur from neural dysfunction. These disruptions in neural connections within the brain is regarded by Bernstein, Steiner, Guest, Dobrowolny, & Bogerts, as an important early event in Schizophrenia (2015). All three of these glial cells play a vital role in the biological basis of schizophrenia and are a key theory as to what causes this disorder.

Oligodendrocytes

Oligodendrocytes are known for their role in the myelination of neurons. These glial cells form a layer of myelin around axons within the Central Nervous System (CNS) to help aid in the electrical conduction of neurons (Wang et al., 2015).  Concerning myelination, Wang et al., claimed that neurons need to be properly myelinated if they want an efficient flow of information and signals between brain areas. When an impairment of the myelin on these neurons occurs, the result is often a reduction in white matter within the brain. This reduction in white matter plays a large role in the pathophysiology of schizophrenia because a reduced brain volume is a common finding when looking at biological components in schizophrenics (2015). According to Bernstein et al., myelin abnormalities are crucial to the cognitive impairments and accelerated brain aging that is observed in schizophrenia. Abnormalities in myelin sheath formation has also been observed in the frontal cortex. In addition, Bernstein et al., thought it was important to note that changes in the composition of myelin did not occur because of treatment by neuroleptic drugs. Its occurrence came from the natural progression of brain deterioration that is often seen in schizophrenia (2015).

White matter tracts are composed of myelinated axons that help with transmitting signals to other parts of the brain. When these are altered, the white matter becomes abnormal and the result is a disruption in brain connections. These findings are often seen in patients with schizophrenia, suggesting that the impact oligodendrocytes have on white matter is crucial to the biological basis of schizophrenia (Wang et al., 2015). Studies that consider the link between white matter abnormalities and oligodendrocytes have found decreased densities of these glial cells as well as changes to their spatial distribution in the brain and overall cell structure. In addition to this, Bernstein et al., found that a reduction in the amount of oligodendrocytes in schizophrenics is not only impacting white matter. Gray matter can also be affected which suggests that the functions oligodendrocytes play beyond myelination are also altered in those with schizophrenia (2015).

One of the largest genome wide associated studies (GWAS) found that there were 29 gene sets related to oligodendrocytes that have a significant relationship to schizophrenia. Both myelin and non-myelin related genes were found to be associated, which again supports the previous evidence on more than just white matter being affected (Bernstein et al., 2015). Overall, the true reason for oligodendrocyte abnormalities in still not completely understood in terms of schizophrenia, but evidence has shown associations between these glial cells and the disease.

Astrocytes

Astrocytes are one of the most numerous cells in the human brain and have a variety of physiological properties and organizations. These glial cells provide nutritional support to their surrounding neurons as well as help synchronize axon activity. According to Wang et al., these glial cells have many other tasks such as controlling water and electrolyte homeostasis, providing neurons with energy, and helping with controlling the activity of axons as they send messages. The idea of astrocyte dysfunction relates to the evidence found that supports hypotheses focused on neurotransmitter dysfunction in schizophrenics. Astrocytes are associated with the onset of schizophrenia due to their supports, structurally and nutritionally, for neurons. This association is important because altered astrocytes are unable to provide sufficient supports to these neurons, resulting in some of the common dysfunctions seen in individuals with schizophrenia. An additional tie between astrocytes and schizophrenia comes from their ability to absorb and release neurotransmitters in the brain. If they are unable to effectively undergo these tasks, messages between the neurons will not send and brain connectivity will then be compromised (2015).

Studies regarding astrocytes and schizophrenia have found results that indicate a decreased amount of these glial cells in different cortical areas of the brain. Some research has suggested that this reduction in astrocytes could be due to antipsychotic treatment medications, however it is still unclear whether this is the case (Bernstein et al., 2015). Bernstein et al, also found that an enzyme associated with astrocytes, called glutamine synthetase, may impact the pathophysiology of schizophrenia. During the process that involves this enzyme at glutamatergic synapses, the glutamate released is taken up by astrocytes and then converted to glutamine. The glutamine is then cycled back to neurons and finally converted to glutamate again (2015). If there is a reduction in astrocytes within the brain, this glutamatergic process will not be able to properly occur and further issues can arise. These disturbances in glutamatergic neurotransmission is partly due to impaired functioning of the glutamine synthetase associated with astrocytes.

Astrocytes also play a key role in the metabolism of glutamate, GABA, and monoamines. Their disruption in functioning has been found to impact neurotransmission in schizophrenia. Evidence supporting the disturbed function of astrocytes has shown that these glia affect the pathogenesis of several disorders within the CNS, including schizophrenia (Bernstein et al., 2015).  Similarly to oligodendrocytes, the impact astrocytes have on schizophrenia’s biological basis is still slightly unclear. More research is needed to truly understand what effects these glial cells have on the disease and what other processes they are associated with.

Microglia

The final category of glial cells are called microglia. These cells originate from the mesoderm and contact synapses while helping with neurodevelopmental synaptic pruning               (Wang et al., 2015).  These cells also play a large role in relation to immune responses in the CNS. Microglia respond to infections and other intruders, making them key players in the immune defense process. These glial cells are related to schizophrenia because of their function with neuroinflammation. Bernstein et al., stated an important finding about these cells that many post mortem studies have indicated regarding microglial activation in the brain. The increased densities of microglia in schizophrenics suggests that the immunological factors are important when considering the pathophysiology of schizophrenia. The effects of microglia on schizophrenia shows similarities to other autoimmune disorders, especially with early adulthood onset (2015). Additional studies have shown that higher levels of these cells have been found in patients with a psychosis who have passed away from suicide (Wang et al., 2015).  This suggests that the increased activation of microglial cells could possibly be associated with suicidality rather than schizophrenia itself (Bernstein et al., 2015).  However, many other studies of microglia have found a significant impact on schizophrenia, and suicidality could potentially be just another factor that contributes. According to Bernstein et al., these cells and the development of inflammation and autoimmunity are important factors in developing a psychosis. These immunological changes may be caused by genetics in those with schizophrenia (2015).

These cells are important in immunological processes. Activation of these glia can disrupt the neurotransmission processes and potentially contribute to the emergence of psychotic symptoms found in schizophrenia (Bernstein et al., 2015). In general, more research needs to be conducted to determine the impact all three glia cells have on schizophrenia. The current findings provide some insight to possibilities of the biological basis of the disease, but to fully understand the contribution microglia have on schizophrenia, more research is needed.

Conclusion

Schizophrenia is an extremely complex disease that leaves researchers with many unanswered questions. There are numerous theories and hypotheses regarding the biological basis of this disorder, many of which have unclear evidence. As the disease progresses, research also progresses and it is important to consider different aspects that can contribute to the causes of schizophrenia. By looking at a variety of hypotheses such as the dopamine hypothesis, the glutamate hypothesis, and the reduced neuropil hypothesis, researchers can provide a basis for future studies. These hypotheses allow scientific advances to occur as they have set the foundation for possible causes of the disease. The dopamine hypothesis has been a long-running theory of the pathophysiology of schizophrenia and has helped advance the knowledge we have on this disease, despite lacking some clear evidence in certain areas. The glutamate hypothesis allows us to expand on the dopamine hypothesis, considering alternative causes and key players in the onset of the disease. The reduced neuropil hypothesis considered the impact of brain matter and volume, providing insight into what mechanism are changing within the brain because of this disease. In addition to these theories, considering other key biological mechanisms such as glial cells help accelerate the research on schizophrenia. Overall, the extensive research that has been conducted on this disease has provided some answers for researchers and patients with schizophrenia. While more research is needed, with better supporting evidence, there is clearly a large role that biology has on the onset of this disease. In addition to environmental influences, the biology aspect can have a great impact on schizophrenia and it is important to continue our efforts in searching for its cause.

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