Holy Family University Schizophrenia And Its Effects On The Brain Karla Juste Dr. Carbone April 2, 2021 A mental illness such as schizophrenia is one of the most serious and frightening illnesses in the medical world. This illness affects different aspects of an individual’s life. For instance, it impacts the individual’s cognitive, emotional, and overall behavioral interaction with the people in their surroundings; including immediate family and friends. Classic symptoms of this psychiatric disorder include delusion, paranoia, auditory hallucination, and speech impairment. Schizophrenia is not a common disease: it affects only 1% of the world’s population and approximately 1.2% of Americans. When an individual is diagnosed with the disease, it not only affects the patient but the family as well. Significant distress can be brought to caregivers, leaving them emotionally drained. Fortunately, schizophrenia is a treatable disease, but if left untreated, the symptoms can worsen and become more persistent. Our understanding of schizophrenia, like all mental illnesses, has a complex history. The different treatments which have been developed for it over time reflect our growing understanding of the disease. In the years leading up to the nineteenth century, mental illness was seen as supernatural, and therefore someone suffering from a mental illness would go through treatments such as exorcism and bloodletting.1 The first description of schizophrenia dates to 1911, when Swiss psychiatrist Eugen Bleuler introduced the term “split-brain.” Bleuler chose this term to describe the atypical way that schizophrenics perceive reality. This origin of the term has led to a persistent assumption that schizophrenia is the same disease as multiple personality disorder (MPD). However, our understanding of the disease has advanced in the century since Bleuer’s initial description. According to the modern understanding of it, schizophrenia involves a specific set of changes to mood, thoughts, and actions experienced by the diagnosee. Although these changes may partially overlap with those of MPD, the two disorders are in fact separate. The similarities between the two disorders often result in a misdiagnosis. Multiple personality disorder involves the distinctive types of personality that one develops on their own as a result of abnormal genetic factors, dysfunctional lifestyles, or their everyday environment. There are different classifications of personality disorders, including some such as obsessive-compulsive personality disorder, schizotypal personality disorder, and more. Schizotypal personality disorder, although different, has similar treatments with schizophrenia due to the similarities they share in symptoms. People with Schizotypal personality disorder are considered to be on the spectrum of schizophrenia with less severe symptoms. Symptoms can include impulsive and risky behaviors, inappropriate emotional responses, angry and hostile reactions, and more. In contrast to multiple personality disorders, people with schizophrenia do not have different personalities. Their brains are hyperreactive to the world around them, resulting in the inability to stay in touch with reality. This means that they are incapable of differentiating false thoughts and ideas when they surface. Based on the symptoms displayed by a schizophrenic person, the difference between the two disorders becomes more obvious. 14 Figure 1: A distinct comparison between schizophrenia and multiple personality disorder (MPS). Symptoms for schizophrenia fall into three major categories, which include positive, negative, and disorganized symptoms. Positive symptoms focus on hallucinatory experiences such as hallucinations, hearing voices or seeing things that do not exist, paranoia, exaggerated perceptions of the real world, and major changes in attitude and behaviors. Negative symptoms express the inability to show emotions, difficulties talking and engaging in social activities, enjoying the things that used to bring joy, and even planning an ordinary day. Disorganized symptoms can range from childlike silliness to unpredictable agitations. When a person suffering from schizophrenia undergoes disorganized symptoms, their thought process becomes hindered, leaving the patient confused and unable to form logical thoughts. Additionally, abnormal behaviors and movements may occur. Symptoms of schizophrenia first appear in the early stages of adulthood. To be diagnosed with the disease, symptoms must be reported for at least six months. Figure 2: The structural changes of a schizophrenia patient 15 These symptoms correspond to the structural changes and functions of several essential brain systems. A person suffering from schizophrenia has changes in their brain cortex as well as different cortical regions. Recent medical searches, mainly using MRI scans, have found a reduction in grey matter volume and white matter in patients during the pre-onset phase of the disorder.2 The cortical grey matter reduction reflects on the complexity of the dendritic cells and the density of synapses, which, in turn, impact interneural communication. This reduction is predominantly found in the medial temporal, superior temporal, and prefrontal areas. The cerebral cortex, which is intertwined with the frontal and temporal lobes, seems to also have a decrease in size and appears thinner due to less brain tissue present. The difference in the size of the person’s brain tissue causes larger than normal fluid-filled spaces in the brain. The abnormalities found in these particular areas are found specifically in the key brain structures responsible for cognitive and perceptual functions. If we were to take a closer look at these brain structures under a microscope, it would be observed that the neurons, as well as other brain cells, are in a specific organized pattern. For instance, the neurons of the cerebral cortex are organized into layers. However, in patients with schizophrenia, the normal organization of these cortical layers is lost, particularly on the frontal and temporal lobes. Scans, such as MRIs, can pick up signals that show abnormal brain activities. There is evidence that these abnormalities appear during the early stages of brain development.3 These particular regions of the brain that are responsible for memory, auditory information processing, and decision making do not develop normally, which then leads to the disorder later in life. The neurotransmitter dopamine, which is recognized by dopamine receptors, plays a big role in neural communication, particularly in the frontal and temporal lobes of the brain. Irregular distributions of dopamine receptors have been implicated in schizophrenia. Dopamine receptors can be divided into D (1), D (2), D (3), and D (4)-receptors. D (1) receptors are reduced in the prefrontal cortex of schizophrenia patients but increased in the parietal-temporal cortex of a schizophrenic patient. The dopamine hypothesis suggests that the hyper activities of the D (2) receptors in subcortical and limbic brain regions contribute to the positive symptoms of schizophrenia. The limbic system is involved in memory, emotion, learning, and motivation and is therefore related to the major changes in attitudes and behaviors that are expressed by a schizophrenic patient. Unfortunately, dopamine receptor activity and distribution are not influenced by antipsychotic medications. However, targeting other neurotransmitters which influence the dopamine system is an option. For instance, the neurotransmitter glutamate has been proposed as a therapeutic agent in schizophrenia, as well as other neurological disorders.4 The pathophysiology of schizophrenia is not a well-understood topic. Based on the clinical course of the disease, along with the number of scientific observations made, pathophysiological formulas can be theoretically tested. When we look at the mechanism that is involved in the brain of a schizophrenic patient, there is an excess or deficiency of neurotransmitters such as dopamine, serotonin, and glutamate. There are four dopaminergic pathways implicated in the neurochemical imbalance of the disease.5 The nigrostriatal pathway connects the substantia nigra to the caudate nucleus and is involved in movement control and motivational behaviors.6 Low dopamine levels within this pathway affect the motor system, which in turn explains the disorganized symptoms experienced by the diagnosee. The mesolimbic pathway, also known as the reward pathway, originates from the ventral tegmental area (VTA) to limbic areas. Dopamine-producing neurons in the brain’s VTA communicate with the nucleus accumbens to process rewards and motivate behavior. This pathway is thought to play a role in the positive symptoms that the patient experiences. This occurs due to the excess amount of dopamine found in the mesolimbic pathway. The mesocortical pathway originates from the VTA to the cortex. The negative symptoms experienced by a schizophrenic patient corresponds to low mesocortical dopamine levels. The tuberoinfundibular pathway stems from the hypothalamus to the pituitary gland. When dopamine is blocked from entering the pathway and levels become low, it results in elevated prolactin levels, leading in turn to galactorrhea, amenorrhea, and reduced sexual drive. Figure 3: Visual understanding of the different dopaminergic pathways.5 The serotonin theory is based on research related to the hallucinogen lysergic acid diethylamide (LSD), which alters serotonin levels and produces psychotic-like symptoms associated with schizophrenia. LSD stimulates the 5-HT2A class of serotonin receptors, which are responsible for the regulation of dopamine release in the mesolimbic and striatal regions of the brain. Additional research has led to the development of drugs that block both dopamine and serotonin receptors. LSD affects auditory and visual hallucinations and synesthesia, which is the activation of one unrelated sense following another sense that was previously activated. It is hypothesized that the excitatory neurotransmitter glutamate also plays a major role in the pathophysiology of schizophrenia. This hypothesis originates from the findings that phencyclidine and ketamine, two non-competitive NMDA/glutamate antagonists, influence schizophrenia-like symptoms. Research suggests that NMDA receptors are inactive in the normal regulation of mesocortical dopamine neurons. NMDA antagonists induce negative, affective, and cognitive symptoms in schizophrenic patients. In other words, low levels of glutamate in the brain will lead to low levels of dopamine in the cortex, resulting in hallucinations. Reduced glutamate receptors have been observed in the brain of schizophrenic patients. Furthermore, clinical studies and basic science data suggest that a reduction in NMDA receptors could facilitate the sensitivity of dopamine in the brain. When glutamate signaling is disrupted by the overdrive of serotonin, it leads to hypometabolism, which results in synaptic atrophy and reduction in grey matter. A diagnosis of the disease is reached through an assessment of the patient’s specific signs and symptoms, which are found in the fifth edition Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The diagnostic criteria of the manual include the persistence of two or more of the following qualifying symptoms (also known as active phase symptoms), where each symptom must last for at least one month. Symptoms such as hallucinations, which consist of the person hearing, seeing, and smelling things that others can not perceive. Delusion, which involves unaltered beliefs even when the person who holds them is presented with facts that prove otherwise. Negative symptoms include a lack of emotional expression and dull language. People with these negative symptoms are unable to follow through and enjoy social activities and show little to no interest in life. In order to be diagnosed with the disorder, the patient must also show persistent disorganized symptoms. People with disorganized symptoms oftentimes fail to remember things, organize their thoughts, and complete tasks. They lack insight and are unaware that they are suffering from the illness. Their lack of insight in turn makes it difficult for providers and medical professionals to help treat their condition because they are unaware of their illness.7 In addition, the manual states that the schizophrenia patient must also exhibit a decreased level of function concerning work, interpersonal relationships, and self-care. The signs for schizophrenia must persist for at least six months including the one-month period of the active phase symptoms mentioned previously. The DSM-5 explicitly states that the overall diagnosis of schizophrenia can not be rendered if symptoms are better attributed to drugs, drug withdrawal, or if symptoms arise from a previous medical condition. Several national public health organizations, such as the CDC, have published guidelines regarding medical tests for patients with onset schizophrenia-like symptoms. Following the psychiatric evaluation, a complete physical medical evaluation is also required to reach an accurate diagnosis. Medical evaluation includes laboratory tests, chest X-rays, and MRI scans. The starting point for laboratory testing is a set of metabolic assays such as thyroid-stimulating hormone (TSH) levels, complete blood count with differential, and liver function tests. These ensure that patients have a baseline with which to gauge the progress of the illness and the presence of side effects to treatment. Additional tests such as renal function tests, prolactin levels, and toxicology screening may also be required based on the disorder’s progress on the patient. The Rorschach test, also known as the inkblot test, is one of the many clinical psychiatric tests commonly used to evaluate schizophrenia patients.8 This test is designed to distinguish the perceptual process and cognitive activities of patients with and without schizophrenia. It is conducted by showing a selection from ten standard inkblot cards to participants wearing eye-mark recorders. In one study, a group of chronic schizophrenic patients, as well as people with normal cognitive perceptions, were all administered the Rorschach test. After each response, five eye movement items that consist of total response time, number of eye-fixation movement, mean eye-fixation time, mean eye-fixation tracking length, and eye-fixation frequency on each detailed area were measured and analyzed.9 From their initial response, subjects were divided into three groups: 1) a popular response group, which shared the most common response to most cards, 2) a non-popular response group, which had other responses, and 3) a rejection group, which did not respond. All cognitive activities of schizophrenic patients are compared to normal patients in the same groups. Figure 4: The ten inkblot cards used in Roarshah tests; the four cards selected for this particular study are achromatic cards I and V and chromatic cards II and VIII.9 On achromatic cards, I and V, the cognitive activity of the popular response group in schizophrenia were compared to those of the normal group. On chromatic cards, II and VIII, eye movements of the schizophrenia patients in the popular response group were compared to those of the non-schizophrenia patients in the same group. On the achromatic cards with the most solid blots, I and V, schizophrenic patients were able to give a popular response just like the normal group. However, visual scanning activities were limited to small detailed areas while inactive in the normal group. The results show the lack of balance between the responses given and cognitive activity. On the chromatic cards with the broken blots, II and VIII, most individuals with schizophrenia failed to provide a response. The negative symptoms experienced by a schizophrenic patient show high attentional impairment. Although the popular group gave color responses throughout the test, they avoided eye contact with the colored areas. For the rejection group, although subjects with schizophrenia searched all over the inkblots, they failed to give any response. Non-schizophrenic patients were not part of the rejection group. These results imply the defect of selective attention in schizophrenia patients. The Rorschach test results prove that the response process in schizophrenic patients is not the same as that of normal people. This reinforces the fact that patients suffering from schizophrenia experience reality differently than others. A combination of therapy, support, skill training, and medications can help manage and treat schizophrenia symptoms. Pharmacological treatments may leave residual symptoms, which are addressed by nonpharmacological treatments such as psychotherapy. These nonpharmacological treatments are also used to ensure that patients remain adherent to their medication. This in turn decreases their risk of relapse and hospitalization. Non-adherence to medication regimes is common in schizophrenia due to the neurological nature of the disease. To overcome this problem, Long-Acting Injectable Antipsychotic Agents (LAI) are a good pharmacological alternative.10 LAIs, such as the antipsychotic paliperidone (sold under the trade name Invega)10, prevent relapses by ensuring that medications are being extended to the brain. Patients receiving LAI treatments do not need to take daily oral supplementations. This antipsychotic treatment (LAI) is administered in the deltoid or gluteal muscles by a medical professional every 2-4 weeks and can last for as long as 3 months. The LAI shot is administered by a healthcare professional, making it easier for the patient’s doctor to know whether they are keeping up with the treatments. Figure 5: Different forms of LAI and range of doses.11 Post-injection delirium sedation syndrome (PDSS) is a serious side effect that occurs in less than 1% of people taking LAIs. Within an hour of taking the shot, it can cause dizziness, confusion, sleepiness, skin rashes, hypertension, muscle stiffness, blurred vision, and uncontrollable movements. Some may experience weight gain and become at risk for diabetes or high cholesterol. Due to these potential side effects, patients are required to be monitored at the hospital for at least three hours after taking the shot. To minimize the rare but potential risk of PDSS, the administering health professional is advised to ensure the syringe aspiration for a minimum of 5s when administering the dose. Patients are advised to not handle heavy machinery and refrain from driving after the shot.11 Augmentation and Combination Therapy is another approach to pharmacological treatment of schizophrenia, consisting of the combination of two or more drugs to achieve better treatment results. In this approach, a patient who has been unsuccessfully treated with an antidepressant will be given a second agent to use while continuing with the first. This second agent may not be necessarily identified as a standard antidepressant but can have antidepressant effects in combination with other drugs. Examples of such drugs can be mirtazapine (a 5-HT-2a serotonin receptor antagonist), and also thyroid supplements. Other augmentation strategies have included buspirone, classified as a 5-HT-1a receptor partial agonist, and pindolol, which is a beta-blocker. Mood stabilizers are common augmentation agents.12 Lithium, for example, improves mood and behavior in some patients but does not have an antipsychotic effect. 13 Generally, augmentation and combination therapy is considered slightly more effective than switching to a different treatment, particularly when patients experience partial response to the first treatment. Disadvantages of this strategy include an increased likelihood of drug interactions and side effects such as agitation and insomnia.13Additionally, potential issues with medication adherence arise from the fact that these medications must be taken on a daily basis to prevent a psychotic relapse. References 1. Alexis Bridley and Lee W. Daffin Jr. Essentials of Abnormal Psychology. https://opentext.wsu.edu/abnormalpsychology/chapter/1-4-the-history-of-mental-illness/. Published January 5, 2018. 2. Karlsgodt KH, Sun D, Cannon TD. Structural and Functional Brain Abnormalities in Schizophrenia. Current directions in psychological science. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235761/. Published August 2010. 3. Garey L. When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits. Journal of anatomy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992411/. Published October 2010. 4. Patel KR, Cherian J, Gohil K, Atkinson D. 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