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Anatomy and Physiology Paper

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.
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
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
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
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.
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