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The Genetics of Schizophrenia

Schizophrenia is a complex disorder that is thought to be multifactorial and typically manifests in early adulthood. It is characterized by profound psychological impairment and has thus been heavily stigmatized in cultures around the globe. Research into this illness has brought new theories into light, but much is still unknown about this disorder which affects 1% of people worldwide.


Research has been inconclusive on what the pathophysiology of schizophrenia is, but there are several theories involving the neurotransmitters dopamine, glutamate, serotonin and the structures of the brain. Dopamine was thought to play a key role in the pathophysiology of the disorder when the chemotherapy phase of psychiatric care was ushered in by the use of chlorpromazine and haloperidol. These first-generation antipsychotics worked by blocking dopamine-2 receptors, leading researchers to believe that the activity of dopamine caused the positive symptoms of schizophrenia.


With the development of second-generation, or atypical, antipsychotic drugs; the action of blocking serotonin suggested that it also played a role. Another would be discovering how atypical agents targets 5-hydroxytryptamine 2A receptors. That would give us another clue to how atypical drugs work on areas involved with the symptoms of schizophrenia. Glutamate may play a role in the abnormal maturation of the central nervous system that is thought to be a factor in schizophrenia.


Brain structural abnormalities have been noted using CT, MRI and PET scanning. Most structural abnormalities involve enlargement of the lateral ventricles of the brain, with dilation or asymmetry, reduced volume of the lobes and increased the size of sulci. It was also observed that there were more cerebrospinal fluid and lower blood flow and glucose metabolism in the frontal lobe. These are thought to worsen as the disorder continues, with more loss of gray matter consistent with more dramatic symptoms.


The latest genetic studies have been very useful in that they have had the opportunity to draw from large sample populations. In an NIH study of gene copy variants, the study showed that genetic factors were responsible for 80% of the phenotype (CI 0.71-0.90). This was cited in the study along with the traditionally suspected risk factors: young maternal age, advanced paternal age, winter/early spring birth, urban birth, pregnancy/delivery complications, toxoplasmosis infection, low birth weight and cannabis use.


Because of its significant heritability; with monozygotic twins of schizophrenics having a 48% empiric risk and dizygotic twins possessing a 17% risk, researchers have looked to factors before and after conception that determines the schizophrenic phenotype. One of these is the deletion or duplication of genes on DNA strands de novo . These spontaneous mutations occur within DNA. They are not inherited and not caused by mutagens, but likely originate as an error of DNA replication.


The NIH study showed that the micro-deletion of 3q29 OR=41.1 (p= 5.8 × 10−8, 95% C.I 5.6–1953.6) [27]. is thought to be the biggest single genetic correlative value, but deletions and duplications of several genes are thought to play a role as well . These spontaneous mutations are difficult to assess, as human generation time is 20-30 years. Incidentally, this is the same age of which the first symptoms often occur.


Environmental factors are thought to play a large role in the phenotype of schizophrenia.


Nutrition during pregnancy may play a large role in schizophrenia. Adequate nutrition is necessary for methyl groups to bind with DNA and if hunger is present, gene expression is disrupted. When these genes are silenced, one gene may have too few methyl group and be over-expressed in the brain, which may lead to the structural and chemical changes that lead to schizophrenia. Studies of Dutch Famine victims reveal this effect through ration records taken at the time. Women exposed to starvation were more likely to have offspring with the schizophrenic phenotype .


Schizophrenia is a collection of illness characterized by thought disorders, which reflect a break in reality or splitting of the cognitive from the emotional side of one’s personality. A schizophrenic individual may exhibit a feeling of happiness when recollecting a terrible event or emotional indifference when describing a joyful occasion. Disorganized thought in schizophrenia is characterized by positive and negative symptoms including auditory hallucinations, paranoid delusions and cognitive deficits.


The onset of schizophrenia usually occurs between the late teens and the mid 30s. For males, the peak age of onset for the first psychotic episode is in the early to middle 20s; for females, it is in the late 20s. Positive symptoms are more likely to remit than are cognitive and negative symptoms. It is difficult to acquire accurate statistics on schizophrenia due to the nature of the illness. Many with schizophrenia do not get treatment and end up amongst struggling homeless population. However, is estimated that approximately 3.2 million Americans are diagnosed with schizophrenia.


The symptoms of schizophrenia are divided into four broad categories of positive, negative, mood and cognitive symptoms. Positive symptoms frequently occur during a psychotic episode, when an individual loses touch with reality. They have psychotic symptoms such as delusions; disorganized speech and behavior and hallucinations which are auditory or visual. Negative symptoms are characterized by disruptions in normal emotional states and expressions, poverty of speech and loss of interest and drive. Cognitive symptoms are fairly common and involve problems with thought processes that severely impair the ability to perform routine daily tasks that involve attention, planning and social skills. Mood symptoms often seems cheerful or sad in a way that is difficult to understand and often depressed. This increases the risk of suicidal ideation and suicide in many schizophrenia patients.


Neuro-imaging studies show anatomic structural abnormalities in the brain and select neurotransmitters of schizophrenic patients. The lateral and third ventricle are enlarged. It is thought that this change exhibits the cognitive impairments and negative symptoms. Reduction in the thalamus size disrupts neurotransmission between the cortex and primary sensory and motor areas. The temporal lobe alterations contribute to production of positive schizophrenic symptoms, such as hallucinations, delusions and thought disorder. Abnormalities of the dopaminergic system are thought to exist and correlate with development of schizophrenic symptoms. Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, and hyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may coexist.


Diagnosing schizophrenia is not easy. Sometimes using drugs, such as methamphetamines or LSD, can cause a person to have schizophrenia-like symptoms. Clinical diagnosis of schizophrenia is highly dependent upon he patient’s symptoms, relying mainly on self-reports, mental status examination, and clinical interviews. The difficulty of diagnosing this illness is compounded by the fact that many people who are diagnosed do not believe they have it. Lack of awareness is a common symptom of people diagnosed with schizophrenia and greatly complicates treatment. The health care provider must rule out other factors such as brain tumors, possible medical conditions and other psychiatric diagnoses, such as bipolar disorder. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), schizophrenia is diagnosed when a individual exhibits delusions, hallucinations, negative symptoms, or social/occupational dysfunctions for at least 6 months and at least two of the common symptoms of the disorder – delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or presence or negative symptoms – must occur for 1 month .


There has been an increased interest in developing of objective tools that help to identity, monitor and stratify patients with psychiatric disorders. “This is particularly due to the fact that molecular tests could enable the accurate identification of schizophrenia early to improve outcomes and reduce healthcare costs”.


Biomarkers have multiple applications. Research done by Cambridge Center for Neuropsychiatric Research (CCNR) reportedly developed VeriPsych test the first blood-based diagnostic test to confirm the presence of recent-onset schizophrenia . It is not a genetic test, but rather an automated test that uses a single serum sample to identify 51 protein biomarkers. It is designed to help mental health professionals arrive at a diagnosis. Bahn’s research was able to link schizophrenia to various biochemical pathways, including inflammation and metabolism, as well as cell-to-cell signaling. The panel of 51 markers yielded an average sensitivity and specificity of 88% Additional research has been exploring microarray analysis as a way to be a diagnostic tool. Microarray analysis of gene expression often is used to diagnose different types of diseases. According to study that developed correlation base selection algorithm results suggest that analysis of gene expression in whole blood could be useful tool for diagnosing schizophrenia. The pathway analysis of feature genes obtained selected had high significant (p< 0.05) difference between patients and control groups. The study suggested high correlation between select diseases and schizophrenia in 103 select genes.


There still remains much work to be done in explaining the pathogenic mechanisms behind diagnosing schizophrenia. Identifying early onset of schizophrenia at a very early stage remains challenging. Research continues to define objective means to diagnosis schizophrenia. Currently providers use the DSM IV for clinical diagnosis of schizophrenia until a better measure in discovered.


Bethany Heath, ARNP-PMHNP and Carolynn Hosey, RN


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