Schizophrenia and genetics

DefinitionSchizophrenia is a chronic, severe, disabling brain disorder that interferes with the way a person interprets reality. People with schizophrenia sometimes hear voices or see things that others do not, become paranoid that people are plotting against them, and experience cognitive deficits and social withdrawal. These and other symptoms make it difficult for them to have positive relationships with others. Schizophrenia is different from split or multiple personality disorders. It affects many different areas of the brain, causing a wide range of behavioral, emotional, and intellectual symptoms.

Risk Factors

Factors that increase an individual’s risk of schizophrenia include having a parent or sibling with schizophrenia and having an abnormal brain structure. Individuals born during the months of February and March as well as those born in a city have a slightly higher than average rate of developing schizophrenia later in life. Researchers believe this can be due to reduced Vitamin D levels in the mother during pregnancy. Additional risk factors include oxygen deprivation during pregnancy and issues at birth, such as a long labor, bleeding during pregnancy, prematurity, a low birth weight, maternal malnutrition, and infections during pregnancy. Loss of a parent during childhood is another risk factor.

Men typically develop symptoms in their late teens or early twenties, while onset for women tends to occur in their twenties or thirties. In rare cases, schizophrenia is seen in childhood.

Etiology and Genetics

Schizophrenia is an extraordinarily complex and variable clinical condition, and its etiology no doubt depends on a host of both genetic and environmental factors. It is safe to assume that there are many genes that contribute either to the susceptibility or the pathology of schizophrenia, but there is no single gene or mutation that exerts an overriding or self-sufficient effect in determining the development of the disease.

In the summer of 2009, three research consortia reported results of their genome-wide association studies on the genetics of schizophrenia, and all identified a region of particular importance on the short arm of chromosome 6 (at position 6p22.1). This region is known to contain a large cluster of genes (the major histocompatibility complex) that helps determine immunity and that also codes for proteins that are important for turning other genes on and off. Since mutations in this region are known to influence susceptibility to several autoimmune disorders, it may be likely that schizophrenia has an autoimmune component as well. Genetic variation in the control of such regulatory mechanisms might also account for the environmental component that has been repeatedly shown to contribute to disease susceptibility.

In March 2014 Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/), an authoritative database maintained by the National Center for Biotechnology Information, listed thirty-four genes scattered throughout the human genome that may be associated with susceptibility to schizophrenia. In July 2014 the Schizophrenia Working Group of the Psychiatric Genomic Consortium reported in the journal Nature that their National Health Institutes–funded genome-wide analysis had revealed 108 genetic loci suspected of being linked to schizophrenia, of which 83 were previously unreported. In 2019, researchers with the Broad Institute of MIT (the Massachusetts Institute of Technology), and the University of Helsinki, Finland, said that they had discovered ten genes in which mutations have been directly tied to schizophrenia.

Evidence from additional molecular studies has suggested that large structural changes in DNA (deoxyribonucleic acid) called copy number variants (CNVs) may play a critical role in the development of schizophrenia. These CNVs are usually duplications or deletions of anywhere from hundreds to millions of base pairs in the DNA, and the largest deletions appear only in people with schizophrenia.

In January 2016, researchers from the Broad Institute and Harvard as well as Boston Children's Hospital published a new report in Nature that explained their discovery of a new genetic pathway, a molecular process in the brain, that contributes to triggering schizophrenia. The researchers found that an individual's risk for developing schizophrenia is noticeably increased if they have inherited a gene that is important to the normal reduction of brain cells that occurs during adolescence. Scientists have found that in people with schizophrenia, there is a variation in the position in the DNA sequence that marks too many brain cells for removal. The brain cell "pruning" then goes out of control and the result is an abnormal removal of the brain's grey matter. This discovery helps explain several theories of schizophrenia that were previously a mystery to scientists, such as the typical onset of the disorder and the thinning of grey matter that was found in autopsies of patients with schizophrenia.

With so many genes possibly acting as contributing factors, it is not surprising that there is no predictable inheritance pattern regarding the development of schizophrenia. Many new cases appear in families with one or more other affected members, yet the majority of new cases appear in families in which there is no previous history of the disease.

Symptoms

Symptoms usually start in adolescence or early adulthood. They often appear slowly and become more pronounced over time, or they may occur in a matter of weeks or months.

Symptoms include visual or auditory hallucinations—seeing or hearing things/voices that are not there, and delusions—and strong but false personal beliefs that are not based in reality. Disorganized thinking; disorganized speech and a lack of ability to speak in a way that makes sense or to carry on a conversation; catatonic behavior, such as slow movement, repeating rhythmic gestures, pacing, walking in circles, negativism, and repetitive speech; emotional flatness, including flat speech, lack of facial expression, and general disinterest and withdrawal; paranoia, a psychosis characterized by systematized delusions of persecution or grandeur; inappropriate laughter; and poor hygiene and self-care are also symptoms. Associated conditions include obsessive-compulsive disorder, substance abuse (of drugs, alcohol, caffeine, or nicotine), and self-injury, including suicide.

Screening and Diagnosis

Early diagnosis is extremely important. Patients who are diagnosed early are able to stabilize their symptoms, decrease the risk of suicide, decrease alcohol and substance abuse, and reduce the chance of relapse and/or hospitalization.

A person must have active symptoms for at least two weeks and other symptoms for at least six months before a diagnosis can be made. The doctor will rule out other causes, such as drug use, medical illness, or a different mental condition.

Treatment and Therapy

Schizophrenia is not curable, but it is highly treatable. Hospitalization may be required during acute episodes. Symptoms are usually controlled with antipsychotic medications. These medications work by blocking certain chemicals in the brain, which helps control the abnormal thinking that occurs in people with schizophrenia. Determining a medication plan can be a complicated process. Often medications or dosages need to be changed until the right balance is found. This can take months or even years. Examples of medications include haloperidol (Haldol), thioridazine, or fluphenazine.

Relapse is common, even for patients taking medication. Treatment compliance can be a challenge, since people often stop taking their medication when they are feeling better. The side effects of traditional antipsychotics can also cause patients to discontinue treatment. The most common are physical side effects, such as slow and stiff movements, restlessness, facial tics, and protruding tongue.

Medications called atypical antipsychotics, have fewer side effects and are better tolerated over long periods of time. However, they may cause weight gain, elevated blood sugar, and elevated serum cholesterol. Examples of these medications include olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify), quetiapine (Seroquel), and ziprasidone (Geodon).

Medications may also be prescribed for coexisting conditions. Conditions often associated with schizophrenia include depression and anxiety. They may be treated with antidepressants, anxiolytic drugs, lithium, and anticonvulsants. Electroconvulsive therapy may be used to treat severe depression, suicidal ideation, or severe psychosis.

Schizophrenia is a lifelong condition. It can be confusing and frightening for the person with the disease and for family members. Individual and family therapy can address social skills, vocational guidance, community resources, coping with the family, living arrangements, general emotional support, and working with the family to help family members deal with the patient.

Prevention and Outcomes

There are no guidelines for preventing schizophrenia because the cause is unknown. However, studies show that early, aggressive treatment leads to better outcomes.

Bibliography

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