Schizophrenia Causes & Risk Factors - OmniMedicalSearch.com

Conditions & Diseases: Psychological & Mental Health

Schizophrenia

Schizophrenia Causes and Risk Factors

Decades of research on schizophrenia did not produce any major breakthroughs, but it slowly helped scientists to understand and identify some of its risk factors. Experts have reached the conclusion that schizophrenia develops "as the result of the interplay" between biological predispositions and environmental factors. Brain development disruptions are the result of genetic predispositions, environmental stressors during early development (such as pregnancy and early childhood), and environmental factors later in life which can either worsen or lessen the expression of genetics by increasing or decreasing the risk to develop schizophrenia. A risk factor is any characteristic (age, sex, race) or variable that can increase a person's chance to develop the disease. However, a single risk factor cannot determine alone the development of the disorder, and nobody can't establish which of the factors contribute to the onset of schizophrenia.

Furthermore, scientists believed for a long time that personality, intelligence, health, or other traits are influenced in certain percentages by nature (genes) and environment (for example through a nature/environment relationship of 60/40 or 50/50). Based on recent studies, the relationship between nature and environment in determining the presence of certain traits is different. Some genes become active only when the person is exposed to a certain kind of environment. Also, according to a new field of research called epigenetics, our DNA is coated with a "second code" that can change during our life as a result of a certain diets, chemicals that we are exposed to, and the way we behave. This means that humans are influenced by DNA, while the DNA is influenced by humans. (9)

Genetic factors

Schizophrenia has a strong hereditary component and is supported by family, twins, and adoption studies. First-degree biological relatives of individuals with schizophrenia have a 10 times greater risk to develop the disorder themselves than the normal population. The risk of developing the disorder is higher in monozygotic (identical) twins than in siblings or dizygotic (fraternal) twins. This vulnerability towards schizophrenia can be partially explained by the presence and involvement of certain genes and mutations associated with this disorder. Although the study of schizophrenia genes is ongoing and researchers believe that 50 to 100 genes can be involved in the development of the disorder, several studies have identified a few of them: DTNBP1, NRG1, G72, COMT, DISCI, PPP3CC, EGR, WKL1, and GRM3. However, no gene alone can cause the disorder and furthermore, schizophrenia inheritance patterns "involves multiple genes acting together or many single genes acting separately into heterogeneous patterns." (10)

DTNBP1 is cited "as one of the most promising candidates for a schizophrenia susceptibility gene". DTNBP1 (dystrobrevin binding protein 1) gene was first associated with schizophrenia in an Irish pedigree study in 2002 and since than it have been intensively studied in many case-control and family-based studies in diverse populations (Germans, Chinese, Swedish, and Irish). This gene is located on the chromosome 6 and encodes the protein product called dysbindin-1. Although, the exact role of dysbindin-1 is not known, the presence of this protein was discovered to be "widely expressed in the brain". However, postmortem studies conduceted on the brain of schizophrenics revealed reduced levels of DTNBP1 in the prefrontal cortex, midbrain, and hippocampus. (11)

NRG1 or Neuregulin-1 is another gene strongly associated with schizophrenia. NRG1 is located on the chromosome 8 and some of the proteins produced by this gene are "growth factors involved in the growth of the brain, especially its supportive cells", in "synaptic plasticity which is important for memory" and growth of motor neurons, while others are signaling proteins which influence the receptivity of the brain cells to several type of neurotransmitter. It is also thought that NRG1 gene may govern the process in which new synapses are made while old ones are unmade in response to the brain's experiences. (12)

G72 is another gene significantly associated with susceptibility for schizophrenia. This gene is located on chromosome 13 and studies suggest that it may indirectly effect NMDA neurotransmitters (which play a critical role in synaptic plasticity, the cellular mechanism for learning, and memory). Postmortem studies of schizophrenics has revealed an overproduced G72 and a lower NMDA glutamate receptor activity.

COMT is another one of the top candidate genes for schizophrenia. COMT (catechol-O-methyltransferate) gene is located on chromosome 22 and is involved in degradation of dopamine. One of the hypothesis highly debated is that schizophrenics' brains produce more dopamine than a normal brain, which can by responsible for some of the schizophrenia positive symptoms. However, the exact mechanism by which altered levels of dopamine in certain areas of the brain (prefrontal cortex, striatum, and limbic system) produce schizophrenia is not known.

DISC1 gene is located on the chromosome 1 and was initially identified as a potential focus for schizophrenia risk, while recently studies focus on the impact of the gene mutation. The DISC1's protein is involved in the development and function of the hippocampus, and acts similar to a conductor agent for the newly formed nerve cells "guiding them to their proper location at the appropriate tempo so they can seamlessly integrate into our complex and intertwined nervous system." When DISC1's protein does not operate properly, the new nerve cells can integrate faster into the brain circuit and cause impairments. Mutation of the gene encoding can effectively reproduce some schizophrenia symptoms (anxiety, hyperactivity, apathy and an altered sense). According to several studies, the distribution of DISC1 is altered in the orbitofrontal cortex cells in individuals experiencing psychosis. (13)

PPP3CC (protein phosphatase 3, catalytic subunit, gamma isoform) gene is located on chromosome 8 and encodes calcineurin, a protein phosphatase which regulates synaptic plasticity (the ability of the synapse formed between two neurons to change in strength) and neuronal adaptation (a change over time in the responsiveness of the sensory system to a constant stimulus). PPP3CC gene is involved in the diagnosis of schizophrenia in Caucasians, African-Americans, and Japanese.

EGR (early growth response) family gene plays an important role in the development of the nervous system and the function of the adult nervous system. EGR protein is involved in cellular growth and differentiation. EGR family gene includes EGR1, EGR2, EGR3, and EGR4. Postmortem studies revealed that expression of EGR1, EGR2, and EGR3 is reduced in patients with schizophrenia.

WKL1 gene is located on chromosome 22 and produces a protein "similar to those which play a crucial role in transmitting electric currents along the nerves." Mutations of the WKL1 gene seems to play an important role in the development of catatonic schizophrenia. (14)

GRM3 (glutamate receptor) gene is responsible with glutamate regulation in synapses and has been associated with some schizophrenia traits. This gene increases the risk for schizophrenia by altering glutamate transmission and brain physiology.

In addition to genes' research, scientists also focus on the study of genetic markers. In 2007, the Feinstein Institute for Medical Research announced that they identified nine genetic markers that can increase the risk for schizophrenia. Genetic markers are phenotypes (observable physical characteristics of an organism) and "represent biological or neuropsychological traits that indicate a genetic tendency towards" developing a certain disorder. (15) Schizophrenia genetic markers include several major neurocognitive deficits (impairments in attention, memory, and problem solving domains), perceptual deficits (olfactory identification deficit, sensory gating, smooth pursuit eye-tracking abnormalities), and social interaction deficits (impairments in verbal fluency, perception of emotion, and social understanding). (16) Based on the discovery of the genetic markers, scientists have conducted studies where they simultaneously examined the genetic information of the patient's parents by trying to identify pieces of chromosomes that are identical. These studies discovered nine regions along the chromosomes that might play a significant role in the development of schizophrenia. Four of the regions also contain some genes previously associated with schizophrenia, while the genes located in the remaining five regions "are involved with structure and survival of neurons." (17) Based on this information, scientists believe that schizophrenia can be inherited in a recessive manner. The risk to develop the disorder is significantly increased when the individual inherits identical copies of the markers from each parent.

Environmental factors

When studing schizophrenia risk factors, scientists use the term environment to include everything else that is not genetic, but influence the development of the disease traits such as: nutritional, hormonal, and chemical factors present during pregnancy, and social factors during childhood and adolescence (social dynamic, stress, the use of different drugs, education, viruses exposure).

Prenatal risk factors

Scientists believe that events occuring during early brain development stages (such as prenatal and perinatal periods) may increase the risk for schizophrenia. This believe is supported by brain imaging studies which revealed premorbid brain abnormalities and minor physical anomalies (minor malformations of the head, eyes, ears, hands, mouth, of feet) in patients with schizophrenia. The presence of infectious agents during pregnancy has detrimental effects on the development of the fetal brain. Recent research suggests that children born to mothers who were affected by viruses (cytomegalovirus - CMV, herpes simplex virus/ HSV, or poliovirus) or infectious conditions (influenza and rubella) during pregnancy have a up to 700 percent higher risk to develop schizophrenia than children not exposed to such conditions. Other medical conditions highly associated with schizophrenia are reeclampsia (a pregnancy condition characterized by maternal hypertension, edema - excessive swelling, and excess protein in the urine) and obesity. Also, a high risk to develop schizophrenia is met among children with mothers that were exposed to toxic agents (such as lead in gasoline or paint, alcohol, painkillers, or smoking) during pregnancy. (18)

Another significant factor that can increase the risk to develop schizophrenia is prenatal nutritional deprivation, especially micronutrient deficiencies. Micronutrients are those nutrients needed by the body in small quantities, such as iron, cobalt, iodine, magnesium, selenium, zinc, etc.

A much more prominent cause of schizophrenia than infections and nutritional deprivation is prenatal trauma (obstetric complications). The most common obstetric complications highly associated with schizophrenia include: hypoxia (lack of oxygen for the fetus), prolong labor (associated with two frequent schizophrenia brain abnormalities - cerebral atrophy and small hippocampi), and placental complications.

Many studies also show that babies born between December and March have a slightly higher risk than average rate to develop schizophrenia. Some scientist suggest that a schizophrenia seasonality risk can be explained by the lack of sunlight which leads to a vitamin D deficiency. Vitamin D deficiency is believed to alter the development of baby's brain before and after birth.

Stress

Stress plays a large role in a wide range of diseases and conditions. Stress was discovered to be particularly harmful in those individuals affected by schizophrenia, although stress does not cause schizophrenia. People that suffer from schizophrenia are more likely to report a stressful event preceding an acute episode of psychosis and stressful events tend to precipitate episodes of illness.

Studies conducted on young individuals revealed that children and teenagers brains are very sensitive to stress, 5 up to 10 times more sensitive than the adult brain. Chronic stress or periods of moderate stress can have damaging effects on the brain of children and adolescents. Some of the regions affected by stress include hypothalamus, pituitary and adrenal gland. Some scientists believe that when the brain is exposed to high level of stress it suffers a neurotoxic reaction that can cause cells' damage. Researchers suggest that children genetically or biological predisposed to schizophrenia if raised in high stress dysfunctional families have a higher risk to develop the disorder than children raised in low stress household.

In adults, the social stress associated with immigration seems to increase the risk of developing schizophrenia. A study conducted in Sweden suggested that first-generation immigrants were three times more likely to develop psychotic disorders. The risk is higher in immigrants with dark skin.

Social factors

Schizophrenia has been associated with several social conditions, such as (1) social isolation and poor or disrupted interpersonal relationships during childhood, adolescence, and early adulthood, (2) social adversity (low socioeconomic status, single-parent households, unemployment), and (3) urban living. In the past 10 years, studies conducted on developed countries have revealed that the incidence of schizophrenia is two times higher in the urban population. It is unclear why there is a higher rate of psychotic disorders in the urban setting than rural areas, but some researchers suggest it might be explained by an increased exposure to toxins and viruses, and the social context people live in. However, living in a very isolated rural area can also increase the risk of schizophrenia due to social isolation.

Article by Alina Morrow,
MS Psychology
OmniMedicalSearch.com