Family, twin, and adoption studies support the role of genetic influences in schizophrenia. Immediate biological relatives of people with schizophrenia have about 10 times greater risk than that of the general population. Given prevalence estimates, this translates into a 5 to 10 percent lifetime risk for first-degree relatives (including children and siblings) and suggests a substantial genetic component to schizophrenia. What also bolsters a genetic role are findings that the identical twin of a person with schizophrenia is at greater risk than a sibling or fraternal twin, and that adoptive relatives do not share the increased risk of biological relatives (see Figure 4-3). However, in about 40 percent of identical twins in which one is diagnosed with schizophrenia, the other never meets the diagnostic criteria. The discordance among identical twins clearly indicates that environmental factors likely also play a role (DSM-IV).

Current research proposes that schizophrenia is caused by a genetic vulnerability coupled with environmental and psychosocial stressors, the so-called diathesis-stress model. Family studies suggest that people have varying levels of inherited genetic vulnerability, from very low to very high, to schizophrenia. Whether or not the person develops schizophrenia is partly determined by this vulnerability. At the same time, the development of schizophrenia also depends on the amount and types of stresses the person experiences over time. An analogy can be drawn to diabetes by virtue of both genetic factors (e.g., family history) and behavioral factors (e.g., diet, exercise, stress) that interact to determine whether or not a given person develops diabetes. How the interaction works in schizophrenia is unknown, yet the subject of ongoing research.

[For more information on possible prevention of schizophrenia - in other (non-affected) family members and children - please see "Part 1- Preventing Schizophrenia in Young Children & Adults, Part 2- Preventing Schizophrenia in your future child, during Pregnancy and Childhood", Part 3- Preventing Schizophrenia].

Despite the evidence for genetic vulnerability to schizophrenia, scientists have only recently begun to identify the genes responsible. The current consensus is that multiple genes are responsible.

[Note: Recently, A number of damaged genes or gene segments have been identified (in multiple independent research studies) as associated with schizophrenia. These genes include the Dysbindin, Neuregulin, COMT and G72 genes. To read some of the recent news on the research on these genes please see the following links:

• Scientists identify more gene defects linked to schizophrenia
• Gene May Play a Role in Schizophrenia - Second Major Study Confirms
• Israeli Biotech: Schizophrenia Associated With the COMT Gene

Numerous brain abnormalities have been found in schizophrenia. For example, patients often have enlarged cranial ventricles (cavities in the brain that transport cerebrospinal fluid), especially the third ventricle, and decreased cerebral size compared with control groups. Several studies suggest this may be more common among men whose families do not have a history of schizophrenia. There is also some evidence that at least some people with schizophrenia have unusual cortical laterality, with dysfunction localizing to the left hemisphere. To explain laterality, some have proposed a prenatal injury or insult at the time of left hemisphere development, which normally lags behind that of the right hemisphere.

Figure 4-3. Risk of developing schizophrenia

The anatomical abnormalities found in different parts of the brain tend to correlate with schizophrenia’s positive symptoms and negative symptoms. Positive symptoms are often linked to temporal lobe dysfunction, as shown by imaging studies that utilize blood flow and glucose metabolism. Such dysfunction possibly is related to abnormal phospholipid metabolism. Disorganized speech (taken to reflect disorganized thinking) has been associated with abnormalities in brain regions associated with speech regulation . Negative and cognitive symptoms, especially those related to volition (desire) and planning, are commonly associated with prefrontal lobe dysfunction. This is perhaps related to unusual neuronal density (Selemon et al., 1998) and may be more prevalent among patients whose families have a history of schizophrenia than those whose do not . However, mapping patients’ symptoms with brain regions is complex and variable. Researchers believe that the dysfunctions are present in brain circuitry rather than in one or two localized areas of the brain.

Excessive levels of the neurotransmitter dopamine have long been implicated in schizophrenia, although it is unclear whether the excess is a primary cause of schizophrenia or a result of a more fundamental dysfunction. More recent evidence implicates much greater complexity in the dysregulation of dopamine and other neurotransmitter systems . Some of this research ties schizophrenia to certain variations in dopamine receptors, while other research focuses on the serotonin system . However, it must be emphasized that in many cases it is possible that perturbations in neurotransmitter systems may result from complications of schizophrenia, or its treatment, rather than from its causes.

The “stressors” investigated in schizophrenia research include a wide range of biological, environmental, psychological, and social factors. There is consistent evidence that prenatal stressors are associated with increased risk of the child developing schizophrenia in adulthood, although the mechanisms for these associations are unexplained. Some interesting preliminary research suggests risk factors include maternal prenatal poverty and depression. Other stressors are exposure to influenza outbreaks , war zone exposure , and Rh-factor incompatibility . Their variety suggests other stressors might also be risk factors, under the general rubric of “maternal stress.”

As a result of such stresses, newborns of low birth weight and short gestation have been linked to increased risk of later developing schizophrenia, as have delivery complications and other early developmental problems . Among children, especially infants, viral central nervous system infections may be associated with greater risk , thereby explaining links between schizophrenia and being born or raised in crowded conditions or during the flu-prone winter and spring months . However, support for these hypotheses is inconsistent and incomplete. In fact, it is possible that prenatal and obstetric complications associated with schizophrenia could reflect already disrupted fetal development, rather than being causal themselves . More generally, across the life span, the chronic stresses of poverty and some facets of minority social status appear to alter the course of schizophrenia.

Presently, it is unclear whether and how these risks contribute to the diathesis-stress interaction for any one person because specific causes may differ . Although genetic vulnerability is difficult to control, certain other important factors can be addressed with current knowledge. An awareness of stressors that increase the likelihood of genetic vulnerability being actualized supports preventive strategies, such as good prenatal health care and nutrition. Furthermore, since life stresses can exacerbate the course of the illness, access to good quality services and social supports, as well as attention to relapse prevention interventions, can have beneficial effects on longer term outcome.

At the same time, researchers and clinicians are striving to integrate findings concerning both diathesis and stress into models of how schizophrenia develops. Not only does brain biology influence behavior and experience, but behavior and experience mold brain biology as well. One promising integrative model is the neurodevelopmental theory of schizophrenia developed by Weinberger and others . It posits that schizophrenia develops from “a subtle defect in cerebral development that disrupts late-maturing, highly evolved neocortical functions, and fully manifests itself years later in adult life” .

The nature of the defect, which has not been identified, may be a product of a pre- or neonatal insult to the brain. Further support for the neurodevelopmental theory comes from abnormalities in brain structure that have long been found in people with schizophrenia. Such findings have been interpreted to reflect abnormal neuronal migration in early development .

Researchers have developed animal models of early neurodevelopmental dysfunctions that manifest in later behavioral and functional deficits and are influenced by genetics. As promising as these theories are, the causes and mechanisms of schizophrenia remain unknown. Nonetheless, research has uncovered several of treatments for schizophrenia that are effective in reducing symptoms and functional impairments.

Table 4-8. Selected treatment recommendations, Schizophrenia Patient Outcomes Research Team

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