Etiology

Causes of schizophrenia are still not known, however, it is believed to be a complex

multi-factorial pathology. The personality disorganization observed in schizophrenia can result
from the interaction of cultural, psychological and biological variables and among these are
genetic factors.

Currently, it is thought that genetic risk for schizophrenia emerges in two basic ways—
the first being the polygenic interaction of multiple common variants of probably thousands of
genes, each with very small individual effects. The second are rare but highly penetrant genetic
events such as deletions or duplications. Of the environmental causes of schizophrenia, most
studies have focused on pre-and perinatal environmental risk factors; three of the gene-
environment studies relevant to schizophrenia focus on these—infection, depression/stress, and
urban birth.

Genetic

Estimates of heritability vary because of the difficulty in separating the effects of genetics

and the environment. The greatest risk for developing schizophrenia is having a first-degree
relative with the disease (risk is 6.5%); more than 40% of monozygotic twins of those with
schizophrenia are also affected. It is likely that many genes are involved, each of small
effect. Many possible candidates have been proposed, including specific copy number
variations, NOTCH4 and histone protein loci. A number of genome-wide associations such as
zinc finger protein 804A have also been linked. There appears to be significant overlap in the
genetics of schizophrenia and bipolar disorder.

Assuming a hereditary basis, one question from evolutionary psychology is why genes

that increase the likelihood of psychosis evolved, assuming the condition would have been
maladaptive from an evolutionary point of view. One theory implicates genes involved in the
evolution of language and human nature, but so far all theories have been disproved or remain
unsubstantiated.
Environment

Environmental factors associated with the development of schizophrenia include the

living environment, drug use and prenatal stressors. Parenting style seems to have no effect,
although people with supportive parents do better than those with critical parents. Living in an
urban environment during childhood or as an adult has consistently been found to increase the
risk of schizophrenia by a factor of two, even after taking into account drug use, ethnic group,
and size of social group. Other factors that play an important role include social isolation and
immigration related to social adversity, racial discrimination, family dysfunction,
unemployment, and poor housing conditions. Childhood experiences of abuse or trauma are risk
factors for a diagnosis of schizophrenia later in life.

Substance Abuse

A number of drugs have been associated with the development of schizophrenia

including cannabis, cocaine and amphetamines. About half of those with schizophrenia use drugs
and/or alcohol excessively. The role of cannabis could be causal, but other drugs may be used
only as coping mechanisms to deal with depression, anxiety, boredom, and loneliness.

Cannabis is associated with a dose-dependent increase in the risk of developing a

psychotic disorder. Frequent use has been found to double the risk of psychosis and
schizophrenia. Some research has however questioned the causality of this link. Amphetamine,
cocaine, and to a lesser extent alcohol, can result in psychosis that presents very similarly to
schizophrenia.

Prenatal

Factors such as hypoxia and infection, or stress and malnutrition in the mother
during fetal development, may result in a slight increase in the risk of schizophrenia later in
life. People diagnosed with schizophrenia are more likely to have been born in winter or spring
(at least in the northern hemisphere), which may be a result of increased rates of viral
exposures in utero. This difference is about 5 to 8%.
Pathophysiology

Abnormalities in neurotransmission have provided the basis for theories on the

pathophysiology of schizophrenia. Most of these theories center on either an excess or a
deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories
implicate aspartate, glycine, and gamma-aminobutyric acid (GABA) as part of the
neurochemical imbalance of schizophrenia.1

Abnormal activity at dopamine receptor sites (specifically D2) is thought to be associated

with many of the symptoms of schizophrenia. Four dopaminergic pathways have been
implicated. The nigrostriatal pathway originates in the substantia nigra and ends in the caudate
nucleus. Low dopamine levels within this pathway are thought to affect the extrapyramidal
system, leading to motor symptoms. The mesolimbic pathway, extending from the ventral
tegmental area (VTA) to limbic areas, may play a role in the positive symptoms of schizophrenia
in the presence of excess dopamine. The mesocortical pathway extends from the VTA to the
cortex. Negative symptoms and cognitive deficits in schizophrenia are thought to be caused by
low mesocortical dopamine levels. The tuberoinfundibular pathway projects from the
hypothalamus to the pituitary gland. A decrease or blockade of tuberoinfundibular dopamine
results in elevated prolactin levels and, as a result, galactorrhea, ammenorrhea, and reduced
libido.

The serotonin hypothesis for the development of schizophrenia emerged as a result of the
discovery that lysergic acid diethylamide (LSD) enhanced the effects of serotonin in the
brain. Subsequent research led to the development of drug compounds that blocked both
dopamine and serotonin receptors, in contrast to older medications, which affected only
dopamine receptors. The newer compounds were found to be effective in alleviating both the
positive and negative symptoms of schizophrenia.

Another theory for the symptoms of schizophrenia involves the activity of glutamate, the
major excitatory neurotransmitter in the brain. This theory arose in response to the finding that
phenylciclidine and ketamine, two noncompetitive NMDA/glutamate antagonists, induce
schizophrenia-like symptoms. This, in turn, suggested that NMDA receptors are inactive in the
normal regulation of mesocortical dopamine neurons, and pointed to a possible explanation for
why patients with schizophrenia exhibit negative, affective, and cognitive symptoms.

The brain tissue itself appears to undergo detectable physical changes in patients with
schizophrenia. For example, in addition to an increase in the size of the third and lateral
ventricles, individuals at high risk of a schizophrenic episode have a smaller medial temporal
lobe.