It is generally accepted, despite the absence of evidence, that schizophrenia is a group of disorders with a common overlapping phenotype rather than a single disease entity

It has a complex mode of inheritance and variable expression. Adoption, twin and family studies carried out in the 1960s established that the vulnerability to develop schizophrenia is largely genetic. What is inherited is an increase in the risk of becoming schizophrenic rather than a gene or genes that absolutely predict the occurrence of schizophrenia. Thus, about half of monozygotic (MZ) twins are concordant for schizophrenia compared to less than 20% of dizygotic (DZ) twins, using psychosis as the phenotype. It is therefore clear that environmental as well as genetic factors are important in the development of the disorder.

The high rate of discordance between MZ twins indicates that what is inherited is a predisposition but not a certainty of developing schizophrenia. In first-degree relatives, percent lifetime expectancy to develop schizophrenia is about 10% if one parent or a sibling has schizophrenia and 45 to 50% for offspring of two schizophrenic parents. In second-degree and third-degree relatives, the expectancy drops to 3.3% and 2.4%, respectively. Furthermore, adoption studies show a lifetime prevalence of 9.4% in the adopted-away offspring of schizophrenic parents and a lifetime prevalence of 1.2% in control adoptees [8].

The distribution of schizophrenia in families indicates a complex inheritance since the risk to relatives declines markedly as the relationship becomes more distant. Studies of extended pedigrees with multigenerational schizophrenia have ruled out single dominant genes as the cause of the illness in the majority of cases. However, there may be a small proportion of cases in which a single major gene, acting either alone or in concert with multiple small genetic and environmental factors, accounts for the vulnerability to become schizophrenic. It is likely that additive effects of several genes of modest effect, termed oligogenic inheritance, or many genes of small effect, termed polygenic inheritance, are the basis for the vulnerability.

Epidemiological studies of the genetics of schizophrenia are well established and have led to numerous studies using diverse methods to identify specific genes. Many studies reporting the involvement of specific genes in schizophrenia have failed replication. One reason for this is differences in the criteria for the phenotype. Linkage results vary greatly as to whether criteria based on symptomatology are restrictive or broad, for example, excluding schizoaffective patients and/or schizophrenia spectrum patients. Additionally, so-called logarithm of odds (lod) scores must be substantially higher than 3, that is, one chance in 1,000, in a complex disorder such as schizophrenia. Early studies accepted lod scores of 2 or 3 as proof of linkage.

Current major strategies to identify the genes in schizophrenia involve genome scanning through linkage and association studies and candidate gene analysis, for example, D2, D4 and 5-HT₂ receptor genes [9]. The latter strategy ruled out the involvement of various genes that are part of the DA system, such as the genes for tyrosine hydroxylase and the D1, D2 and D4 receptors. However, several studies have suggested an association between exon 1 of the D3 receptor and schizophrenia. Despite some nonreplications, this possibility is still the subject of considerable research. Although DA is the main neurotransmitter implicated in schizophrenia, there is also keen interest in 5-HT. Associations between a T to C polymorphism at nucleotide 102 in the 5-HT_2A receptor and schizophrenia, and between a Ser-to-Tyr polymorphism at nucleotide 452 and response to clozapine have been reported in several studies [9]. Positional cloning is most likely to be successful when applied to large families containing multiply affected members, when the disease gene has a major effect, when the mode of inheritance of the phenotype is known and when there are few diagnostic errors. These features are not characteristic of schizophrenia and have led to a number of reports of linkage or association that have not been replicated. For these reasons, the currently favored strategy is based on identity by descent involving the analysis of affected siblings. Evidence of linkage is provided when affected sibling pairs share loci more often than would be expected by chance alone. This method does not require knowledge of the mode of transmission, has the power to detect genes of modest effect, is not very sensitive to misdiagnosis and can be readily applied to schizophrenia.

Using the affected sibling pair method, there have been several replications of a locus on chromosome 6p24-p22 for schizophrenia [8]. This region contains the human leukocyte antigen (HLA) locus, which has been postulated to be relevant to schizophrenia. There is limited and controversial evidence that schizophrenia may be one of a group of disorders in which expanded trinucleotide repeats of variable length are present (see Chap. 40). Advances in the molecular genetics of schizophrenia in the future may lead to identification of the group of genes that convey vulnerability to this syndrome.

The neurodevelopmental hypothesis suggests that the etiology of schizophrenia may involve pathological processes during brain development

This hypothesis is based on the demonstration of behavioral and cognitive disturbances in childhood and adolescence that are eventually diagnosed as schizophrenic [10]. The absence of marked neurodegenerative changes in the schizophrenic brain together with findings suggestive of cortical maldevelopment are consistent with this hypothesis.

According to this hypothesis, the etiology of schizophrenia may involve pathological processes which begin in utero or perinatally and continue to unfold until the brain approaches its adult anatomical state as a result of extensive neuronal loss and synaptic pruning during early and late adolescence. These neurodevelopmental abnormalities are proposed to lead to the activation of pathological neural circuits during adolescence or young adulthood, perhaps due to severe stress, leading to the emergence of positive or negative symptoms or both. Some cases with the phenotype of schizophrenia may be due to embryonic maldevelopment, especially of the corpus callosum and temporal lobe, for example, temporal lobe epilepsy. The emergence of evidence for cortical maldevelopment in schizophrenia and the development of several plausible animal models, which are based on neonatal lesions that produce behavioral abnormalities or altered sensitivity to dopaminergic drugs only in adolescent or adult animals [11], have made the link between maldevelopment and schizophrenia more tenable.

A consistent finding in schizophrenia is cerebral ventricular enlargement [12]. A large number of computed tomography (CT) and magnetic resonance imaging (MRI) studies indicate lateral and third ventricular enlargement and widening of cortical fissures and sulci; these are present at the onset of the illness, progress very slowly if at all and are, therefore, unrelated to the duration of illness or the treatment received. Affected MZ twins discordant for schizophrenia have larger ventricles than unaffected twins. The loss of gray matter is correlated with poor premorbid social and educational adjustment during early childhood as well as obstetric complications. These findings are not specific for schizophrenia, however, as they are also found to almost the same extent in manic-depressive illness.

Despite extensive efforts to discover a neuropathological basis for schizophrenia, no consistent characteristic lesions, at either the micro- or the macroscopic level, have yet been identified

However, various abnormalities in the temporohippocampal and frontal lobes, the two brain regions most likely to be abnormal in schizophrenia, are currently being studied. There is extensive evidence that gliosis is not present, indicating that there is no neuronal death due to traumatic, inflammatory processes or infection in schizophrenia. However, an abnormality of programmed cell death, that is, apoptosis, has not been ruled out. Increased density of neurons in the prefrontal cortex, loss of interneurons in the cingulate and prefrontal cortices and abnormalities in migration of cells from the cortical plate to the gray matter of the cortex are among the most interesting recent findings. However, they are based on a small number of samples and have not been shown to be specific for schizophrenia.

Since the mid-1980s, there has been an increasing reliance on anatomical methods to reveal neurochemical changes in postmortem studies of schizophrenia. This has been due in large part to a growing appreciation of the diversity of neurons within what were once considered by most neurochemists, and indeed most neuroscientists, to be single classes of neurons. For example, studies of the gene encoding the GABA biosynthetic enzyme glutamic acid decarboxylase (GAD), as a marker of cortical GABA cells treat these interneurons as a unitary class of cells. However, well over a dozen different types of interneurons can be distinguished morphologically, and the morphological distinctions are paralleled by physiological and neurochemical distinctions. Anatomical methods have proven very useful since they allow subpopulations of interest to be distinguished.

Recent studies have revealed various neuropathological changes in the brain, particularly in the prefrontal cortices, including the pregenual anterior cingulate cortex, and the medial temporal lobe, including the hippocampus, parahippocampal gyrus and entorhinal cortex. Unfortunately, the types of changes reported (ranging from cell loss and changes in cell density in the absence of cell loss to changes in neuronal size, position or orientation) are inconsistent. With increasingly rigorous application of quantitative, computer-assisted, neuroanatomical methods, a greater degree of consistency may emerge. It is clear that representative samples of adequate size must be studied and the comparison groups (such as bipolar disorder and major depression) be included in such studies.

Since schizophrenia typically first occurs in late adolescence or early adulthood, developmental processes are considered key to its pathogenesis. The developmental hypotheses of schizophrenia implicitly assume that changes in neurochemical and neuroanatomical markers represent the culmination of a process and that such end points may be indirect or direct.