Schizophrenia is characterized by psychotic symptoms such as hallucinations and delusions (often referred to as “positive” symptoms), negative or deficit symptoms such as lack of motivation and social withdrawal, and cognitive impairments affecting attention, working memory, declarative memory, language fluency, and diverse aspects of social cognition.
Bipolar disorder is characterized by extreme mood swings between mania (characterized by euphoria or irritability, grandiosity, increased energy, and decreased need for sleep) and depression (characterized by sadness, loss of interest, decreased energy, disturbed sleep and appetite, ideas of worthlessness, guilt, and suicidal ideation). Affected individuals may return to normal mood states (euthymia) between acute episodes, but many have residual symptoms. Psychotic symptoms may occur in either manic or depressed episodes, most often congruent with mood. Bipolar patients with psychosis may have cognitive deficits similar to those seen in individuals with schizophrenia.
A milder form of the illness, bipolar II disorder is also recognized in which hypomania (mild mania) alternates with depression. Such patients do not generally suffer psychotic symptoms.
Some individuals experience a mixture of symptoms characteristic of schizophrenia and bipolar disorder and are currently given the diagnosis of schizoaffective disorder.
The heritability of schizophrenia and bipolar disorder is estimated to be very high, in the range of 65% to 80%. In contrast, the heritability of unipolar depression is less, approximately 35%, with greater environmental influence.
Despite their high heritabilities, the genetic risk of schizophrenia and bipolar disorder is highly polygenic, with many hundreds of genetic variants each contributing small increments of risk in the population, with different combinations of loci acting in different individuals. Genetic studies have found significant sharing of genetic risk variants between schizophrenia and bipolar disorder.
Schizophrenia is characterized by loss of gray matter in frontal and temporal regions of the cerebral cortex. Unaffected first-degree relatives may have milder gray matter loss with similar spatial patterns.
First-degree relatives of individuals with schizophrenia may have attenuated symptoms such as suspiciousness, social isolation, eccentric beliefs, and mild cognitive impairments without psychosis. This condition is currently diagnosed as schizotypal disorder.
Antipsychotic drugs are effective for the positive (psychotic) symptoms of schizophrenia, for acute manic episodes, and when combined with an antidepressant for psychotic depression. They are also efficacious in preventing acute relapses in schizophrenia, and often in combination with mood-stabilizing drugs in bipolar disorder. They lack efficacy for the negative and cognitive symptoms of schizophrenia.
The therapeutic action of antipsychotic drugs depends on their ability to antagonize D2 dopamine receptors. This mechanism of action can also cause significant Parkinson-like motor side effects. Second-generation antipsychotic drugs partly mitigate motor side effects by blocking other neurotransmitter receptors (most significantly 5HT2A receptors) but have their own significant side effects, in particular, weight gain and elevation of serum glucose and lipids.
Lithium is effective both for acute mania and for mood stabilization in bipolar disorder. Certain anticonvulsant drugs, such as valproate, are also effective. However, which of these drugs’ many pharmacological actions is responsible for their therapeutic efficacy remains unknown.
Schizophrenia, bipolar disorder, and schizoaffective disorder, like all psychiatric disorders, are still diagnosed solely by clinical observation and history of illness. Despite increasing knowledge of these conditions, objective diagnostic tests have not yet been identified that can be applied with great enough sensitivity (avoidance of false-negatives) and specificity (avoidance of false-positives) to be acceptable for clinical or research use. Thus, neither of the two major diagnostic manuals, the Diagnostic and Statistic Manual of Mental Disorders, 5th ed. (DSM-5), published by the American Psychiatric Association, nor the International Classification of Diseases, 10th ed. (ICD-10), published by the World Health Organization, lists any objective medical diagnostic tests for these disorders. In fact, the difficulty in finding objective tests or biomarkers may partly result from reliance on current diagnostic systems as the “gold standards.” Even for schizophrenia, bipolar disorder, and major depression, which have been closely studied for more than a century, it is clear that the DSM-5 errs in drawing them as discrete, discontinuous categories. Such a categorical model works well for most infectious diseases, for example, but most common, chronic human illnesses tend to be highly heterogeneous with respect to symptoms, severity, disease course, and treatment responsiveness. Psychiatric disorders, including those discussed in this chapter, would be better captured as quantitative deviations from health on multiple dimensions (similar to type 2 diabetes or coronary artery disease). One artifact of the excessively narrowly drawn categories of the DSM-5 is that a substantial fraction of patients with any psychiatric diagnosis have two or more or, as is common with the disorders discussed in this chapter, shifting diagnoses over time. Genetics is now providing some insight into this complex picture as both shared and unshared genetic and environmental risk factors have been discovered for schizophrenia and bipolar disorder. (Overlapping genetic risk factors are well documented for many disorders in medicine including rheumatoid arthritis and psoriasis as well as Crohn disease and ulcerative collitis.) Ultimately, as science progresses, psychiatric diagnosis is likely to look very different from the DSM-5.
Despite the serious shortcomings of DSM-5 diagnoses, well-studied disorders such schizophrenia, bipolar disorder, and autism are not arbitrary fictions; these clinical diagnoses yield very high heritabilities (0.65–0.80) across different countries and cultures. That “rough and ready” utility of these diagnoses for some areas of research such as genetics, however, does not mean that they are useful for others, or that they represent valid “natural kinds.”
Schizophrenia is associated with very severe symptoms and significant disability. It typically begins in late adolescent years or the early twenties; it may rarely begin in childhood, or as late as the early forties. The global mean prevalence of schizophrenia is between 0.5% and 1.0% with local variation. The male to female ratio is approximately 1.4 to 1, with males also tending to have earlier onset. The lifetime prevalence of psychoses of all causes has been estimated to range between 3% and 4% of populations worldwide. Because of its early age of onset, chronic course, and severely impairing effects, schizophrenia ranks among the top 20 global causes of years of healthy life lost to disability, despite its relatively low prevalence.
Schizophrenia is characterized by three major symptom clusters denoted as positive (or psychotic), negative (or deficit), and cognitive 17–1. In addition, many patients with schizophrenia have disturbances of mood, most often depression.
17–1 Schizophrenia: A Case History
Martin is a 35-year-old man who is currently homeless and living in shelters or on the street. His childhood was unremarkable until high school, when he began to withdraw from his peers. He tended to eat and play by himself at school and spent much of his time reading science fiction. In college Martin developed a preoccupation with mysticism and religion, often writing lengthy but confusing manifestos that described his beliefs. His parents became concerned at the end of his sophomore year when final exams were approaching, and he seemed to become more and more preoccupied with his theories that he believed would revolutionize society. Finally, Martin broke off contact with his parents, believing that they had been recruited into a conspiracy to prevent him from developing his philosophy. During his junior year, Martin’s behavior continued to change. He began to wear large hats because he believed that people could hear his thoughts and were trying to steal them. When he heard news stories about overseas civil disturbances or wars, he believed that they were being waged between forces trying to help him and others who were trying to stop him. One night, as Martin was putting aluminum foil around his dorm room to prevent people from using electrical devices to steal his ideas, he began to hear two voices discussing his work and his philosophy. Their discussion confirmed his fear that his ideas had been stolen. He became more and more frightened and angry as the voices began to ridicule his ideas, until finally he fled his apartment. On the street he saw a policeman he believed was sent to kidnap him. Martin attacked the policeman in what he believed to be self-defense.
Martin was brought to a psychiatric hospital where he was given antipsychotic medication combined with short-term treatment with a benzodiazepine in order to calm him until the antipsychotic drug could begin to exert its therapeutic effects. With treatment, his auditory hallucinations and paranoid delusions subsided over the course of a few weeks, but he remained adamant that he did not want to see his parents. Soon after he was released from the hospital, Martin stopped taking his medications because they made him feel tired and gain weight. He attempted to continue his studies but within 6 months dropped out of school because of the return of paranoid delusions about people stealing his ideas and because he was having great difficulty keeping up with his assignments. For the next 6 years he tried to work at a series of jobs but was unable to keep any of them because of unexplained absences and frequent clashes with his supervisors and coworkers. During these years he was hospitalized involuntarily six times and tried on many different first- and second-generation antipsychotic drugs. Each time he was given an antipsychotic medication, there was an initial reduction in his paranoia and auditory hallucinations. He rarely continued to take these drugs for more than a few months, however, because of the side effects he experienced or because the hallucinations began to return despite medication.
At one point Martin reconciled with his parents and lived with them for several years, but they became increasingly frustrated with his resistance to taking his medications followed by frightening outbursts and hospitalization. Because discussions about this issue caused considerable tension, Martin would occasionally become very angry and disappear to live with his one remaining friend or on the street for weeks at a time. He began drinking alcohol and using marijuana and cocaine, because he was bored and because these substances would help him ignore the voices that frequently bothered him. Eventually, when he was 29, Martin had a major fight with his parents over his illicit drug use and he moved out of their house, never to return.
During the past 6 years Martin has been living in shelters and on the street. He receives medication from a local public health clinic. Although he continues to take such medication inconsistently, he takes it more frequently because he has come to recognize that it helps him stay out of the hospital. He knows some of the other people at the shelters he visits, but in general people make him uncomfortable and he keeps to himself. His parents occasionally send him money, but he only talks to them about once a year. Although he still thinks of his philosophy occasionally, it makes less sense to him than it used to. Mostly he spends time alone, making small talismans out of wire and glass to help him feel safe.
The positive (psychotic) symptoms of schizophrenia include hallucinations and delusions 17–2. Negative (deficit) symptoms represent significant impairments of normal functions including loss of motivation, a marked decrease in adaptive social interactions, blunting of affect, and impoverishment of the content of thought and speech. The cognitive symptoms of schizophrenia impair many measurable functions including attention, working memory, declarative memory, verbal memory and fluency, and diverse aspects of social cognition. Most significant as a cause of inability of patients to function at school or work is impaired cognitive control: the reduced ability to regulate thought, emotion, and behavior in accordance with goals. Long before the advent of modern cognitive science, the German psychiatrist Emile Kraepelin described the mind in schizophrenia as an orchestra without a conductor. Because of cognitive impairments and negative symptoms, people with schizophrenia continue to be disabled even when their psychotic symptoms are successfully controlled with available medications.
17–2 Psychosis
Schizophrenia is the best known, but by no means the only, condition in which individuals experience psychotic symptoms. Psychotic symptoms also can occur in bipolar disorder (during both manic and depressive episodes) and in unipolar depression (Chapter 15). There are also nonaffective psychoses that are relatively rarely seen in the clinic, for example, paranoid disorder in which a person may have delusions as his or her most salient or perhaps only symptom. In such cases the affected individual, lacking the other severe impairments of schizophrenia, might establish a lifestyle in which his or her delusions are not challenged—and might never doubt these beliefs—and thus never seek treatment. Finally psychotic symptoms may occur in the context of dementia, delirium, or intoxication. For example, as a person with Alzheimer disease begins to lose track of possessions, he or she may develop the delusion that his or her caregivers are stealing from him or her, leading to significant distress and occasionally disruptive behaviors (Chapter 18).
Psychosis is generally defined as the experiencing of abnormal subjective phenomena, combined with an inability to recognize that these experiences are not “objectively real.” Hallucinations, for example, are sensory perceptions disconnected from external or physiological stimuli. Individuals may report hearing voices that others cannot hear or seeing things that others cannot see, but the experience seems to be coming from the external world. In schizophrenia the most common form that hallucinations take are auditory, often in the form of voices. For example, affected individuals may hear voices carrying on a conversation, perhaps about them or directed to them. The voices can be derogatory or can issue commands (often a highly dangerous state). Illusions cannot be considered psychotic symptoms if they are problems intrinsic to sensory systems or common misperceptions such as mirages. They are counted as psychotic symptoms when they are severely distorted perceptions or misinterpretations of real stimuli, for example, seeing an object as pulsating that others clearly see as still. Delusions are fixed, false beliefs (ie, impervious to evidence or reasoning) that are not shared by others in an individual’s culture. In schizophrenia delusions are often bizarre or paranoid. An example of a bizarre delusions is the belief that the dental fillings in one’s teeth are radio transmitters. A paranoid delusion is a fixed, false, and untestable belief that one is being spied upon, followed, or persecuted. Individuals with psychosis, most often those with schizophrenia, may also describe an experience of thought insertion or deletion, that is, that some outside agent has added or removed thoughts from their brain.
When psychotic symptoms occur as a component of a mood disorder, they are generally, but not always, congruent with the person’s elevated, depressed, or irritable mood. Thus, during a manic episode a person may have the delusion that he or she is a prophet or deity, or endowed with supernatural powers. During psychotic depression a person may hear voices hectoring him or her as worthless or may have a delusion that he or she is rotting from the inside and emitting an intolerable odor. When psychotic symptoms occur as a component of a mood disorder, they remit when the underlying mood disorder responds to treatment (which usually includes an antipsychotic drug).
Symptoms of depression or mania can also occur in cases in which chronic schizophrenia-like symptoms predominate; these patients are often said to have schizoaffective disorder, although evidence from family and genetic studies suggests that this is an artificial, highly heterogeneous grouping.
It is hypothesized that the different symptom clusters characteristic of schizophrenia result from abnormalities in different, although partially overlapping, neural circuits. For example, psychotic symptoms are thought to reflect abnormalities in subcortical dopamine systems, while impairment in cognitive control is thought to reflect abnormalities in circuits based in the prefrontal cortex. The involvement of diverse neural circuits is thought to result from pathological processes that unfold during development and affect diverse cells, synapses, and circuits in the brain.
A diagnosis of schizophrenia is typically made only with the first episode of florid psychotic symptoms, but there is generally—perhaps always—a prodromal period in mid to later teen years. The schizophrenia prodrome may first manifest with declining school or vocational performance, increasing social isolation, unstable mood, irritability, anxiety, and increasingly odd and eccentric thoughts. It may initially be challenging to distinguish the schizophrenia prodrome from depression, drug use, or other pathological conditions of adolescence. As the schizophrenia prodrome progresses, however, the affected individual begins to have mild or attenuated psychotic symptoms (see 17–2), at which point it becomes easier to distinguish from other forms of adolescent psychopathology.
When individuals with the schizophrenia prodrome are carefully examined, they exhibit broad declines in cognitive functioning from their earlier baselines as well as the emergence of negative symptoms 17–1. These cognitive impairments and negative symptoms are not typically as severe as they will become after a first psychotic episode. Nonetheless, a significant fraction of the impairment that characterizes schizophrenia may be established before the first psychotic symptoms emerge. It has been hypothesized that cognitive and negative symptoms may, in fact, be a risk factor for psychosis. In some studies using structural magnetic resonance imaging (MRI), individuals with prodromal schizophrenia show cerebral cortical thinning, most severe in frontal and temporal cortices 17–2, that occurs more rapidly and to a greater extent than that observed in typically developing adolescents. However, measures of cortical thickness cannot currently be used as biomarkers of the schizophrenia prodrome since adolescence is a period in which synaptic pruning normally occurs 17–3. If measures of change in cortical thickness are to yield useful diagnostic information, they will have to meet the challenging test of reliably showing a faster rate of change or a distinctly more significant degree or spatial pattern of loss than control subjects, a difficult proposition against a normal background of dynamic cortical remodeling.
17–2
Statistical brain atlases plotting differences in the mean annualized rates of change in cortical thickness among clinical high-risk (aka “prodromal”) subjects who converted to psychosis (n=35) as compared with clinical high-risk subjects who did not convert (n=239) over a 12-month interval. Converters showed a greater rate of thinning (warmer colors) in left and right superior frontal, middle frontal, and medial orbitofrontal gyri and in the right superior and inferior parietal cortex, superior temporal gyrus, and parahippocampal gyrus. After applying a correction for multiple testing (p ≤ 0.01), only the differences in right superior frontal, middle frontal, and medial orbitofrontal regions remained significant. The small clusters showing greater expansion (cooler colors) in the converters did not survive correction for multiple comparisons. (Used with permission from Tyrone Cannon, PhD and Yoonho Chung, BS, Based on results reported in Cannon TD, Chung Y, He G, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2014 Jun 12 [in press].)
17–3 Synaptic Pruning
Synaptic pruning is the process of synapse elimination that is an essential component of brain development, but which is also recognized as playing a pathological role in both neurodevelopmental and neurodegenerative disorders. The precise topography of brain circuitry and the strength of synaptic connections that emerge during development result from an interplay of genetic information and experience. For example, activity-dependent processes play an important role in strengthening and promoting the survival of active synapses versus weakening and eliminating synapses that are less active. Such activity-dependent developmental mechanisms have been best studied in models of the formation of binocular vision, but similar principles play a role in diverse neural systems throughout development.
Adolescence initiates the last major stage of brain maturation. Changes in executive function and social cognition have been well documented (and are reflected in the separation of juvenile from adult criminal law). The characteristic neurobiological processes of this stage of brain development are increasing myelination of axons in prefrontal cortex and synaptic pruning, the elimination of weak, inefficient synapses. Both of these processes extend into early adulthood. The degree of synapse elimination is so significant that it presumably explains the thinning of the cerebral cortex that can be observed even in typically developing adolescents by longitudinal MRI studies.
The mechanisms underlying adolescent synapse elimination are not fully understood, nor are the signals by which it is initiated—although a role for gonadal steroids or other mediators involved in sexual maturation has been suspected. The mechanism by which weak synapses are eliminated appears to involve the complement cascade, which, in the periphery, is an important component of innate immunity, serving, eg, to kill pathological cells and clear away cellular debris (Chapter 12). In the process of synapse elimination, microglia, some of which appear to be derived from blood monocytes, produce C1q, the first molecule in the complement cascade (see figure); in addition, astroglia induce C1q expression in neurons. C1q from both sources then tags weak synapses; the precise molecular signals that identify weak synapses have not yet been elucidated. C1q binding activates the classical complement pathway, leading to cleavage of complement component C3 and binding of its fragment C3b. Synapses tagged by C3b are then phagocytosed by microglia. Given this role, it has been hypothesized that the complement system may play a pathological role in the excessive synapse elimination that occurs in schizophrenia. There is also evidence from Alzheimer disease models that microglia and the complement system become activated and contribute to the loss of synapses and cells characteristic of that disorder.
The figure illustrates a hypothesized role for complement in synapse elimination. According to this scheme, strong synapses (formed by yellow neuron), which are effective in driving postsynaptic responses, actively eliminate nearby, weaker synapses (formed by blue neuron) by inducing two signals: a local protective signal and a longer-range elimination signal. Astrocytes are proposed to secrete unknown factors (factor X) that induce complement C1 complex expression in active neurons along with unknown protective factors. Activation of complement pathways (C1 complex, C3, activated fragments of C3) then drives elimination of weaker neurons via microglial-dependent mechanisms.
(Adapted with permission from Stephan AH, Barres BA, Stevens B. The complement system: An unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–389.)
The schizophrenia prodrome creates the possibility of early intervention, ideally before severe pathophysiological changes have occurred, such as excessive and inappropriate dendritic pruning and synaptic loss. In multiple clinical trials conducted in prodromal subjects, antipsychotic drugs have convincingly failed to delay the onset of psychosis (but do produce serious side effects), suggesting that entirely different mechanisms of action will be needed. Indeed, the therapeutic goals should be to alter pathological developmental processes, and thus to move beyond the palliation of late-stage psychotic symptoms. Such efforts will require an improved understanding of the molecular and cellular basis of the underlying abnormalities. Cognitive remediation designed for prodromal subjects has shown early promise in delaying conversion to psychosis. As many as 20% of apparently prodromal individuals at high risk of conversion to psychosis make a durable recovery independently of treatment for reasons that are not understood.
Once a first psychotic episode has occurred, the course of schizophrenia is chronic, with periods of milder “residual” psychotic symptoms punctuated by relapses of florid psychosis. Treatment of a first episode with antipsychotic drugs generally brings a full remission of the positive symptoms. Unfortunately, while antipsychotic drugs extend the period between relapses, relapses do occur and over time respond less completely to treatment. In addition, negative and cognitive symptoms, which are generally present before the onset of psychosis, worsen over time, eventually reaching a plateau well below the affected person’s baseline, and are unresponsive to current pharmacological treatments. The side effect burden of antipsychotic drugs contributes to their discontinuation by patients, which can lead to more frequent relapses.
Based on twin studies, it has long been recognized that genes play a major role in risk of schizophrenia and bipolar disorder. Monozygotic (MZ) twin pairs, whose DNA sequences are 100% identical, have a concordance for schizophrenia of nearly 50%. Given a population prevalence of 0.5% to 1.0%, this is a 50- to 100-fold increase in risk for the MZ cotwin of an affected member of the twin pair. In contrast, dizygotic twin pairs, who share, on average, 50% of their DNA sequences, have a concordance for schizophrenia of approximately 15%. In addition, adoption studies found that risk of schizophrenia is determined by the biological rather than adoptive families. Overall, twin methodologies give heritabilities of 0.65 to 0.8 for schizophrenia and bipolar disorder, meaning that 65% to 80% of the phenotypic variance is explained by genes. This is among the highest rates of heritability for relatively common human diseases. (Diseases caused by highly penetrant single gene mutations—so-called Mendelian disorders—are rare because they more strongly diminish the likelihood of having offspring.)
Family and twin studies have also found that nonpsychotic first-degree relatives of individuals who meet criteria for schizophrenia often exhibit cognitive impairment and cortical thinning intermediate between population norms and their relatives with schizophrenia. An observation first made in adoption studies, but highly replicated in family studies thereafter, is that individuals genetically related to persons with schizophrenia may exhibit social isolation, suspiciousness, eccentric beliefs, and magical thinking, but lack frank psychotic symptoms such as hallucinations and delusions. When such symptoms produce impairment in functioning, the individual is diagnosed with schizotypal disorder (or in some older nomenclatures, by the misnomer, schizotypal personality disorder).
Despite the high heritabilities of schizophrenia and bipolar disorder, success in discovering specific disease risk–associated genetic variants was unsuccessful until recent advances in genomic technologies made it possible to search for genetic risk factors at the scale necessary to investigate a highly polygenic phenotype, that is, one in which each of a very large number of genes contributes small increments of risk. While the aggregate risk conferred by genes is large for schizophrenia and bipolar disorder, it is partitioned among numerous genes—likely many hundreds, perhaps more than 1000—of which no single gene is necessary or sufficient.
At the time of this writing, a global consortium has used DNA microarrays to genotype more than 40,000 patients with schizophrenia and 40,000 control subjects for common genetic variants and has determined the complete DNA sequence for the exomes (all protein-coding genes) of several thousand schizophrenia patients and control subjects. The microarrays (“gene chips”) permit the determination of the version of a DNA segment a person has at approximately 750,000 genomic loci and then enables the investigator to ask whether each variant studied increases the risk of schizophrenia in the population studied. The result has been the discovery of more than 100 genetic loci that influence the risk of schizophrenia and a prediction that there are likely to be more than 1000 genes (5% of the human genome) in which variation influences the risk of this syndrome. Some of the risk variants that have been identified influence such well-known neural proteins as L-type and T-type Ca2+ channel subunits 17–3 as well as components of the postsynaptic specializations of excitatory synapses (see 5–1 in Chapter 5). Given the goal of understanding disease pathogenesis and developing disease-altering treatments, efforts are under way to discover the majority of risk-associated loci. This will permit the identification of pathways that can yield targets for treatment development. The genetic analysis of bipolar disorder is lagging somewhat behind schizophrenia, based on the identification of populations and collection of samples, but is likely to catch up soon.
17–3
An emerging molecular “parts list” for schizophrenia. Analysis of both common and rare genetic variants associated with schizophrenia is beginning to yield an initial list of proteins that appear to be associated with risk. Most common risk-associated variants likely affect levels of gene expression, while rare variants within exons may influence protein function. Shown here is an α1 subunit of the L-type Ca2+ channel (encoded by CACNA1C), which forms a pore, and a β subunit (eg, encoded by CACNB2), which is regulatory. Functioning channels include additional regulatory subunits (depicted by orange oval). A common variant linked to CACNA1C is among the most strongly associated risk alleles for both schizophrenia and bipolar disorder; common variants within CACNB2 are strongly associated not only with schizophrenia but also with risk for several other psychiatric disorders. In addition, both common and rare variants associated with schizophrenia cluster in postsynaptic specializations of excitatory synapses (see 5–1 in Chapter 5). (Adapted with permission from McCarroll SA, Hyman SE. Progress in the genetics of polygenic brain disorders: significant challenges for neurobiology. Neuron. 2013;80(3):578–587.)
Syndromal forms of autism (ie, autism associated with such features as low IQ, seizures, and dysmorphic facies), and less commonly schizophrenia, can be associated with chromosomal deletions, duplications, or more complex rearrangements, all referred to as copy number variants (CNVs). CNVs may affect DNA segments ranging from several hundred kilobases to several megabases in length and may affect multiple genes. Several CNVs are among the most penetrant genetic risk factors for schizophrenia, for example, the 22q11.2 syndrome, which results from a deletion of variable length affecting approximately 3 megabases of DNA and up to 44 genes in the middle of chromosome 22. The 22q11.2 syndrome, previously called velocardiofacial syndrome (for its facial and cardiac defects) or DiGeorge syndrome (for its discoverer), is characterized by cleft palate, congenital heart disease, facial dysmorphology, hypoparathyroidism, and other abnormalities. Approximately 25% of individuals with the 22q11.2 syndrome develop schizophrenia; however, approximately 20% receive a diagnosis of autism and the majority warrant neither psychiatric diagnosis. As is the case with most CNVs that have been studied, the most penetrant central nervous system (CNS) phenotype is intellectual disability (mental retardation). To summarize an evolving story, CNVs that cause neuropsychiatric symptoms primarily produce impairments across multiple cognitive domains (intellectual disability), but may also significantly increase the risk of autism or schizophrenia. The resulting psychiatric phenotypes, if any, depend not only on the presence of a particular CNV but also on the polygenic background in which the CNV occurs. The incomplete penetrance and variable expressivity (multiple phenotypes) exhibited by the 22q11.2 deletion and most other CNVs illustrate the genetic complexity of the risk for neuropsychiatric disorders.
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