Schizophrenia and Affective Disorders

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112

Schizophrenia and Affective Disorders Jonathan D Picker Division of Genetics, Departments of Medicine and Child and Adolescent Psychiatry, Children’s Hospital Boston, Boston, MA, USA

GLOSSARY Psychiatric disorder – A state in which an individual’s behavioral actions and state are not within the norms of their society. Schizophrenia – A psychotic disorder with symptoms including hallucinations, delusions, thought processing defects, mood effects and social withdrawal. Affective disorder – A disorder of emotional state that results in excessively negative and/or positive mood states, which may not be congruent to the individual’s situation and which are protracted. This disorder may include swings from one state to the other and include psychotic elements.

112.1 INTRODUCTION Psychiatric disorders exert a unique and profoundly negative effect on individuals, their families and society in general. Although not isolated to our species, they are often thought of as uniquely human because of their impact on the individual’s personality and challenge our perceptions of what it is that constitutes a human individual (1). Psychosis in particular has elicited contemplation, with etiological theories, and management recommendations recorded in some of the earliest written records from the Mesopotamian region (2). Indeed, extensive and diverse descriptions of psychopathology were offered throughout the ancient world (3). This is likely a result of the florid effects of this group of disorders and the fact that most members of society are, in one way or another, impacted by them. Interest not only was of an intellectual nature but also reflected the need to deal with the effects of the psychopathology, for the individual and/or society’s sake. This chapter, by focusing on classic schizophrenia, bipolar disorder 1 (BPD1) and major depressive disorder (MDD) will review current understanding of schizophrenia and the affective disorders from a genetic perspective.

The milder variants, e.g. bipolar disorder 2 (BPD2), schizophreniform disorder and other subclassifications as well as intermediate states such as schizoaffective disorder (which has elements of each of the primary disorders), are no less valid; however, understanding of these disorders is yet too tenuous to do more than complicate a field already challenged by diagnostic complexities and conflicting data. Therefore, except in so far as these diagnoses inform the classic disorders, they will not be discussed.

112.1.1 Incidence of the Disorders Almost half of all Americans are at risk for having a major psychiatric disorder at some point in their life. The affective, or mood, disorders affect one in five people in their lifetime. The prevalence of MDD accounts for 17%, and BPD (type 1 or 2) for 4%, of the prevalence, respectively. Affective disorders are the leading cause of disability in young adults (under 45 years of age) (4). Schizophrenia is reported to occur around the world with a prevalence ranging from 1.4 to 4.6 per 1000 of the population in most groups (5). There are some notable exceptions, including the significantly elevated incidence in some immigrant groups (6) as well as the significantly decreased rates found among the Hutterites of both Dakota and Manitoba (7). The high incidence of these disorders therefore has significant implications on health, well-being and the economy; although the costs to individuals and society can be difficult to fully measure (8). It is estimated that BPD1 and schizophrenia each have annual public health costs in the tens of billions of dollars in the United States alone (9). The costs to a degree reflect the fact that management remains problematic. The reason for limited management capabilities, in part at least, is a consequence of our limited understanding of these disorders. The human genome project may offer the first novel approach to unraveling the pathoetiology of these

© 2013, Elsevier Ltd. All rights reserved.

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disorders since ancient times and as a result has generated tremendous excitement and hope (10). In order to realize the potential of genetic research, however, it is crucial to be aware of the basic assumptions that underlie these disorders and psychiatry in general, in order to avoid simplification and misinterpretation of the data.

112.2 HISTORY AND DEFINITIONS OF THE DISORDERS The primary problem facing psychiatric research and management is knowing what we are dealing with. In order to understand what psychiatric illnesses are, it is crucial to view them from a historical context, as current understanding remains deeply rooted to previous concepts. This is evident in society’s ongoing separation of the physical illnesses from the psychiatric ones, with the implication that there is something other than “physical” that underlies them. Furthermore, even within the field of psychopathology, conditions managed by psychiatrists and psychologists are defined as “disorders” or “behaviors,” with the former considered to have a biological etiology, whereas the latter are considered “volitional,” as, for example, cannabis use would be considered. Despite the recognition that there are underlying components to the behavior nonetheless, the supposition is that the behavior is secondary and, hence, once removed from the biology. Heritability estimates from modern twin studies, however, provide no evidence to support a differentiation of involuntary (disease) or voluntary (behavior), suggesting that mainstream psychiatric concepts remain detached from biology (11). With respect to the etiological theories for psychiatric disorders, it appears that hypotheses are proposed that largely fit into the cultural views of the societies then extant. Thus it has been suggested that trephining holes found in the skulls of stone age people represent treatments designed to allow an escape portal for evil spirits (12). It is perhaps not surprising that preoperational, animistic and polytheistic societies develop such views. Interestingly, however, the theme of behavioral disorders occurring as a consequence of a spiritual vector re-emerged in late medieval Christian Europe. This is well described by Christian Brandt in his Das Narrenschiff, or “ship of fools,” in which the passengers, as a consequence of their sins, were led to acts of “folly” or madness. Despite running counter to the professed free will beliefs of the society, the intelligentsia yet rationalized previous ideological systems into the framework of beliefs then current. There is no reason to believe that our society is less susceptible or that our current hypothesized etiological constructs for these disorders is less wedded to beliefs au courant than those of the past. This may be exemplified by the commonly accepted hypothesis that psychiatric disorders are largely multifactorial in origin; however, it has also been proposed that the fit is more semantic than data driven (13).

Regardless of potential cultural influences, observational descriptions of the psychopathology provide an additional layer of complexity. Focusing for the moment on schizophrenia, the current definition, according to the Diagnostic and Statistical Manual of Mental disorders 4th edition revised (DSM-IV-TR™) (14), includes the presence of at least two category A symptoms of delusions, hallucinations, disorganized speech, disorganized behavior and negative symptomatology, which includes flattened affect, alogia (poverty of speech) or avolition for at least 1 month coupled with a failure to maintain function in at least one domain of work, school, self-care or interpersonal relationships. Overall symptoms should be present for at least 6 months, although this time frame may include the presence of “prodromal” symptoms, e.g. odd beliefs or unusual perceptions. Fulfillment of these criteria defines one as having schizophrenia, whereas failure to do so may result in an alternate diagnosis. The subclassifications of paranoid, disorganized (hebephrenic), catatonic, undifferentiated and residual types of schizophrenia themselves have stated symptomatology required for diagnosis. Similarly, mood disorders involve characterized symptomatology that is required for a “scientifically” valid diagnosis. A major mood disorder is classified by DSM-IV as having an at least 2-week period of depression that is not a part of bipolar disease, an underlying medical disorder or substance abuse. Depression is characterized by anhedonia or dysphoria and symptoms that may include changes in sleep, appetite, loss of sense of selfworth, guilt and suicidal ideations. BPD may or may not have a history of a mood disorder but includes a period of mania, as demonstrated by a period with expansive, persistently elevated or irritable mood, and may include increased self-esteem, grandiosity, talkativeness, distractibility, goal-oriented activity, disinhibited potentially reckless activities and decreased need for sleep. Psychotic symptomatology may be present in both disorders. Notably, the diagnosis of bipolar disease requires a diagnosis of schizophrenia to be excluded and the diagnosis of a major depression additionally requires bipolar disease to be excluded, reflecting a close relationship between the three disorders. These diagnostic criteria are descriptive and arbitrary definitions lacking a pathological basis upon which to ground them. The field of psychiatry has been cognizant of this since the inception of these definitions and seeks to improve upon them with the DSM-V (currently anticipated for release in May of 2013). This has been in development since 1999 and is charged with expanding the scientific basis for psychiatric diagnosis. As a result, the definitions for many disorders will be changing. Schizophrenia, for example, will no longer include subtype classification. This will result in a broader overall definition of the disorder. This change in subject definition will have a knock-on effect for research, albeit the nature of this effect being unknown.

CHAPTER 112  Schizophrenia and Affective Disorders From a research perspective, however, psychiatric diagnosis, including schizophrenia and the affective disorders, have another layer of complexity. In addition to the DSM conceptualization (which is the product of the American Psychiatric Association), there coexists the International Classification of Diseases (ICD), which is supported by the World Health Organization. The ICD is a system ratified by the majority of countries in the world. While the two systems have much in common, there are differences. The ICD provides alternate diagnostic criteria for psychiatric disorders that are probably of etiological significance. For example, within the schizophrenia spectrum of disorders, DSM10 does not include schizotypal disorder like DSM, but rather places it within a personality disorder classification. In addition, individuals with medical and substance abuse specified precipitants are also not included in the schizophrenia group of disorders. At this time, it remains unclear whether these changes increase the diagnostic stringency and therefore the likelihood of finding discrete genetic factors, or exclude important groups of subjects, significantly reducing the power of population studies. The classification issue becomes further complicated by cultural attributes, which may lend differing emphasis to elements of the diagnostic criteria as applied to different populations. This is well exemplified by the differences in categorizing catatonia depending on if one is in Wales or in India (15). Regardless of this and of which criteria are used, the definitions of schizophrenia and the affective disorders remain mutable, and this will not change with the introduction of DSM-V or ICD 11, as each reflects the most recent iteration of consensus opinion rather than concrete objective diagnostic standards. This should not be viewed as a fault, given that we do not have sufficient understanding of these disorders to be both specific and sensitive. As far as currently possible, DSM-V is attempting to classify on an etiological basis (16). Lacking measurable criteria, these diseases must be described phenomenologically, but with awareness that what is defined may not represent discontinuous disorders with well-defined boundaries. As a consequence, research into psychiatric disorders, genetic or otherwise, is based on studies of perceived symptom clusterings and not necessarily discrete disorders. One way to get around the difficulties involved in comparing individuals with these arbitrary and quite likely heterogeneously derived disorders is to identify endophenotypes to use as a proxy. Endophenotypes are quantifiable traits that may be chemical, anatomical or physiological and that are reliably present in affected individuals. They are considered to be biological intermediates between the underlying pathology and symptomatology, and as such, may provide greater sensitivity for the purported underlying disorder. The applicability of the endophenotype concept in psychiatry appears legitimate, although optimal candidates are lacking (17).

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There are limitations because of sensitivity and specificity issues with currently identified endophenotypes, but they may still aid in second-level studies of candidate genes. For example, although the term neurotocism is used in some cases, MDD still lacks a well-agreed endophenotype (18). The options appear to be better for schizophrenia. Prepulse inhibition (PPI) of startle is recognized to be deficient in schizophrenics and their first-degree relatives (19). It is, however, also deficient in other situations, including drug usage, stress and fragile X syndrome (20). This lack of sensitivity limits its use diagnostically. PPI provides a measurable outcome for an experimental stimulus, e.g. the effect of candidate gene activity, particularly in animal models, and therefore can be very useful (21). Endophenotypes with higher sensitivity and specificity are being sought to improve experimental studies (22) and also to aid in improving diagnostic acumen. Interestingly, gene expression levels are themselves being postulated as endophenotypic measures in neurological research (23), although insufficient understanding means this is not yet an option with the neuropsychiatric disorders.

112.3 BIOLOGY OF THE DISORDERS 112.3.1 The Evolution of a Biological Perspective Drugs heralded the approach to understanding schizophrenia and the affective disorders from a biochemical perspective. The first modern pharmacological agent proposed for these disorders was the use of lithium as a treatment for BPD1. William Hammond of New York pioneered the use of lithium specifically for mania in 1871. This likely followed both the work of Silas Mitchell, who prescribed lithium bromide for a variety of neuropsychiatric conditions from 1870, and from observations of specific European mineral wells and American “crazy waters” used therapeutically, which include lithium in their composition (24). This role for lithium continued to be explored and used, particularly among the Danish and French, but did not start to receive mainstream attention until Cade published his case series in 1949 in Australia (25). It was not until the late 1960s, however, that American psychiatrists, well behind many others, really started using the drug. Despite this long history, our understanding of how lithium exerts this effect remains unclear. Lithium inhibits the second messenger inositol pathway involved in the release of intracellular calcium in the frontal cortex and hippocampus, among other roles (26). In addition, lithium also regulates a number of other molecules, including protein kinase 3 and glycogen synthase kinase 3 (GSK3). Both are involved in signal transduction pathways in the brain. Providing an alternate pathway and possibly reducing the relevance of the inositol pathway to bipolar disease (27). Some genetic support for an inositol role is

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suggested by the identification of the lithium-regulated protein, inositol monophosphate, in both the amoeba Dictyostelium and human cells (28). This finding may further be supported by the reported association of this gene with BPD in some families (28b,29) as well as for schizophrenia in the Japanese population (30). Despite the early pharmacological beginnings in BPD, research into the biochemical processes underlying schizophrenia and psychiatric disorders generally received their most significant stimulus with the identification of chlorpromazine as a treatment for schizophrenia. This was recognized in Europe in 1951 but not until 1954 in the United States. The lag reflected the resistance of the psychoanalytic community, which was the arbiter of American psychiatric practice and theory at that time (31); also in 1954, iproniazid, which was under trial for tuberculosis, was found to elevate mood (32). This was confirmed in follow-up studies focusing specifically on its antidepressant role (33), although the drug’s pharmacological mechanism of monoamine oxidase inhibition (MAOI) was not identified until 1963 (34). Interestingly, one of the most widely prescribed classes of drugs for depression, the tricyclic antidepressants also evolved in 1954 from the identification of the drug imipramine, a congener of chlorpromazine. Notably, all these drugs function by modulating monoamine neurotransmission. Thus, for the first time a biochemical direction from which to develop etiological clues to pathogenesis had become available for both schizophrenia and the affective disorders (35). From these beginnings, other pharmacological agents notably mood stabilizers, selective serotonin reuptake inhibitors, atypical antipsychotic agents and others have evolved. These drugs both informed and developed out of the biochemical theories underlying these disorders. Despite this evolution, our understanding of these disorders remains limited and the biological role of these drugs is in some cases questionable (36). This is in part because of the above-discussed difficulty in providing defined measurable indices of the disorders and in part because of our limited understanding of neuropharmacological processes. The biochemical pathways implicated by drugs have different effects in different parts of the brain. These brain regions are not functionally independent, but operate within an organ system in which multiple components are involved in variably integrated ways. Furthermore, while neurons themselves are stable, their connections to other neurons are not. The brain as an organ is perhaps unique in its functional plasticity, allowing it to remodel in response to its environment. Thus, there are multiple variables co-occurring and the different factors are influenced by genetic and environmental effects (GXE) (37) to a variable degree, depending on the stage of development (38). With respect to developmental influences, genetic control is generally greater early in development and it has been hypothesized that the very early in utero

environmental sensitivity may even provide an evolutionary advantage via brain response sensitizing the fetus preparatory to life ex utero (39). This fetal GXE interplay itself appears to have psychopathological effects. Stressors result in altered hypothalamic–pituitary–­ adrenal (HPA) axis functioning, and depending on the subsequent postnatal environment, may predispose toward depression, which is associated with disturbances of this axis (40). This itself may have positive competitive evolutionary advantages. Depressive elements such as fatigue would reduce energy usage in winter and times of deprivation and sadness could evoke support from the group in settings where real benefit to these emotions occurred, unlike in modern society where these are counterproductive (41). A potential confounder is, of course, a genetic predisposition to stress; however, in an elegant assay, the effects of maternal stress on in vitro fertilization (IVF) pregnancies, in which the implanted embryo was either related or not to the mother, demonstrated that maternal stress was associated with depression and anxiety, whereas ADHD was present only in the biologically related offspring, suggesting that the former had a less heritable component than the latter (42). Biochemical motifs associated with schizophrenia may also have environment-dependent benefits. The level of dopamine activity in the prefrontal cortex is closely linked to schizophrenia, as discussed later. Metabolism of dopamine occurs via catechol-o-methyl transferase (COMT). The COMT gene has different polymorphisms affecting activity. Comparison of the met158Val polymorphism appears to show that those with the Val gene have better working memory under stress but poorer at baseline (43). This may indicate that there could be a competitive advantage for carriage of putative schizophrenia risk genes under specific circumstances. Extrapolating the carrier advantage concept could, at least in part, explain the enduring incidence of the disorder in the population.

112.3.2 Biology of Schizophrenia It is important to recognize that schizophrenia is a consequence of antecedent factors that prime the individual for the disorder and the pathology necessary to precipitate and possibly maintain the disorder itself. The genetic and environmental factors that predispose an individual to develop schizophrenia are therefore not necessarily all the same as those that are involved in expressing the disorder. From an etiological perspective, there is a large body of evidence pointing to the origins of schizophrenia as a neurodevelopmental disorder (44). Many of the risk factors implicated in schizophrenia appear to relate to environmental deficits in prenatal factors. These factors were originally posited as a consequence of the WWII Dutch hunger famine. Approximately 20 years after the Nazi blockade, there was a spike in schizophrenia among

CHAPTER 112  Schizophrenia and Affective Disorders individuals who were mid-late trimester fetuses to malnourished mothers at the time (45). Investigations including the Chinese great leap forward famine and others (46) have supported this initial finding. Micronutrients have been implicated to varying degrees (47). Most evidence points to low folate in combination with elevated maternal homocysteine levels in the third trimester being associated with an increase in risk of developing schizophrenia (48). Biologically this may support the glutamate hypothesis of schizophrenia wherein hypofunction of the N-methyl-d-aspartate receptor (NMDAR) is centrally involved in schizophrenia, (49) as discussed later. Hyperhomocystinemia, which can be a consequence of folate deficiency, appears to regulate NMDAR activity, which itself regulates neural crest formation in utero (50). Iron deficiency, a very common finding in pregnancy, has also been implicated (51). This is perhaps not surprising, as some of the same nutritional deficits involved in folate deficiency would also predispose to iron deficiency. Iron is a cofactor for dopamine formation (52) as well as myelin and oligodendrocytes (53), both of which are abnormal in schizophrenia (54) and therefore there is biological plausibility. In addition, a fourfold increase in schizophrenia was seen in the offspring of Hb-deficient mothers (51) and a national Danish cohort demonstrated a dose-response of hemoglobin level to risk of schizophrenia (55). Although the cause for the anemia was not specified, iron deficiency is the most common recognized cause in pregnant women (56). There is also a large body of evidence supporting the role of prenatal infections, inflammation and immune dysfunction predisposing an individual to neural stress, culminating in schizophrenia with immunological and brain maturation (57). The relative role and possible interrelationships of each of these components remains unresolved. It is likely that our understanding will improve as the pathways continue to be worked out, although it is clear each of the hypothesized risk factors involves a GXE model and is neither genetically predetermined nor wholly a reflection of the environmental milieu. Considering the disorder itself, schizophrenia appears to involve multiple disrupted neurotransmitter circuits (58) (particularly those involving dopaminergic and glutamatergic pathways). The role of dopamine in schizophrenia is supported by multiple different approaches; thus pharmacological, neurochemical, pathological, imaging and molecular studies all support a role for dopamine dysfunction (59). Striatal D2 overactivity, secondary to presynaptic stimuli and release of excess dopamine, appears to reflect the positive symptoms of schizophrenia, specifically the psychotic elements (60); indeed, this striatal dopamine excess is not present in other disorders such as bipolar disease and major depression in the absence of psychosis. In addition, prefrontal dopamine D1 levels are decreased and may be involved in the negative symptoms, including a possible learned

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anhedonia secondary to an aberrant dopamine-related reward system, whereby received signals are miscued, resulting in blunted affect (61). Postmortem and genetic studies have yet to provide strong support for the dopamine hypothesis. Furthermore, extensive use of dopamine D2 targeted therapies only provide limited benefit to the majority of individuals for whom schizophrenia remains a chronic disabling condition. This implies a role for alternate pathways (62). Hypofunction of GABAergic interneurons in the prefrontal cortex and hippocampus of postmortem samples, as well as NMDA receptor hypofunction, particularly in the corticolimbic GABAergic tracts, is well characterized in schizophrenia and is supported by electrophysiological and pharmacological studies. Furthermore, the dissociative anesthetics ketamine and phencyclidine (PCP) can induce a psychosis indistinguishable from that seen in schizophrenia (63). Both drugs act by binding to and antagonizing the NMDAR, both in healthy volunteers and in schizophrenics in remission who experienced their previous unique positive symptomatology (64). NMDAR hypofunction appears to result in reduced GABAergic function in the regions seen in schizophrenia. Whether these are primary to the underlying pathology or supportive remains unclear, although a causative role may be implied via studies with clozapine. This atypical antipsychotic demonstrates unique efficacy in a subset of schizophrenics. Prescribing glycine and d-cycloserine with clozapine resulted in a worsening of effect. It appears that clozapine acts at the glycine modulatory NMDAR agonist site, causing these other coagonist agents to become, in effect, antagonistic in behavior, further implicating a direct role for the NMDAR in the schizophrenia phenotype (65). Whether the dopaminergic or glutamatergic pathways are primary may be irrelevant, as both appear to be disrupted in schizophrenia. Therapeutic targets and candidate genes have been found in both pathways, as will be discussed later.

112.3.3 Biology of Affective Disorders As mentioned earlier, disruption of the HPA axis may be a risk factor predisposing to depression. In general, however, major depression appears to be the result of a confluence of environmental and intrinsic factors interacting dynamically with altered receptive pathways and subsequent memory retrieval in response to stimuli (66). Low neuropeptide Y levels have been associated with depression, possibly via a role in decreasing activity of hypocretin, a peptide involved in arousal and appetite in the hypothalamus (67). Being female is a well-described risk factor for depression (68); while there may also be a sexual disparity in schizophrenia with a slight preponderance toward males it is less pronounced (69) and also does not appear to be as relevant to BPD (70). The explanation for this sexual disparity is thought to be an admixture of psychosocial

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environmental causes coupled with hormonal and immunological differences, possibly interfacing with the HPA axis (71). Medical disorders such as hypothyroidism, Cushing syndrome, cancers, Parkinson disease and dopamine deficiency are risk factors for depression (72). Some of these disorders clearly interact with the HPA, which appears to be dysfunctional in depression (73). This is not the only region affected by depression, however. Reductions in gray matter in the hippocampus and cortex are seen in postmortem samples, as are deep white matter hyperintensities (74), whereas activation in the amygdala is associated with dysphoria (75). Connections between forebrain regions are modulated by monoamines, the compounds targeted by the early drugs. Depletion of monoamines is insufficient to induce depression and the rapid rise secondary to treatment does not remit symptoms (76). While depression appears to have less of a genetic component than schizophrenia and less of a relationship than BPD, there are overlapping links; thus use of ketamine, an NMDAR antagonist, can reverse depressive symptoms (77). In addition, the role of peripheral molecules such as grehlin, neuropeptide Y, melanocyte stimulating hormone, and other compounds associated with arousal and activity states such as appetite remain unclear (78).

112.3.4 Biology of Bipolar Disorder A comprehensive pathoetiological model for BPD is still lacking, despite treatments that are often effective. Excess dopamine appears to play a central role in symptomatology (79). It is recognized that psychostimulants such as amphetamine elevate dopamine and lead to effects very similar to mania, even in normal subjects with elevations in mood, with increased drive and less need for sleep via increasing synaptic dopamine (80), although in bipolar patients it appears that postsynaptic sensitivity, possibly via increased dopamine transporter levels, is increased rather than dopamine levels themselves (81). Reduction in dopamine production via tyrosine-free diets attenuates this effect and improves the symptoms in manic patients (82). Dopamine’s action at the mesocorticol pathway appears to increase impulsivity and reward-seeking behavior, possibly regulated by the DRD2 gene (83). As mentioned earlier, dopamine may also play a role in the biology of depression (dopamine may be central to the depression of Parkinson disease and dopamine agonists can improve the depression in these patients) (84). Alleviation of depression in BPD2 patients with dopamine agonist pramipexole appears to be via dopaminergic agonist activity in the prefrontal cortex (85). Indeed, it has been suggested that the primary difference between BPD1 and schizophrenia is not that they are different disorders but rather that schizophrenia reflects additional developmental disorders (86). Both share many of the same risk factors and significant overlap in symptomatology, along with MDD, as well

as coaggregation between these disorders within families (87) that is suggested most likely to reflect shared genetics (88).

112.4 EVIDENCE SUPPORTING A GENETIC COMPONENT 112.4.1 Heritability Perhaps the first to quantify heritability in psychopathology was Jenny Koller, who in 1895 compared psychiatric symptoms in family members of affected individuals and unaffected controls and noted that the hereditary loading was highest for psychosis (5). Comparing family members for pathological traits is, not surprisingly, a pursuit that has taken place throughout civilization. Twin studies in particular have occurred since at least the time of Hippocrates. It was not until the first decade of the twentieth century that the potential of monozygotic and dizygotic twins to separate out environmental from genetic factors was realized by Wilhelm Weinberg (89). As a consequence of numerous twin and family studies, the heritability of these disorders has resolved, demonstrating a differential between the disorders. Depression appears to have a heritability around 37–50%, with a two- to four fold increased risk of developing MDD overall in first-degree relatives compared to the general population. This figure rises to up to an eight-fold increase for recurrent early-onset depression (90). Nonetheless, depression appears to be about half as heritable as bipolar disease, with heritability rates for BPD reported to range from 60 to 93% (88b,91), with concordance in monozygotic twins for BPD estimated at 0.67 as compared to 0.1 for dizygotic twins and first-degree relatives (9a,90c). Schizophrenia, similarly to BPD, appears to have a heritability of over 80% (92). Overall it is clear that there is a significant heritable component for each of these disorders, but particularly BPD1 and schizophrenia. This has raised hopes that specific genes could be identified. It has proved to be more of a challenge than was anticipated, however, and the early linkage and population studies have evolved into more sophisticated and powerful genome-wide association studies (GWAS).

112.4.2 Molecular Studies 112.4.2.1 Affective Disorders.  Linkage for MDD has been suggested for various chromosomal regions, including 15q25-26, 17p12 and 8p22-21.3 (93). Linkage studies led to a possible association for the NTRK3 gene in the 15q25-26 region (94). In addition, the 2q3335 locus was raised as a possible candidate region for women with severe depression, possibly associated with the CREB gene, which interacts with estrogen receptors (95). Most recently, regions within chromosomes 2 and 17, as well as further support for the chromosome 8

CHAPTER 112  Schizophrenia and Affective Disorders locus, have been raised as having a possible association (96). Unfortunately, replication of these results has been challenging, with little support for any specific region(s) (97). The disappointment has, however, been tempered by the advent of GWAS, offering a variety of approaches to provide denser coverage of the genome. As a consequence, an increasing number of candidate genes and loci of interest have been identified. The initial meta-analysis of GWAS studies for depression identified the strongest association for APOE (apolipoprotein E), with lesser associations for variants in GNB3 (guanine nucleotide-binding protein, beta 3), MTHFR (methylene tetrahydrafolate reductase), and SLC6A4 (serotonin transporter) (98). GWAS findings also raised an association with GRM7 (metabotropic glutamate receptor 7) as well as associations with intronic markers suggested for ATP6V1B2, GRM7, and SP4. The ATP6V1B2 locus is also potentially associated with BPD (99), which is also associated with ATP6V1G1, a gene that contributes to the same molecular complex. A further GWAS association with mood disorder and GRM7 (18) noted earlier is interesting, as GRM7 is a group III metabotropic glutamatergic receptor, possibly interacting with antidepressants (100). A number of studies have suggested an association of this molecule with BPD as well as MDD (101). In addition to the GWAS polymorphism association, there also appears to be a link involving GRM7 and BPD within copy number variants (CNVs) (102). CNVs are deletions or gains (from duplications to multiple repeats of a given sequence) that are currently testable to a resolution as small as 1 kilobase pair (kb) in size. They may include one or more genes potentially altering gene dosage. In addition, they may disrupt gene function directly by bisecting a gene, creating novel fusion products and/or affecting regulatory elements. In depression, duplication at 5q35.1 is the first GWAS CNV variant identified for MDD. This locus includes three genes, including SLIT3, a potentially promising functional candidate, as it is involved in axon development (103). Other CNV regions of interest in affective disorders include the 3p21.1 locus. This has emerged in a number of studies to be associated with mood disorders including BPD (104,105). With respect to BPD an increased frequency of the 3q13.3 duplication CNV has been reported. This appears to disrupt the 3′ coding region of GSK3β (106), a bipolar candidate gene involved in the Wnt signaling pathway and sensitive to lithium, although, as is typical in the field, studies conflict on the significance of any association (107). Linkage analysis for BPD, like MDD, has raised candidates that are not consistently replicated. Furthermore, the data are often confounded by the variable inclusion of the broader spectrum of affective disorders of BPD1, BPD2, and sometimes MDD altogether. Nonetheless, meta-analysis of 11 linkage studies implicated susceptibility loci on 6q and 8q for BPD (108).

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GWAS studies have also implicated a greater number of genes for BPD than for MDD. Diacylglycerol kinase, a protein involved in the phosphatidyl inositol pathway that is targeted by lithium, has been associated (109). Similarly, the CACNA1C gene has been implicated in BPD (99,110), as have C15Orf53, ANK3 and SLITRK2. GWAS studies appear to have demonstrated a differential between Americans of European or African ancestry (111). The ANK finding as well as other candidate regions has also been demonstrated in GWAS SNP analysis of both Europeans and Han Chinese (104b,112). While these studies have limitations, they offer the possibility of identifying potential candidate genes. For example, ANK3 is a protein responsible for regulating sodium channel-dependent action potentials and may impact cognitive attentional processing, which in turn may have relevance to BPD (113). Subsequent candidate ANK3 SNP analysis for polymorphic susceptibility to BPD is further supported by studies in different European and Asian populations (114). Similarly, CACN1A1 gene polymorphisms were found to be associated with anatomical and functional brain changes congruent with BPD, as well as in schizophrenic patients, and appeared to segregate to BPD patients and schizophrenics in further studies (115). Even when there appears to be biological plausibility and other investigations such as animal studies coupled with GWAS SNP assays are suggestive of a relationship, there remains lack of clarity. For example, GRM7, Homer1 and the 2p16.1-15 region have been proposed as relevant candidates for MDD but meta-analyses have not supported the data (18,116). In an attempt to better assess candidate genes, those strongly associated with mood disorders (BDNF, NTRK2, SLC6A4, TPH2, P2RX7, DAOA, COMT, DISC1, and MAOA) as identified from multiple studies (117) were sequenced from three separate population cohorts to determine if variants cosegregated with mood disorders. Only P2RX7 appeared to associate with both BPD and MDD, although the common alleles of SLC6A4 (also known as HTTPLR, the serotonin transporter linked polymorphic region) appeared to have an association with mood disorders (117). Further data are required to validate this study and the many others implicating these and other genes. 112.4.2.2 Schizophrenia.  Over 4000 articles have been written on the role of genes in schizophrenia. This is twice as many as for BPD and perhaps reflects the intense interest and high expectation from this field. Indeed, the field is so active that a gene database on the Schizophrenia Research Forum (http://www.schizophreniaforum. org) provides systematic and regularly updated metaanalysis of genetic association studies as well as candidate genes to assist interested parties in keeping abreast of the studies. Candidates for schizophrenia appear to have been less elusive, although work is still required to determine

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if there are unifying biochemical pathways involved in all cases. Individuals with schizophrenia appear to have an increased number of CNVs relative to both the general population and bipolar patients (118,119). Many CNVs appear to be de novo and occur at a six fold higher frequency compared to unaffected individuals (120). Deletions and duplications in various regions have been reported from large-scale GWAS and implicated in numerous studies across ethnicities, including 1q21.1, 15q13.3, 15q11.2, 22q11.21 as well as exondisrupting deletions in the NRXN1 gene. In addition, duplications in 16p11.2, dup16p13.1 and 17q12 have also been reported (121). Many of these changes have also been associated with other neurodevelopmental disorders. Apart from NRXN1, these regions contain numerous genes, including potential candidates, such as BCL9 in the 1q21.1 region (122), but further studies are required to conclusively determine relevance. In addition, although the odds ratios were relatively high and the data have been replicated in a number of studies, the majority of individuals with schizophrenia did not possess these changes. Characterized CNVs are present in only 3% of individuals (123). This raises the possibility that a relatively small number of genes may carry higher risk for schizophrenia in a subset of affected individuals, supportive of the “common disease, rare variant” model. Alternatively, a proportion of these CNVs may not exert a profound role. Determining the significance of a CNV involves assessing the biological plausibility of the CNV against the clinical phenotype (124). One small study of 3 monozygotic twins discordant for schizophrenia did not identify CNV variation between them (125). Although this is not surprising, given both the very small scale of the study and the monozygosity, it does raise an interesting perspective on analyzing very early somatic mutations as a source for variability (126). This applies to CNVs, which can differ in monozygotic twins with phenotypic variability (127), and, together with genomic sequencing techniques, offers the potential benefit of identifying candidate gene differences in otherwise relatively homogenous backgrounds. This approach could potentially return monozygotic twin studies to the center of genetic research. 112.4.2.3 Candidate Schizophrenia Genes.  As implied earlier, multiple gene candidates are proposed and over 1000 genes have been studied in connection with schizophrenia-related biology; however, evidence remains limited and only a proportion of these genes are currently of high interest. Among the many genes under active investigation a small number deserve mention on the basis of possessing both biological plausibility and genetic survey candidacy. COMT, also a BPD candidate gene (128), is of particular interest in schizophrenia given its central role in the enzymatic degradation of catecholamines including dopamine (129), a key hypothesized molecule in

the etiology and symptoms of schizophrenia. COMT, together with proline dehydrogenase (PRODH), is haploinsufficient in 22q11.2 deletion syndrome (also known as velocardiofacial syndrome (VCFS)), a genetic disorder with a 25% incidence of schizophrenia (130). Furthermore, genetic polymorphisms in COMT and PRODH are associated with morphological changes found in schizophrenic brains (131), as well as in affected individuals (132). Conflicting results of relevance with hypofunctioning alleles, specifically the COMT Val158 Met alleles (133), have confounded interpretation. More recent analysis, however, suggests that the effect of the COMT allele is epistatically regulated, and thus the genetic milieu may ameliorate potential effects (134). With respect to PRODH, this gene itself also merits serious consideration. PRODH polymorphism has been linked to schizophrenics independently (135). Key to the metabolism of proline to glutamate, haploinsufficiency potentially impacts NMDAR activation. Polymorphisms, as well as haploinsufficiency, have been associated with schizophrenics (136). Neuregulin (NRG1) and its receptor ErbB4 are candidate susceptibility genes for schizophrenia and appear to stimulate synaptic connectivity of GABAergic interneurons (137). Furthermore, another major candidate gene for schizophrenia appears to be intimately involved with both NRG1 and ErbB4. This protein, the NR2 subunit of NMDAR is centrally involved in the development of negative as well as positive symptoms of schizophrenia. The NR2 subunit appears to share a common anchoring domain with ErbB4, with perturbations of NRG1 and the subunit potentially impacting the function of each other (138). The identification of a chromosomal translocation that segregated with schizophrenia and related disorders in 2000 (139) created enormous excitement. This was particularly because the translocation disrupted a gene subsequently named DISC1, disrupted in schizophrenia 1. In the intervening time, further evidence of an association has evolved (140), although with it, the usual negative associations (141). It has also become clear that DISC1 is not specific to this group of disorders but rather appears to be involved in neurodevelopmental processes through inhibition of GSK3β activity of the Wnt1 pathway involved in cortical neurogenesis (142). It would appear that DISC1 may be involved in the developmental predisposition, rather than concurrent pathology of schizophrenia.

112.4.3 Overview of the Genetic Data Although numerous candidate genes of interest have been identified for all three disorders, of the 50–90% heritability identified for these psychiatric disorders, less than 2% appears to be attributable to the identified candidate genes. It has been suggested that epigenetic and post-transcriptional modifications may account for some of this unexpected discrepancy (143), but to what degree

CHAPTER 112  Schizophrenia and Affective Disorders remains to be determined. The data available nonetheless provides useful directions for research but is of limited applicability to practice.

112.5 ROLE OF GENETICS IN CLINICAL PRACTICE 112.5.1 Genetic Counseling Affected individuals and family members are concerned about the risk of inheriting or passing on affective dis­ orders or schizophrenia. Perceptions about just how likely this is vary widely across the population. Studies suggest that people both overestimate and underestimate risk (144). While providing definitive risk figures is difficult, there is benefit in tackling family perceptions on the disease etiology, as they are often misinformed. Although people consider both genetic and environmental factors to be involved, there is often a significant sense of guilt and shame as well as blame. It appears that there is not generally strong conviction in the held views. Indeed, the counseling is of interest particularly with respect to obtaining an etiological understanding more than for the recurrence risk itself. The exception appears to be if the clients have children themselves, and even in this instance, this appears to be in hopes of being able to identify possible ameliorating factors (144). Counseling not only allows for a clarified perception but itself can provide a therapeutic effect for patient and family (145). Just as psychiatric illness carries stigma so too does genetic illness. Concern that a genetic discussion implies that the disorder is inevitable and untreatable, and may result in discrimination to the individual and their family, may need to be addressed before the counseling can take place (146). It is essential to provide accurate information, and while genetic counselors, who are the experts in providing counseling, are generally unfamiliar and uncomfortable with psychiatric issues, psychiatrists, to date generally appear to be unprepared with sufficient knowledge of genetics to provide this service (147). Risk figures are themselves challenging to provide, as these depend on the individual circumstances. Empiric data are available (148), and provides a starting point from which specific risk figures can be extrapolated. These figures are influenced by the number of family members who are affected, age of onset of affected family members, relative number of females or males who are affected, and presence of a disorder such as deletion 22q11 syndrome in the family (148b). A careful individualized risk determination taking the various factors into account may give quite different risk to the patients/ clients seeking this information. Given the potential disparity in risk figures, it is recommended that this be provided through a genetic counselor determining risk from the starting point of the a priori risk and working from there (149).

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Another area where genetic counseling/analysis may be helpful is in pharmacogenetics. The identification and characterization of drug metabolizing alleles provides an opportunity to better determine appropriate dosing and indeed choice of drug(s) for an individual, based on their specific situation and their predicted response. Numerous CLIA (Clinical Laboratory Improvement Amendments) certified laboratories are offering this testing on a limited basis. The most experience right now for relevant pharmacogenetic testing is the cytochrome P450 enzyme system, which is central to the metabolism of many antidepressants (150). The role for pharmacogenetics is rapidly expanding and it is likely that care will improve significantly for both the affective disorders and schizophrenia as the relevance and utility of pharmacogenomic screening is realized.

112.6 SUMMARY Family and twin studies have demonstrated a genetic basis for schizophrenia and the affective disorders. Application of the human genome project has generally been disappointing, perhaps more so for these disorders (and the rest of the psychiatric field) than any other area in medicine. While this may support the notion that psychiatric disease and possibly with it, the psyche, is unique and not subject to the same rules as the rest of biology, it is too early to make such pronouncements. Limited data appear to be emerging. Evidence for candidate genes is increasing, raising the possibility that, while no one gene or group of genes will likely dominate the risk for schizophrenia or the affective disorders, the roles of the many candidates will clarify the pathways involved in these disorders. The ability to determine the steps necessary to develop the disorders will provide further therapeutic targets that may be of direct relevance to individuals for whom the genetic evidence is scant but who nonetheless may be predicted to have unidentified perturbations in pathways, or in whom consolidation of pathways may help counter undefined defects. Thus, it may not be necessary to have a comprehensive explanation for a disorder that potentially has as many paths to symptomology as there are individuals affected by the disorders. The identification of themes rather than specifics may be sufficient to improve treatment. The inability to develop a comprehensive genetic overview also forces us to question our understanding of the relationship of the genome to cellular function in the brain. This is already starting to evolve into a search for new etiological frameworks that may ultimately help us to understand brain function at a new level. It may be that the current challenges in preventing a simplified mechanistic theory from evolving is ultimately fortunate.

CROSS REFERENCES Medicine in a Genetic Context; Twins and Twinning; Pharmacogenetics and Pharmacogenomics; Genetics Counseling and Clinical Risk Assessment.

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FURTHER READING AND OTHER SECTIONS REFER TO PPMG ARTICLE TEMPLATE DOC

American Psychiatric Association. Diagnostic Criteria from DSMIV-TR. Washington, DC, 2000. World Health Organization The ICD-10 Classification of Mental and Behavioral Disorders; Diagnostic Criteria for Research; WHO: Geneva, 2007. Faraone, S. V.; Tsuang, M. T.; Tsuang, D. Genetics of Mental Disorders: A Guide for Students, Clinicians and Researchers; Guilford press: New York, 1999. Finn, C. T.; Smoller, J. W. Genetic Counseling in Psychiatry. Harv. Rev. Psychiatry 2006, 14 (2), 109–121.

American Psychiatric Association. American Psychiatric Association Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders; DSM-IV-TR. Washington, DC, 2000.

Biography



J onathan Picker is a geneticist focused on the interface between genetics and psychiatry, particularly from a developmental perspective. Following medical school in Aberdeen, Scotland he pursued behaviorally oriented pediatrics training in Newcastle upon Tyne, England. While at Newcastle University he also carried out Masters in Biochemistry and Genetics followed by a PhD in the Faculty of Agriculture investigating molecular regulatory mechanisms. This was followed by further training in clinical genetics and child and adolescent psychiatry at the Boston Children’s Hospital (BCH), where he has remained since. At BCH his clinical work has specialized in the genetics underlying behavioral problems, primarily in children. As a part of this interest he founded and currently directs the BCH Fragile X Program. He is currently developing a detailed phenotyping registry with a view toward integrating this with translational genetic research endeavors. In addition, from a basic science perspective, he has been working with Joseph Coyle at McLean Hospital investigating epigenetic developmental risk factors for schizophrenia.