Risk and Protective Factors for the Onset of Mental Disorders
During the past 30 years a growing body of research has elucidated some of the risk factors that predispose children and adults to mental disorder. Recent research has also helped to change the concept of a risk factor from a fixed, specific circumstance or life stress to a broader, more general phenomenon that may be modifiable, or malleable, and related to a developmental phase (Avison, 1992). These findings have led to a shift in risk factor research in both emphasis and complexity.
Risk factors are those characteristics, variables, or hazards that, if present for a given individual, make it more likely that this individual, rather than someone selected at random from the general population, will develop a disorder (Werner and Smith, 1992; Garmezy, 1983). To qualify as a risk factor, therefore, a variable must be associated with an increased probability of disorder and must antedate the onset of disorder. Variables that may be risk factors at one life stage may or may not put an individual at risk at a later stage of development. Risk factors can reside with the individual or within the family, community, or institutions that surround the individual. They can be biological or psychosocial in nature. Some risk factors play a causal role, although this may not be known prior to an intervention study. Others merely mark or identify the potential for a disorder rather than cause the disorder, and for these, therefore, malleability is not an issue. For example, unusual eye movement is often associated with and predates schizophrenia. Its presence increases the likelihood that an individual will develop schizophrenia, but any efforts to alter such eye movements
would be fruitless-for preventing schizophrenia because it is not thought to have a causal role. The committee uses the term marker for both biological and psychosocial risk factors of this sort. Incorporated into this definition of risk factor is the concept of vulnerability, which is a predisposition to a specific disease process. Vulnerability traits are identifiable and measurable (and may sometimes be referred to as markers). They are not intrinsically the disease, but they may be necessary for a specific mental disorder to develop. Having vulnerability traits may increase an individual's risk for developing a disorder, but other risk factors also may be necessary for the illness to be expressed.
For years, mental health workers devoted their energies to the study of maladaptation and incompetence (Garmezy, 1983) as attempts were made to identify patterns of functioning in childhood that might portend the future development of mental disorders. Rutter (1985b) described this preoccupation as a “regrettable tendency to focus gloomily on the ills of mankind and all that can and does go wrong. ” But not everyone with risk factors goes on to develop a mental disorder, and the importance of protective factors is becoming more recognized. Recently, research has been directed toward understanding why some children appear to be resilient, and why they come to maturity relatively unscathed by the organic and psychosocial insults that prevent so many of their peers from achieving optimal intellectual, social, and emotional functioning (Werner and Smith, 1992). Werner and Smith (1992) defined resilience as “an unusual or marked capacity to recover from or successfully cope with significant stresses, of both internal and external origin.” Theoretical explanations for the phenomenon of resilience (Rutter, 1985b; Garmezy, 1983) involve the interaction of risk factors, including individual vulnerability, and protective factors to explain why some are spared and others are not. Vulnerable individuals are considered to be those who, by virtue of genetic predisposition, chronic illness, hardship, deprivation, or abuse, are more susceptible to life stressors than others. Thus “they are at risk for failure to master, mature and adapt” (O'Grady and Metz, 1987). Rutter (1985b) defined protective factors as “those factors that modify, ameliorate or alter a person's response to some environmental hazard that predisposes to a maladaptive outcome.” Protective factors seemingly function in a catalytic fashion. They do not necessarily foster normal development in the absence of risk factors, but they may make an appreciable difference on the influence exerted by risk factors. Protective factors also can reside with the individual or the family, community, or institutions and can be biological or psychosocial in nature.
Reviews of community surveys and longitudinal epidemiological studies have emphasized that each mental disorder is likely to have multiple risk factors (Hawkins, Catalano, and Miller, 1992; Werner and Smith, 1992; Offord, Boyle, and Racine, 1989; Rutter, 1989; Offord, Boyle, Szatmari, Rae Grant, Links, Cadman et al., 1987). Thus, in order to look for possible opportunities for intervention, it is necessary to identify as many risk and protective factors that impinge on individuals at different stages of development as possible. The process of critically examining risk factor research on mental disorders is part of the foundation for preventive interventions. Not all evidence from risk research is conclusive enough to warrant the design of a preventive intervention. Even where the evidence is strong, it is still worth seeking other potential markers and causal risk factors because targeting multiple risks may increase the success of a preventive intervention program.
This chapter examines the factors that current research indicates may potentially operate to predispose or protect against the occurrence of mental disorders. The examination proceeds first within a categorical framework organized around the five major mental disorders that are used as illustrations throughout this report—Alzheimer's disease, schizophrenia, alcohol abuse and dependence, depressive disorders, and conduct disorder. Because these are disorders in which the relative potential contribution of biological risk factors (including genetic vulnerability) and psychosocial risk factors (including individual, family, and community issues) varies greatly, as a group they provide an opportunity for a review of a wide range of diverse risk factors and the interplay among them. The discussion then moves away from a focus on specific disorders to a broad view of general risk and protective factors that are common to many disorders and dysfunctional states. The sequence of the disorders has been reversed in this chapter and emphasizes the range of risk factors along a continuum from heavily biological to heavily psychosocial.
Studies of epidemiology, biochemistry, pathology, and genetics have uncovered several biological risk factors related to Alzheimer's disease (AD), and there is limited evidence for the role of some psychosocial factors, particularly level of education. This section reviews knowledge about biological and psychosocial risk and protective factors for Alzheimer's disease and then discusses their implications for research and for prevention.
Biological Risk Factors
Over the past decade, evidence that genetic factors play a major role in vulnerability to AD has accumulated. In a distinct minority of cases, AD begins early, in the fourth or fifth decade, rather than the more typical onset after age 70 or 75. This early onset, “presenile” form often clusters in families in a pattern consistent with inheritance of a single gene of major effect. (The pattern is most consistent with “autosomal dominant” inheritance, whereby 50 percent of the children of an affected parent are expected to inherit such a gene and develop the disease.) Breitner and colleagues have raised the question whether the absence of a familial pattern in the senile form of AD may be an artifact of “bias of ascertainment” (Breitner, Folstein, and Murphy, 1986a; Breitner, Murphy, and Folstein, 1986b). Because many first-degree relatives may have died of other causes before living through the period of risk, their loss leads to underestimates of the number who actually carry the gene. Using AD patients identified in nursing homes, Breitner and colleagues attempted to estimate the true prevalence among first-degree relatives (siblings and children) by taking a careful family history in a subpopulation marked by language disorders. If family history was ruled out only for cases in which both parents lived to at least age 85, they found that the risk for AD in first-degree relatives of AD patients approached 50 percent, consistent with autosomal dominant inheritance, even in cases of late onset (Breitner et al., 1986a; Breitner et al., 1986b). European case-control studies, however, showed that although family history was an important risk factor, it did not account for all cases (van Duijn, Clayton, Chandra, Fratiglioni, Graves, Heyman et al., 1991).
It is clear that there are several genetic forms of AD, but it is also clear that there are cases of “sporadic” AD that are not inherited. The relative prevalence of genetic and sporadic forms is subject to considerable debate among investigators. Investigators have turned to genetic studies, not only to identify the molecular events underlying AD, but also to ascertain the importance of environmental factors more precisely.
Twin Studies. Twin studies could theoretically be particularly useful in sorting among genetic and nongenetic contributions to the genesis of AD (Murphy and Breitner, 1992). One case report describes identical twins, only one of whom developed AD over a 20-year follow-up period (Renvoize, Mindham, Stewart, McDonald, and Wallace, 1986). This case
of apparent twin discordance must be interpreted with some caution, however, as previous reports of discordance have proved to be premature. In one pair of identical twins initially reported as discordant, the second twin developed AD 13 to 15 years after her twin sister (Cook, Schneck, and Clark, 1981). AD in both twins could be a mere coincidence, or it could reflect factors that caused the age of onset to differ by more than a decade despite a genetic predisposition to AD. In surveys of twin studies, the age of onset may differ by as much as a decade between identical twins (Li, Silverman, and Mohs, 1991; Breitner, Murphy, Folstein, and Magruder-Habib, 1990; Nee, Eldridge, Sunderland, Thomas, Katz, Thompson et al., 1987). Because identical twins share their genes, if both do not develop AD, this is strong evidence of nongenetic factors.
At the very least, when the age of onset is different for a pair of identical twins, it indicates that environmental factors influence when symptoms begin, suggesting that prevention might work by delaying onset. In one twin study, for example, investigators found that symptoms of dementia began later among female than male twin pairs, an intriguing finding that merits further inquiry (Nee et al., 1987). The differing ages of onset between a pair of identical twins imply that even genetic factors underlying AD may be malleable to environmental interventions. Breitner notes that delaying onset of AD by only five years would reduce its clinical impact by half, because onset is typically delayed until late in life (Breitner, 1991). If the disease began five years later, many individuals would die before showing symptoms. Finding strategies to delay onset is thus a primary focus of epidemiological and other biomedical research.
Twin studies to date have been hampered by a bias, because the twins studied are likely to have volunteered. A more reliable population-based study that should not suffer from this flaw is under way, using a twin registry of U.S. veterans. This data set includes a heavy predominance of males, and clinical data are incomplete. This study cannot verify the preliminary finding that age of onset differs between the sexes, but its analysis should nonetheless illuminate the importance of many other nongenetic factors among identical and fraternal twins (Breitner, Welsh, Magruder-Habib, Churchill, Robinette, Folstein et al., 1990).
Studies of Down's Syndrome. Down's syndrome (DS), the most common genetically identified cause of mental retardation, has provided another line of evidence supporting genetic factors in the risk for AD (Coyle, Oster-Granite, and Gearhart, 1986). DS, or trisomy 21, results from having three copies, instead of the normal two, of all or part of
chromosome 21, especially the distal end of its long arm. Thus DS does not result from “mutant genes” but rather from the altered gene expression from an abnormal gene copy number. Post mortem studies indicate that virtually all DS individuals develop the neuropathology of AD by the time they reach their fourth decade. The distribution and density of the pathological stigmata in DS brains are indistinguishable from AD. Furthermore, the DS brains with AD exhibit the same selective vulnerability of nerve cell populations. Nevertheless, some older DS individuals do not exhibit the cognitive deterioration expected on the basis of the microscopic findings in brain tissue, and thus do not fulfill the standard criteria for “dementia,” which by definition entails cognitive decline.
Molecular Studies of Amyloid. Recent molecular biological studies have begun to shed light on the cellular processes leading to AD pathology by focusing upon amyloid (Mueller-Hill and Beyreuther, 1989). Amyloid in the senile plaque is an obvious target for analysis, because the density of senile plaques correlates both with cognitive impairment and with biochemical deficits in AD. Amyloid has been purified to homogeneity from the brains of individuals with AD or DS/AD, demonstrating that it is a peptide of approximately 42 amino acids. From the sequence of amino acids in amyloid, it is possible through molecular biological methods to clone the gene that contains the amyloid sequence. These studies demonstrate that amyloid is a breakdown by-product of a much larger protein (designated amyloid precursor protein, or APP) that is normally expressed on the surface of many cells in the body, but especially nerve cells in the brain's cerebral cortex. The gene encoding the APP protein is located on the long arm of chromosome 21 and can be processed inside cells into at least four proteins of varying length.
A critical question concerns the mechanisms that favor a breakdown pathway for APP that generates amyloid (Hardy and Higgins, 1992). In the case of DS, the three copies of the APP gene, due to its presence on chromosome 21, could result in a marked overexpression of APP in brain. As a consequence, amyloid might accumulate in the DS brain much more rapidly than normal. In AD, an aberrant enzyme that degrades or modifies APP and its metabolites could play a role. There are many possible explanations for how amyloid deposition relates to disease, and this will be a main target for AD research in coming years.
Preclinical studies suggest that aberrant addition of phosphate groups to the APP protein favors a metabolic route that generates amyloid instead of protein cleavage. One strategy for prevention focuses on delaying the degradation of APP. If amyloid accumulation is indeed a
cause of cell death, then slowing its accumulation could delay this, and presumably also the onset of clinical dementia.
Genetic Mutations. An obvious possible cause of abnormal disposition of APP is an alteration of the DNA constituting its gene—a mutation. Indeed, several families with autosomal dominant forms of presenile AD have been shown to have just such a mutation, localized to a specific position (codon 717) of the APP gene (Goate, Chartier-Harlin, Mullan, Brown, Crawford, Fidani et al., 1991). In other cases, a different mutation, at codon 670/671, has been found in the same gene, again associated with AD (Mullan, Crawford, Axelman, Houlden, Lilius, Winblad, and Lannfelt, 1992). Another mutation complex, affecting codons 713 and 715, was found in a 64-year-old woman with AD, but also in her 88-year-old mother and four siblings, all of whom were older than 62 and clinically unaffected (Carter, Desmarais, Bellis, Campion, Clerget-Darpoux, Brice et al., 1992). The significance of this double mutation is thus unclear, and it may represent a mere coincidence. Mutations in the APP account for only a very small percentage of early-onset familial AD cases, although they strongly suggest that the APP gene can be functionally related to AD in these few cases. This seems likely to prove but the first of many molecular aberrations that can lead to AD.
Genetic Heterogeneity. There appear to be multiple genes that can cause AD in different families. The first report of linkage between AD and DNA markers appeared in 1987, implicating a region on chromosome 21, and was later confirmed by other groups (St. George-Hyslop, Haines, Farrer, Polinsky, Van Broeckhoven and Goate, 1990; St. George-Hyslop, Tanzi, Polinsky, Haines, Nee, Watkins et al., 1987). In addition to the very small fraction of familial cases associated with a mutation of the gene encoding the APP protein on chromosome 21 (Schellenberg, Anderson, O'dahl, Wisjman, Sadovnick, Ball et al., 1991), there is also evidence of a gene elsewhere on the same chromosome (Goate, Haynes, Owen, Farrall, James, Lai et al., 1989; St. George-Hyslop et al., 1987). Most of the evidence for another chromosome 21 gene, however, comes from a large Italian family that shows even stronger evidence of a gene on chromosome 14. A second chromosome 21 AD gene, in addition to the APP gene, is thus possible but by no means certain. A second gene on chromosome 21 may also modify the action of the APP gene or another gene, and hence show genetic linkage.
It was already clear in 1988 that the molecular defect among several different families with an inherited form of AD resided on sites other
than chromosome 21 (Schellenberg, Bird, Wijsman, Moore, Boehnke, Bryant et al., 1988). Since that time, evidence has accumulated for another possible gene on chromosome 19 in a few families (Corder, Saunders, Strittmater, Schmechel, Gaskell, Small et al., 1993; Pericak-Vance, Bebout, Gaskell, Yamaoka, Hung, Alberts, and Walker, 1991), and a more common gene defect, perhaps accounting for most families with early onset, on chromosome 14 (Mullan, Houlden, Windelspecht, Fidani, Lombardi, Diaz et al., 1992; St. George-Hyslop, Haines, Rogaev, Mortilla, Vaula, Pericak-Vance et al., 1992; Van Broeckhoven, Backhovens, Cruts, DeWinter, Bruyland, Cras, and Martin, 1992). A few large families, called the Volga Germans for their common pattern of ethnic migration from Germany to Russia and thence to the United States early in this century, also have an inherited form of AD. In the Volga German families, the inheritance pattern is not consistent with any of the chromosomal locations associated with other families. This suggests one or more as yet undiscovered genes associated with AD or a mixture of genes on different chromosomes in the same family.
Continuing Investigation. Viewed in aggregate, these studies indicate that AD is a common disorder with genetic heterogeneity, meaning that several genetic defects can cause a clinically and neuropathologically similar syndrome. AD can result from mutation in the APP gene, may possibly follow from overexpression of APP due to gene triplication (DS), and clearly can also be caused by mutations elsewhere in the human genome. AD may develop from one or more genes on chromosome 21 (the APP gene and perhaps one other), a gene on chromosome 14, perhaps another on chromosome 19, and one or more genes among the Volga German families. Because of the complexity of APP metabolism, there is reason to expect that mutations of genes encoding for enzymes that process amyloid protein could cause an accelerated rate of accumulation of amyloid, leading to AD. The clinical and pathological features of AD may also appear in response to entirely different biochemical defects not yet discovered. Those studying familial forms of AD hope to identify and isolate specific gene defects, which would lead to the protein those genes encode, and to possible clues about the causes of Alzheimer 's disease.
The common conception that genetic disorders are resistant to intervention has proved untrue in many disorders. There are dietary treatments for phenylketonuria, and many genetic disorders require an environmental trigger. Twin studies, genetic linkage studies, and searches for specific genes not only provide logical paths for scientific
investigation toward a causal explanation of AD, but also may provide clues for prevention, depending on what the genes do. Genetic studies to date have solidly established the role of genetic factors, but the implications for prevention are not yet clear.
History of Head Trauma
A history of head trauma has appeared as a risk factor for AD in several epidemiological studies (Henderson, Jorm, Korten, Creasey, McCusker, Broe et al., 1992; Mortimer, van Duijn, Chandra, Fratiglioni, Graves, Heyman et al., 1991; Graves, White, Koepsell, Reifler, van Belle, Larson, and Raskind, 1990; Amaducci, Fratiglioni, Rocca, Fieschi, Livrea, Pedone et al., 1986; French, Schuman, Mortimer, Hutton, Boatman, and Christians, 1985; Mortimer, French, Hutton, and Schuman, 1985; Heyman, Wilkinson, Stafford, Helms, Sigmon, and Weinberg, 1984). Recent studies show correlations with nonfamilial cases of AD, rather than familial cases (Henderson et al., 1992; Mortimer et al., 1991), suggesting it is an independent risk factor and may or may not contribute to dementia through an entirely different causal pathway from that of the genetic forms. These studies have rekindled interest in trauma as a cause of AD.
A clinical syndrome, dementia pugilistica, has long been described in the clinical literature (Mendez, 1993). Microscopic plaques and tangles are found at autopsy, but they are distributed more widely than in typical AD. Dementia pugilistica is most likely to occur among those who sustain repeated closed head injuries, especially boxers. Dementia typically begins several years after exposure to trauma. It is most common among those with a history of vascular disease, alcoholism, or low IQ (Mendez, 1993). Recent studies show a correlation between severe head injury and presence of plaques, which appear in one of three individuals subjected to repeated head trauma such as boxing (Clinton, Ambler, and Roberts, 1991; Roberts, Allsop, and Bruton, 1989).
Prevention of head trauma is itself a laudable goal. Head trauma can be reduced by use of seat belts and air bags in automobiles, wearing helmets while riding motorcycles or bicycles, and reducing exposure to events likely to result in trauma (e.g., boxing), and other measures. The immediate benefits include reduced risk of spinal cord injury and acute brain injury. Trauma, including head trauma, is a major cause of premature mortality, especially among young adults. Preventing AD several years hence may be but an additional, delayed, benefit from measures commendable in their own right. The association between
repeated head trauma and dementia suggests that the sport of boxing carries a significant long-term risk.
Medical Risk Factors, Including Thyroid Disorders
Several other risk factors have been identified by one or more epidemiological studies. However, a recent study concluded that despite enormous efforts to gather clinical data on a large number of subjects, “ we have been unable to identify any important candidate [medical] risk factors that may account for a substantial proportion of the cases of AD occurring in the community” (Kokmen, Beard, Chandra, Offord, Schoenberg, and Ballard, 1991). But there may be one exception. A recent review of several studies corroborated previous reports of an association with thyroid disorders (Breteler, van Duijn, Chandra, Fratiglioni, Graves, Heyman et al., 1991; Treves, 1991), although the effect was much smaller than that of family history or head trauma.
Maternal Age at Time of Birth
An even weaker association was found between AD and maternal age at time of birth, with AD prevalence increased among those born to either unusually young or unusually old mothers (Rocca, van Duijn, Chandra, Fratiglioni, Graves, Heyman et al., 1991). These preliminary results suggest future research directions.
Psychosocial Risk and Protective Factors
Several studies have shown a higher prevalence of dementia among those with less education, although findings are not entirely consistent from study to study. Projections of AD prevalence in the United States in 2050 yield estimates of 10.3 million cases of probable AD if the trend to increased education in the U.S. population is taken into account, but 15.4 million without this adjustment factor for education (Evans, Scherr, Cook, Albert, Funkenstein, Smith et al., 1990). Studies in Italy and China show more dementia among the less educated (Rocca, Bonaiuto, Lippi, Luciani, Turtu, Cavarzeran et al., 1990; Zhang, Katzman, Salmon, Jin, Cai, Wang et al., 1990; Amaducci et al., 1986), similar to previous North American and European studies. One recent community survey in Baltimore, Maryland, however, found the opposite effect, with higher AD prevalence among the more educated (Folstein, Bassett, Anthony,
Romanoski, and Nestadt, 1991). This effect was relatively weak and depended on a small number of cases in the higher-educated categories, and thus should be interpreted with some caution.
Katzman (1993) recently reviewed the literature on education and Alzheimer's disease, observing that several epidemiological criteria of causality have been met, but he still urges caution in interpreting results. He concluded that if education has the effect of increasing synaptic density in some brain regions, and if it is indeed loss of cells in these regions that predisposes to clinical dementia, then the epidemiological and biological data could be integrated into a plausible theory. The effect of education would not be to alter the underlying biological cause of cell loss, but rather to delay its clinically detectable effects, so that dementia does not ensue for an additional five or so years.
Epidemiological case-control studies looking for associations between AD and smoking over the past decade have produced conflicting results. Graves and colleagues recently reported a meta-analysis of data from eight of these studies, which individually had reached different conclusions (Graves, van Duijn, Chandra, Fratiglioni, Heyman, Jorm et al., 1991). The reanalysis of pooled data disclosed a statistically significant inverse correlation between smoking and AD prevalence —that is, those who smoked more were less likely to have AD. The analysis included one study that had found a positive correlation (higher prevalence of AD among smokers), but the population in this study was unusual and even when cases from this study were included, the meta-analysis reached the same conclusion of an inverse correlation.
An association between reduced AD prevalence and smoking is an intriguing lead. It has some biological plausibility because nicotine, an active agent in tobacco products, binds to the acetylcholine receptors, whose loss is associated with AD. It is thus not unreasonable to postulate that smoking might delay onset of symptoms. Against this, however, the studies did not show a later onset in smoking than nonsmoking cases of AD, although one of the component studies from the Netherlands did find that when two or more family members developed AD, one of whom smoked and the others not, the onset was later for the smokers. This was based on a very small number of cases and is thus only a tantalizing but uncorroborated finding. The authors of the meta-analysis urge caution in interpreting the findings, as there are many possible confounding factors that could be controlled only by prospective longitudinal population-based studies, rather than case
control studies. Pursuing an AD-tobacco association is clearly a high priority in AD risk research.
Alzheimer's disease exemplifies how basic biomedical research can address a complex disorder of unknown cause. For the most part, investigators have based molecular inquiry on clues derived from what is known about the pathology of AD, for example, the composition of plaques and tangles, or what is known about clinically similar disorders such as Parkinson's disease or Creutzfeldt-Jakob disease (CJD). CJD is a very rare dementia caused by an atypical transmissible agent (sometimes called a slow virus). Limited evidence suggests that some cases of AD may also be related to a transmissible agent (Manuelidis and Manuelidis, 1991). Following a different line of research, several reports of association with aluminum toxicity drew attention in the 1970s and 1980s, but a more recent study with a highly sensitive method suggests that findings in previous reports may have been laboratory artifacts (Landsberg, McDonald, and Watt, 1992). The high aluminum concentrations may have been due to the affinity of plaques and tangles for aluminum introduced during laboratory analysis, after the tissue was removed from the body, rather than the aluminum causing cell death.
If viruses or environmental toxins prove to be important in the causation of AD, then prevention measures would obviously follow. The evidence for these hypothetical environmental triggers, however, is not currently strong enough to warrant aggressive preventive measures.
Future Directions in Identification of Risk and Protective Factors
In a recent minireview, Drachman and Lippa (1991) listed 17 different causal hypotheses for AD, and each has been pursued by one or more research groups. Biomedical research on AD has flourished over the past decade. The federal research budget has risen from $3.9 million in 1976 (OTA, 1987) to an estimated $297 million in 1993 (DHHS, 1993). This profusion of funding has led to a dramatic rise in annual publications. A literature search for 1980 found 113 AD publications, whereas a similar search covering a 42-month period from 1989 to 1992, done as background for this report, found 4,189—almost 100 per month, and a more than tenfold increase in publication rate during the 1980s. Future research will entail a complex interplay among further biomedical research studies pursuing specific causal hypotheses, more refined epidemiological investigations to tease apart risk factors, and health
services research aimed at improving services for those who develop AD.
Heterogeneity of cause is one highly plausible explanation for the inconsistency among epidemiological studies and the weak predictive power among those risk factors analyzed to date. Future studies may more successfully dissect out risk factors by segregating disease subtypes, perhaps through identifying genetic subgroups (those showing linkage to different chromosome regions, for example), or by separately analyzing cases arising from currently known risk factors such as head trauma or level of education.
Drugs to reverse the cognitive impairments of AD have been pursued vigorously for the past decade. One main line of attack has focused on drugs to sustain the action of the neurotransmitter acetylcholine. Farlow and colleagues recently conducted the largest clinical trial of the drug tacrine to date and reported that it measurably improved cognitive function in just over half the subjects, roughly equivalent to a six-month delay in the course of the disease (Farlow, Gracon, Hershey, Lewis, Sadowsky, and Dolan-Ureno, 1992). An editorial accompanying Farlow's publication suggested that the drug might prove clinically useful for a subset of patients who do not develop liver toxicity and are carefully monitored (Small, 1992). Drugs to address the loss of neuronal systems, using peptide transmitters, growth factors, and other possible approaches, remain of intense interest, but most are early in development and are being tested in exploratory clinical trials.
Hopes for prevention are pinned to understanding the biology of nerve cell death. Why do certain cells die? The discovery of hormones and growth factors that stimulate cell growth suggests that their absence may lead to cell death. Examples of genetically programmed cell death in nematode worms and other organisms also offer clues to possible reasons for the death of nerve cells. For the most part, these hypotheses have suggested lines for further research that may eventually suggest prevention strategies, but none is sufficiently advanced to merit even a prevention trial.
Advances in understanding how amyloid is deposited offer several strategies for intervening in the process (Katzman and Saitoh, 1991). Attention has turned recently to the development of drugs that could slow the formation of amyloid from APP or enhance the clearance of amyloid. Prophylactic administration of such drugs might be effective in slowing progression for patients in the early stages of AD or in preventing the onset of AD in individuals genetically at risk. Such pharmacological prevention is analogous to the use of cholesterol-lowering drugs in atherosclerosis, and the development of such drugs
will be aided greatly by molecular biological studies to identify gene mutations that lead to AD vulnerability. Thus identification of these genes will permit gene-based diagnosis of AD vulnerability as well as lead to an understanding of the role of the mutant gene products in causing AD. Together, these current lines of investigation hold promise for the development of specific, pharmacological preventive interventions for those at genetic risk for AD.
The widely documented stress experienced by relatives caring for elderly, demented persons exacts a heavy toll. Several studies have sought to measure this impact on families, including the adverse effects on the caregiver's physical and mental health (George and Gwyther, 1986; Pratt, Schmall, and Wright, 1985). One of the determinants of distress in caregivers is depletion of their social support network, leaving them feeling abandoned, isolated, and without assistance and recognition. The Office of Technology Assessment noted a surprising lack of correlation between a patient's characteristics and behaviors and the caregiver's subjective experience of burden, although it is clear that coping skills and education can reduce that subjective experience (OTA, 1990). Caregivers differ markedly, as do the patients and the availability of support services. It is simplistic to assume that caregivers will respond consistently to any given intervention, but it is reasonable to assume that the availability of information and support services will reduce the stress and stress-related health effects among caregivers. Preventive intervention strategies for these high-risk family members—no matter what the nature of the prevailing mental disorder—therefore might include methods already in use, but inadequately evaluated, such as self-help support groups and psychoeducational programs (Falloon, Boyd, McGill, Razani, Moss, Gilderman, and Simpson, 1985; Bernheim, Lewine, and Beale, 1982; Vine, 1982). In addition to formal services, caregivers appear to benefit from group support, information, and the availability of someone they trust to answer questions when they need help (K. Maslow, personal communication, 1992; OTA, 1990). An improved care system may prevent the new incidence of stress-related disorders among caregivers. Better management of patients—particularly with regard to the troublesome behavioral symptoms of agitation, wandering, insomnia, and emotional outbursts—might also have positive effects for caregivers, although clinical literature to support this common-sense conclusion is surprisingly scant despite the intense assessment of family burden in recent years. This is a critical gap in research.
The study of care-related disability among caregivers continues to be an important area for research. The first wave of studies over the past decade has served mainly to describe differences among patients, caregivers, and the service system. This information is now laying the base for a second wave of more refined caregiver burden studies with more precise outcome measures, interventions, and service availability measures.
Findings and Leads
At this time, there is no research base sufficient to mount a preventive intervention campaign with potential AD victims. Research must continue to be focused on identification of risk factors, through research on genetics, continued basic research, and further epidemiological studies. It must also begin to identify the relative and attributable risks associated with each of these factors. The best hope for prevention in the near future lies in the research focused on delaying the onset of AD, either through education early in life or through the prophylactic use of drugs to improve cognitive function or to impede amyloid deposition in high-risk individuals. Although effective prevention often does not require a complete causal theory, it does require more robust risk and protective factor studies than exist for AD. The literature to date has netted three malleable factors—education, smoking, and head trauma—that are plausibly associated with AD. In all three cases, the reasons to change behavior are even stronger for other purposes than prevention of dementia. Reducing head trauma and promoting education are laudable social goals that may reduce future AD prevalence. Promoting smoking as a protective factor for AD is absurd given tobacco's serious health risks for cancer and heart disease. A more targeted prevention strategy depends either on discoveries that come from basic research or stronger epidemiological evidence of malleable risk factors than has been discovered to date. On the other hand, research trials on interventions to prevent stress-induced effects among caregivers of AD patients are warranted. Such studies will require rigorous methodology, including valid outcome measures.
Schizophrenia is a heterogeneous disorder with different disease entities, subtypes, and pathological processes. Therefore the risk and protective factors associated with onset may be different for the various syndromes included within the disorder. Risk factors may bear different
relationships to the three main domains of the psychopathology—psychosis as defined by hallucinations and delusions, dissociative thought processes, and primary negative symptoms such as emotional flatness. They may also have different patterns of heritability. On the other hand, they may be seriously confounded.
Biological Risk Factors
Family Studies. The most prominent biological risk factor is heredity, although some legitimate controversy exists. Although there is widespread acceptance that genetic factors contribute to schizophrenia, two studies have questioned whether narrowly diagnosed schizophrenia is a familial disorder (Abrams and Taylor, 1983; Pope, Jones, Cohen, and Lipinski, 1982), claiming that earlier studies suffered from a lack of controls, bias in diagnoses, and inconsistent diagnostic criteria. In the 1980s, five careful studies reported a greater than fivefold increased risk in first-degree relatives (Kendler, Masterson, and Davis, 1985). Bolstered by more recent studies, this suggests genetic and/or shared environmental factors in families that increase the risk of schizophrenia (see Box 6.1). On the other hand, absence of a positive family history does not ensure freedom from risk. Positive family history shifts probabilities, but it is still not sufficiently clarifying except among identical twins, who actually share the same genetic material.
Twin Studies. An estimate of genetic influence can be established by using twin studies. The genetic contribution can be estimated by comparing concordance rates between monozygotic (identical) and dizygotic (fraternal) twin pairs. Kendler (1988) summarized 11 studies and derived a monozygotic mean concordance rate of 64 percent and a dizygotic mean concordance rate of 16 percent. This suggests a major role for genetic factors, although the estimate may seem high in light of the other, nontwin data. The fact that 36 percent of identical twins were discordant also clearly demonstrates the importance of nongenetic factors. Methodological issues include the assumption that monozygotic and dizygotic twins have an identical trait-relevant environment and the possibility of selection bias in the recruitment of monozygotic twins. Such criticisms are not supported by adoption studies. Twin studies have been updated (Gottesman, 1993), and there is now evidence that the risk to offspring of discordant monozygotic twins is remarkably similar. That is, the children of an unaffected identical twin have almost
Children of Parents with Schizophrenia: Family History as a Risk Factor
The proportion of individuals with schizophrenia who marry is less than in the general population (25 to 47 percent for males and 39 to 82 percent for females), but the rate of reproduction among them has been increasing (from 58 percent of the general population rate in the 1930s to 70 percent in the 1960s), perhaps due to improvement in treatment (Erlenmeyer-Kimling et al., 1980) and to the remarkable diminution in the pattern of prolonged segregation by gender encountered during the era of long-term custodial care in public facilities.
The children of parents with schizophrenia are a high-risk group. First of all, they have an increased genetic vulnerability for schizophrenia. Second, their other parent is likely to have a mental disorder. The prevalence of assortative mating (i.e., the tendency of people to select as mates people with the same or similar characteristics) in schizophrenia has yet to be determined rigorously, but the best available data suggest it may be high. Rosenthal (1974) found that 58 percent of spouses of schizophrenic subjects themselves had a schizophrenic spectrum disorder. Fowler and Tsuang (1975), in a blind comparative study, found that 39 percent of spouses were psychiatrically disturbed, with alcoholism and personality disorders accounting for 70 percent of the problems. These additional disorders could have an additive effect on the genetic and/or psychosocial risk for the child. Third, capabilities of the schizophrenic parent to care adequately for the child may be adversely affected by the disorder, especially if the disorder is chronic and severe (Grunbaum and Gammeltoft, 1993).
Cohorts of children with at least one schizophrenic parent have been studied with a view toward understanding the premorbid state of this disorder and isolating factors that may either contribute to the onset of schizophrenia or serve as markers of children at high risk to express schizophrenia. Mednick and Silverton (1988) reviewed 22 studies in the literature and pointed out that the major logistical problem is the long time period between beginning to study the children and having them complete the risk period for developing the disorder.
Szatmari and Nagy (1990) reviewed the literature on children with schizophrenic parents and concluded that between 20 and 40 percent develop a mental disorder during their childhood, a rate that is very similar to that in children of parents with other mental disorders (Rutter and Quinton, 1984). Rarely, however, do these children develop childhood schizophrenia. Their adult outcome may be more influenced by genetic factors related to schizophrenia. Children who have two schizophrenic parents are at especially high risk (46 percent lifetime) for developing schizophrenia (Gottesman, 1991), but they are also at considerable risk for developing other mental disorders.
the same risk as the children of the affected twin. The risk in the offspring of schizophrenic identical twins is 16.8 percent; it is 17.4 percent in the unaffected twins' offspring (Gottesman and Bertelsen, 1989). This evidence that inheritance can “pass through” apparently asymptomatic, unaffected individuals suggests a strong genetic component but again clearly indicates that nongenetic factors are also involved.
Adoption Studies. Two strategies have been used to estimate genetic effects in adoptive families. One approach is to evaluate offspring of schizophrenic parents who have been adopted away from their biological parents into another environment and measure the rates at which such children develop schizophrenia. The second approach is to study the rearing, adoptive families of adopted children who have developed schizophrenia as adults. Heston (1966) studied adopted-away offspring of schizophrenic mothers and found a significant rate of schizophrenia in these children (10.4 percent prevalence, which became 16.6 when necessary age corrections were made), compared with children from unaffected mothers (no children with schizophrenia). A study by Rosenthal (1974) showed a similar result (13.9 percent from biologically affected families and 3.4 percent of controls), but the data did not achieve statistical significance. In a much larger Finnish study (Tienari, 1991a,b,c), 10.3 percent of schizophrenic women's children also became schizophrenic, even when raised by adoptive families, confirming Heston's results. Kety and co-workers, on the other hand, began their study with adoptees who grew up to be schizophrenic (Kety, Rosenthal, Wender, Schulsinger, and Jacobsen, 1978). The adoptees' adoptive and biological families were located and evaluated. Both schizophrenia and the schizophrenic spectrum disorders were significantly higher in the biological relatives than in the adoptive families. These results have been subject to extensive reanalysis, including careful diagnostic reevaluations (Kendler and Gruenberg, 1984). Taken as a body of work, these studies collectively indicate that the offspring of schizophrenic individuals have a greatly increased risk of developing schizophrenia and that schizophrenics do not transmit this vulnerability to their nonbiological families. This evidence points to a strong role for genetics as a risk factor. The genetic data also make clear that nongenetic factors, such as environmental influences and acquired brain damage, must have a role in accounting for the incidence of the disease (Gottesman and Bertelsen, 1989).
Linkage Studies. Linkage studies in schizophrenia using conventional markers and assuming a single major locus have been inconclusive.
With the development of polymorphic DNA markers, careful studies of specific candidate genes such as the D2 receptor (Moises, Gelerneter, Giuffra, Zarcone, Wetterberg, Civelli et al., 1991) and various regions of chromosomes 2, 5, 11, 12, and 22 have been examined. No reproducible linkage or association has been found (Waddington, Weller, Crow, and Hirsch, 1992). There are several possible reasons for the lack of progress in spite of the rapid increase in the power of molecular genetics. The limits of the mathematical models used to calculate the probability of linkage between a gene and the disorder mean that only one or two gene models are usually considered, and recent evidence suggests that this disorder is polygenic, involving several genes (Carter and Chung, 1980). If this is true, then linkage studies, at least of the type that have been undertaken so far, are of limited value. In addition, heterogeneity in the diagnosis of schizophrenia is probable, and this makes linkage studies considerably more difficult. The report of a linkage in Icelandic and British families by Sherrington and colleagues (Sherrington, Brynjolfsson, Petursson, Potter, Dudleston, Barraclough et al., 1988) had been thought to represent a case of heterogeneity because this linkage has not been reproduced in other studies (St. Clair, Blackwood, Muir, Bailie, Hubbard, Wright, and Evans, 1989; Kennedy, Giuffra, Moises, Cavalli-Sforza, Pakstis, Kidd et al., 1988; Detera-Wadleigh, Berrettini, Goldin, Boorman, Anderson, and Gershon, 1987). However, the Sherrington linkage has not held up with the addition of more informative markers.
Pregnancy and Birth Complications, Winter Births, and Viral Exposure
A recent study by Bracha and colleagues provides new evidence that second prenatal trimester insult may be associated with the expression of schizophrenia (Bracha, Torrey, Gottesman, Bigelow, and Cunniff, 1992). These researchers found that monozygotic twins discordant for schizophrenia had more differences in their fingerprints than normal twins. This finding suggests that disturbances occurred in the development of one of the fetuses that may be related to the fact that only one twin expressed his or her genetic predisposition toward schizophrenia.
In a variety of studies carried out with adult schizophrenics in the United States and Europe, an excess of obstetrical complications in the mothers of subjects who later became schizophrenic compared with control groups has been documented (McNeil, 1987). These complications appear to be related to infant anoxia during birth. Birth complications also appear to be associated with larger cerebral ventricles and may
be negatively associated with a strong genetic history of schizophrenia in the family (Canon, Mednick, and Parnas, 1989). Thus individuals whose schizophrenia arises from brain trauma during birth may not have a genetic form of the illness. Such individuals are “phenocopies, ” because they have an illness that resembles one caused by genetic factors, but which arises from a nongenetic cause or in interaction with a subset of such factors. However, caution must be exercised in using birth complications as a risk factor to target in preventive interventions. A positive history for birth complications does not indicate whether an individual has suffered an insult to central nervous system development that is associated with the onset of schizophrenia, and a negative history for gestational and birth complications gives no assurance of this absence. It is also possible that genes associated with schizophrenia could cause gestational or birth complications. Finally, a recent, high-quality study by Done and colleagues had inconclusive results regarding birth trauma as a risk factor for the onset of schizophrenia (Done, Johnstone, Frith, Golding, Shepard, and Crow, 1991).
It has been suggested that there is an excess of winter births among schizophrenic patients (Dalen, 1988), but overall results of season-of-birth studies are highly inconsistent (Lewis, 1989). It has also been suggested that winter births of schizophrenics are related to maternal exposure to influenza. Barr, Mednick, and Munk-Jorgenson (1990) studied births in Finnish mothers exposed to the influenza epidemic in 1957 and found an increase in schizophrenic offspring among this cohort of births. However, population data from Scotland, England, and Wales failed to replicate this finding (O'Callaghan, Sham, Takei, Glover, and Murray, 1991; Kendell and Kemp, 1989). Furthermore, winter birth does not fit the viral hypothesis, which holds that maternal viral infection in the second trimester of pregnancy is related to higher rates of schizophrenia. If this were true, and if flu is more common in the winter months of January, February, and March, then children born in the spring should have higher rates of schizophrenia. To the degree that maternal or gestational viral infection might result in damage to the fetus's brain, these viruses could contribute to the development of schizophrenia, but there is no conclusive evidence for this, and at this time viral exposure cannot be considered a documented risk factor. Winter birth may be a risk factor, but season of birth does not provide evidence that any given individual will develop schizophrenia. Most winter-born schizophrenics presumably get schizophrenia for the same reason as nonwinter-born, and at this point it is impossible to determine which of the small minority have some other special risk associated with winter birth.
The major biological markers under consideration to identify high-risk populations of children include (1) smooth pursuit eye tracking deficits (Holzman, Solomon, Levin, and Waternaux, 1984); (2) attentional deficits (Garmezy, 1978); (3) neurointegrative defects (Erlenmeyer-Kimling, Cornblatt, Freidman, Rutschmann, Simmons, and Devi, 1982); (4) electrodermal hyperresponsivity (Mednick and Schulsinger, 1968); and (5) increased cerebral ventricular size (DeLisi, Goldin, Hanovit, Maxwell, Kurtz, and Gershon, 1986). Like all risk factors, these markers do not necessarily mean that the disorder is or will be expressed. Although they may be apparent in high-risk children and some have been shown to be present in a high proportion of children who go on to develop schizophrenia (Erlenmeyer-Kimling, Rock, Squires-Wheeler, Roberts, and Yang, 1991; Erlenmeyer-Kimling et al., 1982), their presence does not necessarily predict the development of the disorder. Moreover, none of the markers have clearly established themselves as linked with a genetic vulnerability for schizophrenia, although a few remain viable candidates. (See the review by Hafner and Gattez, 1991.)
Smooth Pursuit Eye Tracking Deficits. One of the most investigated markers for schizophrenia is deviant smooth pursuit eye movements (Grove, Clementz, Iacono, and Katsanis, 1992; Clementz and Sweeney, 1990; Iacono, Bassett, and Jones, 1988; Holzman et al., 1984). When given the task of visually tracking a moving target, most individuals exhibit smooth, coordinated eye movements. Schizophrenics, however, show choppy disruptions in the tracking pattern. Although the nature of the link to schizophrenia is not clear, it has been a consistently replicated finding, and one that has attracted considerable attention. The marker is found in schizophrenics as well as their affected and unaffected family members (Iacono, 1985). This has led to speculation as to whether the marker reflects a genetic vulnerability to schizophrenia. The results, initially described by Holzman and colleagues (Holzman, 1983; Holzman, Proctor, and Hughes, 1973), have been widely replicated and suggest that between 50 and 85 percent of schizophrenic subjects, as well as 40 to 50 percent of their first-degree relatives, may have disrupted smooth pursuit movements, in contrast to a general population prevalence of 5 percent. Unfortunately, deficits in smooth pursuit eye tracking are induced by lithium administration (Levy, Dorus, Shaughnessy, Yasillo, Pandey, Janicak et al., 1985). Thus the weight of evidence suggests the marker is not specific for schizophrenia, but smooth pursuit eye tracking is clearly strongly associated with increased risk and may be a latent trait marker.
Attentional Deficits. Attentional deficits have also been suggested as possible markers with a linkage to schizophrenia. These deficits can also occur in other mental disorders, but the disturbance may be more pervasive in schizophrenics. In one study using a combined measure of attention and information processing, Cornblatt and Erlenmeyer-Kimling found that 27 percent of children of schizophrenics had impaired attention and information processing, compared with 11 percent of children from affectively ill parents (Erlenmeyer-Kimling and Cornblatt, 1992; Cornblatt and Erlenmeyer-Kimling, 1985). There are few data thus far on the specificity of the marker for subsequent development of schizophrenia.
Performance on a specific measure of focused and sustained attention, the continuous performance test (CPT), has received considerable attention as a possible marker for schizophrenia. Asarnow and colleagues showed that children of schizophrenic subjects performed significantly worse on this test than children of control subjects (Asarnow, Steffy, MacCrimmon, and Cleghorn, 1977). This finding has been replicated and extended to cohorts of schizophrenic patients. Nuechterlein and colleagues reviewed this work and suggested that because the abnormalities can be seen in actively psychotic patients, patients in relative remission, and children of schizophrenics, the CPT may represent a stable vulnerability marker (Nuechterlein, Dawson, Venture, Fogelson, Gitlin, and Mintz, 1990). Thus the CPT defect may reflect a trait marker with genetic potential, but a genetic analysis of this behavior has not been carried out.
Neurointegrative Defects. In infancy and early childhood, neurointegrative defects, including sensorimotor problems, visual motor defects, and soft neurological signs, may be a risk factor for the onset of schizophrenia (Marcus, Hans, Mirsky, and Aubrey, 1987; Mednick, Parnas, and Schulsinger, 1987; Erlenmeyer-Kimling et al., 1982; Marcus, Auerbach, Wilkinson, and Burack, 1981). In a review of nine prospective studies of infants at risk for schizophrenia, Fish and colleagues concluded that there is evidence that a schizophrenic genotype may be manifested in infants by a neurointegrative defect called pandysmaturation (Fish, Marcus, Hans, Auerbach, and Perdue, 1992). (Occurring during the first two years of life, pandysmaturation is the earliest manifestation of an enduring neurointegrative defect.) Again, there is little specificity in these clinical signs. For example, one small adult follow-up study of children with soft neurological signs found an excess of affective disorder, but not schizophrenia (Schaffer, Stokman, O'Connor, Shaffer, Barmack, Hess et al., 1986). Children with neurointegrative signs appear
to be at higher risk for developing schizophrenia only if they have other risk factors for schizophrenia. Marcus and colleagues followed prospectively the offspring of schizophrenic parents and found that the group at highest risk had a schizophrenic parent, showed early neurointegrative deficits, and experienced troubled parenting (Marcus et al., 1987). Those children with schizophrenic parents and neurointegrative deficits who had positive parental experiences did not develop schizophrenia. This finding is of special importance to prevention research; it suggests placing greater attention on the parenting situation of high-risk children.
Electrodermal Hyperresponsivity. Electrodermal hyperresponsivity was proposed as a marker for schizophrenia in the Copenhagen high-risk project (Mednick et al., 1987) and was the variable used to choose a population of high-risk children for the Mauritius prevention project (Mednick, Venables, Schulsinger, Dalais, and Van Dusen, 1984). Electrodermal hyperresponsivity was first suggested by Mednick and Schulsinger (1968); subsequently, they suggested it was useful only for males. Subsequent studies suggested there is little evidence of a reproducible association between electrodermal hyperresponsivity and schizophrenia (Erlenmeyer-Kimling, Freidman, Cornblatt, and Jacobsen, 1985; Kugelmass, Marcus, and Schmueli, 1985).
Increased Cerebral Ventricular Size. Cerebral ventricular size has been shown to be enlarged in about 30 percent of schizophrenics. Evidence suggests that increased ventricular size is present early in the illness, and the enlargement is stable over time. The specificity of this variable is not clear, however. For example, patients with bipolar mood disorders also have increased ventricular size (Swayze, Andreasen, Alliger, Ehrhardt, and Yuh, 1990). Ventricular size, like many other attributes of bodily structures, is highly heritable. Twin studies have shown a slight increase in ventricular size for the schizophrenic monozygotic twin in twins selected to be discordant for schizophrenia (Revely, Revely, and Murray, 1984).
Psychosocial Risk Factors
Low Socioeconomic Status
Social status has been assessed in at least 25 epidemiological studies, most of which show heightened prevalence of risk for schizophrenia in the lower class (Eaton, 1974). This association could be the result of adversities and stresses connected to living in a lower social class, or it
could result from downward mobility due to the disease's disability. There is evidence to support the idea that schizophrenia is linked to lower or lessened upward mobility (Turner and Wagenfield, 1967; Goldberg and Morrison, 1963). A study by Dohrenwend and co-workers supports a downward social drift hypothesis, which posits that schizophrenic individuals end up in lower social classes because of their disease-related impairments, rather than developing schizophrenia because of the stress of living in a low social class (Dohrenwend, Levav, Schrout, Schwartz, Naveh, Link et al., 1992). Thus poverty or low social class may be a consequence, rather than a cause, of this disease. There is, however, some highly speculative evidence that one consequence of extreme poverty—acute starvation during the first trimester of pregnancy—may play a role in the onset of schizophrenia, as demonstrated by Susser and Lin (1992) in a study of Dutch births following the famine of the winter of 1944–1945. However, serious but less severe starvation was not associated in one cohort, nor was starvation in the second and third trimester.
Disturbed Family Environment and Family Communicative Problems
An ongoing adoption study in Finland by Tienari (1992, 1991a,b), has given us the first evidence that family problems and communication disturbances within families may play a role in the onset of schizophrenia. This study demonstrates the overexpression of schizophrenia among a cohort of adoptees having biological mothers with the diagnosis of schizophrenia, confirming the role of genetic factors. The study also looks retrospectively at family environment and finds that 9 of the 13 adoptees (of a total of 138 adoptees with schizophrenic biological mothers) who expressed functional psychosis, which includes schizophreniform and delusional disorders, grew up in “severely disturbed ” households. When the factors that can be reliably rated from contemporary discourse were examined, it was found that disrupted communication was the major risk factor predicting the onset of psychopathology. The authors have suggested that this supports a notion that genetic factors confer a vulnerability that requires an environmental trigger for the development of the disorder. Aside from a need for replication, the question of the role of a sick child in disrupting communication has not been fully addressed, and it appears that a higher proportion of families with children from schizophrenic mothers had “severe disturbances” than control families.
Serious Behavioral and Emotional Problems in Childhood
One precursor pattern in children who may develop schizophrenia is poor impulse control and aggression. These children have temper
tantrums, are destructive, and receive frequent disciplinary action. This pattern is superimposed on the neurointegrative dysfunctions and attention deficits seen earlier in development. This pattern of behavior in children who would become schizophrenic was reported initially by Bender (1937) and has been confirmed by Emery, Weintraub, and Neale (1982) and Mednick and Schulsinger (1968).
Another precursor pattern is social withdrawal or awkwardness in interpersonal relations, diminished emotional expressiveness, and lack of feeling during childhood and adolescence. These problems define a population at high risk for the initial onset of schizophrenia during young adulthood (W. Carpenter, personal communication, 1993; Erlenmeyer-Kimling and Cornblatt, 1987; Garmezy, 1974; Mednick and Schulsinger, 1968).
Although there is some consistency in these two precursor behaviors exhibited by high-risk children who ultimately develop schizophrenia, there is little specificity. For example, the aggressive symptom pattern is also seen in a variety of other childhood disorders, such as attention deficit hyperactivity disorder, mood disorders, and conduct disorder. However, children who are aggressive and have a family history of schizophrenia have an increased likelihood of developing schizophrenia (Mednick and Silverton, 1988), so it may be the combination of risk factors that is most important.
The contribution of social dysfunction, or social incompetence, as a risk factor in the onset of schizophrenia is not well understood. Whereas childhood behavior problems may be an expression of the disorder itself at an early developmental stage, social incompetence may relate to inherited genetic personality patterns, such as schizoid personality. In contrast, the role of social incompetence in the course and outcome of schizophrenia has been well established. For more than three decades, investigators have repeatedly replicated the strong predictive relationship of premorbid level of social incompetence or social maladjustment in areas such as occupation, education, peer friendships, and heterosexual intimacy to course and outcome (Strauss and Carpenter, 1974; Zigler and Phillips, 1961; Garmezy and Rodnick, 1959). The predictive correlations have been significant for a variety of measures of outcome, including symptomatic relapse, rehospitalization, and global ratings of improvement (Kokes, Strauss, and Klormann, 1977; Hersen and Bellack, 1976; Gittelman-Klein and Klein, 1969).
Because many substances, such as stimulants and PCP, can induce psychotic states that closely mimic schizophrenia, it has been postulated that recurrent drug abuse may lead to an increased risk of developing schizophrenia in vulnerable individuals. Bowers (1987) demonstrated that the increase in the proportion of schizophrenic patients admitted to Connecticut state hospitals paralleled an earlier increase in the level of drug abuse in Connecticut. To determine whether drug abuse could cause the expression of more schizophrenia, Bowers examined the family history of substance abusers with chronic psychosis. The greater the drug abuse, the less family history of schizophrenia was present (Bowers and Swigar, 1983), suggesting that high levels of drug abuse might lead to chronic illness without high levels of genetic vulnerability. In a study of first-episode schizophrenic patients, DeLisi et al. (1986) reported threefold higher levels of drug abuse in patients (35 percent) than in matched population controls (12 percent). Other researchers have also looked at the role of cannabis, hallucinogenics, and alcohol in the etiology of schizophrenia (Tien and Anthony, 1990; Andreasson, Allebeck, Engstrom, and Rydberg, 1987; Breakey, Goodell, Lorenz, and McHugh, 1974). This evidence suggests that schizophrenia-like illnesses may be precipitated by heavy drug abuse. It is possible that these individuals had precursor symptoms of schizophrenia and were self-medicating with these drugs, which then led to an exacerbation of the symptoms and acute onset of schizophrenia. The existence of uncontrolled variables, including type and duration of drug abuse, make this a hypothesis in need of rigorous testing.
Schizophrenia in a family member can become a risk factor for stress-related disorders in other family members. Many factors affect caregiver burden, including financial difficulties, self-blame, degree of severity of the disease, social isolation, the caregiver's own health, the caregiver's coping skills, and the stigma attached to mental illness (Geiser, Hoche, and King, 1988; Fadden, Bebbington, and Kuipers, 1987).
The degree to which caregiver burden is linked with the development of stress-related problems such as depression, irregular sleeping and eating patterns, aggravated health problems, increased use of alcohol or tranquilizers, marital strain, and irritability is not well known. Several
studies have found variability in caregivers' ability to cope (Oldridge and Hughes, 1992; Scottish Schizophrenia Research Group, 1985; Gibbons, Horn, Powell, and Gibbons, 1984). Oldridge and Hughes (1992) found that the levels of psychological distress of family members who care for a person with schizophrenia are about twice the level expected in the general population. Further risk studies are needed to determine which family members are most likely to experience these ill effects and what aspects of caregiver burden are the most frequent and the most malleable.
Findings and Leads
Although genetic vulnerability may predispose to schizophrenia, and may even be necessary in order for the disorder to appear, genetic factors by themselves cannot account for the illness. Many of the data are consistent with a developmental disorder that is set in place via genetic and biological factors early in life. This developmental pattern may be susceptible to psychosocial stress, which may trigger the symptomatic expression of the disorder or which may cross a threshold for disease expression.
For the last decade, research on the causes of schizophrenia has been focused on biological rather than psychosocial risk factors (Yank, Bentley and Hargrove, 1993; Gottesman, 1991). Results regarding the importance of most of these risk factors—both biological and psychosocial—remain equivocal. Only genetic factors have been demonstrated and quantified in repeated and varied experimental designs, but researchers are as yet unable to specify a mode of inheritance, a chromosomal localization of schizophrenia genes, or what function such genes might carry out. Hints with regard to factors that might affect onset, such as prenatal viral infection or food deprivation, are weak and nonspecific. The evidence for familial communicative disorders, neurointegrative defects in infancy, and prenatal developmental disturbance during the second trimester of gestation is preliminary and needs replication, as does the suggestion that substance abuse could play a role in the onset of schizophrenia. More work remains in identifying relative and attributable risk for all these factors.
Universal and selective interventions to prevent the onset of schizophrenia are not warranted at this time. Much more risk factor research is needed, and this must necessarily be limited to narrow populations based on positive ascertainment of risk factors. The best hope for identifying a group of individuals at high risk for the onset of schizophrenia is through the identification of a combination of risk factors whose relative and attributable risks are known.
To date, very few, if any, studies have attempted to examine carefully both environment and genetics. It is essential to know how genetic and environmental factors interact. This can best be done through interdisciplinary collaborative research. Some people in the field believe that such an understanding will be possible only when the genes associated with schizophrenia are characterized. On the other hand, it may be possible to identify genes of import only if there is a better understanding of the environment in which they function. Even if the gene or genes for subtypes of schizophrenia could be found, twin studies indicate that genetic vulnerability alone would not account for all the variance; there is a clear opening for other risk factors to operate.
The best hope now for prevention of schizophrenia lies with indicated preventive interventions targeted at individuals manifesting precursor signs and symptoms who have not yet met full criteria for diagnosis. The identification of individuals at this early stage, coupled with the introduction of pharmacological and psychosocial interventions, may prevent the development of the full-blown disorder.
The children of schizophrenic parents are at increased risk for emotional problems of many types, including schizophrenia, and preventive intervention research should continue to study this high-risk group. (Early efforts along these lines at the NIMH Prevention Research Branch have been discontinued.) The parents, spouses, and siblings of schizophrenic individuals can suffer an immense caregiver burden, both emotionally and financially, but as yet, little is known about specific risks within this family group or about the outcome of specific preventive interventions provided to them.
ALCOHOL ABUSE AND DEPENDENCE
Why some people continue to seek alcohol in the face of adverse consequences is not fully understood, and this puzzle marks an important area of study in alcohol research. The reinforcing properties of alcohol —those properties that produce euphoria—may explain, in part, why some people begin to drink. Drinking behavior cannot be explained solely by the direct pharmacological effects of alcohol, however. Genetic and psychological factors as well as the environment shape drinking behavior. Alcohol abuse and dependence arise through a complex interaction of biological risk factors, including genetic factors, and psychosocial risk factors, including personality features and contextual factors, involving the social environment in which an individual lives.
Biological Risk Factors
Family Studies. Family studies have clearly shown that alcohol dependence is familial. The evidence for genetic factors for alcohol abuse is less well substantiated (Schuckit, 1994, 1992). About 70 percent of alcoholics have a positive family history of alcoholism in first- or second-degree relatives (M. Schuckit, personal communication, 1993). Sons and daughters of alcoholics have a threefold to fourfold increased risk for developing this disorder (Schuckit, 1986; Cotton, 1979). This suggests that either the environment of an alcoholic family or the genetic contribution from parents influences the development of alcoholism. However, family studies by themselves cannot distinguish nature versus nurture influences on etiology.
Twin Studies. The relative contribution of environment and genetics has been examined through twin studies as in the case of Alzheimer's disease and schizophrenia. If a trait has a high heritability, the concordance in monozygotic twins, who share 100 percent of their genes, will be greater than the concordance in dizygotic twins, who share only 50 percent. In general, this is what has been observed in the research (Hrubek and Omenn, 1981; Schuckit, 1981). A study with a small sample of psychiatric inpatients by Murray, Clifford, and Gurling (1983), however, showed no difference between monozygotic and dizygotic concordance using both male and female probands, so although the evidence from twin studies of the importance of genetic factors in the etiology of alcohol abuse and dependence is strong, it is not entirely conclusive.
Adoption Studies. Adoption studies are another way to untangle the environmental and genetic contributions leading to the expression of a disease state. Adopted-away sons and daughters from alcoholic families who are raised by nonalcoholic adoptive parents have a significantly increased risk for alcohol abuse and dependence. This risk may be as high as three or fourfold (Goodwin, 1985; Bohman, Sigvardsson, and Cloninger, 1981; Cadoret, 1980; Cadoret and Gath, 1978; Goodwin, Schulsinger, Hermansen, Guze, and Winokur, 1973; Schuckit, Goodwin, and Winokur, 1972).
The data from Bohman, Sigvardsson, and Cloninger's (1981) large Swedish adoption study was used to hypothesize another step in the data analyses (Cloninger, Sigvardsson, Gilligan, von Knorring, Reich, and Bohman, 1989). They have postulated two forms of alcoholism with
considerably different risk factors. The type I alcoholic begins drinking after age 25, infrequently demonstrates spontaneous alcohol-seeking behavior or serious legal problems due to drinking, shows psychological addiction and feels guilt over his or her alcohol use, and demonstrates a rather dependent, sentimental, and introverted personality. The type II alcoholic begins drinking well before age 25, is usually a male, demonstrates alcohol-seeking behavior, and has frequent legal problems due to drinking. These individuals do not show guilt or psychological dependence on alcohol. They demonstrate high novelty seeking and extroverted behavior. The type II alcoholic might have a higher genetic risk than the type I alcoholic.
Finding potential markers for people susceptible to alcohol abuse and dependence has been the focus of a number of research studies. Biological markers may prove valuable in targeting high-risk populations for prevention trials.
Electrophysiological Markers. Event-related potentials, which are electrophysiological brain reactions to stimuli (Porjesz and Begleiter, 1983), have been studied in males with and without a family history of alcoholism. A low P3 amplitude, a measure of one brain wave pattern, has been demonstrated in subjects with increased genetic risk (Begleiter and Porjesz, 1990). It occurs in at least one third of the sons of alcoholic fathers (Hill, Steinhauer, Park, and Zubin, 1990; Noble, 1990; O'Connor, Hesselbrock, Tasman, and DePalma, 1987; Begleiter, Porjesz, Bihari, and Kissin, 1984). Low P3 amplitude has been replicated in other samples, even in alcoholics who are abstinent, suggesting its potential use as a trait marker.
Electroencephalograph synchrony, which appears to be under genetic control, has also been reported as a possible trait marker in women (Propping, 1980). This could prove to be the first marker that is specific for identifying women at risk.
Biochemical Markers. Studies of platelet enzymes have led to two potential markers of increased risk for alcohol abuse. First, stimulated adenylyl cyclase activity was found to be lower in a group of alcoholics than in nonalcoholics (Tabakoff, Hoffman, Lee, Saito, Willard, and De Leon-Jones, 1988). Second, monoamine oxidase (MAO) activity was found to be lower in alcoholics, and on further analysis the finding was shown to be specific to type II alcoholics (von Knorring, Bohman, von Knorring, and Oreland, 1985). This finding has been replicated in
several laboratories (Pandey, Fawcett, Gibbons, Clark, and Davis, 1988; Tabakoff et al., 1988). MAO is an enzyme that is important in the metabolism of a variety of brain neurotransmitters that affect behavior, including dopamine, norepinephrine, epinephrine, and serotonin.
Decreased Sensitivity. Studies of individuals at high risk for alcohol abuse and dependence have also used challenge paradigms in which responses are measured to both placebos and ethanol. Results from some investigations (Moss, Yao, and Maddock, 1989; Lex, Lukas, Greenwald, and Mendelson, 1988; Savoie, Emory, and Moddy-Thomas, 1988; O'Malley and Maisto, 1985) suggest that in general these high-risk individuals may be less sensitive to the effects of alcohol than controls. They have less intense subjective feelings of intoxication following modest doses of alcohol (Schuckit, 1992). This is seen in such diverse measures as body sway, blood alcohol levels, and cortisol release following challenge. This again suggests that a genetic factor that decreases sensitivity to alcohol may play a role in the development of the illness. Schuckit (in press, 1994) has recently demonstrated that a low level of response to alcohol at age 20 was associated with a fourfold increased likelihood of future alcoholism in both sons of alcoholics and sons of controls.
Cognitive and Motor Functioning. There is some research that indicates that cognitive impairments are present in some children of alcoholic parents (Drejer, Theilgaard, Teasdale, Schulsinger, and Goodwin, 1985; Knop, Teasdale, and Schulsinger, 1985; Schaeffer, Parsons, and Yohman, 1984; Tarter, Hegedus, and Gaveler, 1984; Gabrielli and Mednick, 1983). The impairments are in lower verbal intelligence quotients, lower levels of reading comprehension, and problems with logic and abstract reasoning in achievement tests. These results have not been widely replicated. Some studies have found few differences on these measures when children of alcoholics are compared with controls (Drake and Valliant, 1988; Schuckit, Butters, Lyn, and Irwin, 1987), and the results that are found may pertain only to subgroups of children with multiple risk factors, such as those whose mothers had high-risk pregnancies and those with fetal alcohol effects.
Psychosocial Risk Factors
The majority of studies on psychosocial risk factors focus on adolescent onset. Many of the studies focus on the risk of initiating use, whereas the risk of escalating to abuse or heavy use has received less attention. Unfortunately, much of the work done in this area is cross-
sectional, and so the results cannot distinguish factors associated with alcohol use from true risk factors that precede the onset of alcohol abuse or dependence. Because early and frequent use may lead to alcohol abuse, these factors are included in this review. Almost all of the studies on psychosocial risk factors fail to control for parental alcoholism or other mental disorder. Finally, many studies do not differentiate between alcohol use and other substance use.
There is little evidence that individuals at risk differ from controls on baseline measures of personality. The lack of evidence may at this time reflect methodological limitations in the studies that have been done or a true lack of association. However, there is one major exception to the lack of conclusiveness of personality measures —antisocial behavior. Antisocial behavior during childhood has been consistently related to alcohol problems in adulthood.
Difficulty in achievement-related activity among adolescents also has proved important, with studies documenting the following problems among those who later became alcoholic: poorer school performance, less productivity in high school, greater truancy, and greater incidence of dropping out (IOM, 1989). Aggressive behavior and the combination of aggressive behavior and shyness in the first grade have been found to predict heavy alcohol use at ages 16 and 17 (Kellam, Brown, and Fleming, 1982). Another study yielded similar results, indicating that males who were judged to be shy as children were least likely to become heavy alcohol users, but those who were rated as both shy and aggressive as children were most likely to develop drinking problems (McCord, 1988a,b). The relative risk of alcoholism has been found to be higher among males in their thirties who previously used alcohol with their peers when they were younger than 14 years of age (Hagnell, Isberg, Lanke, Rorsman, and Ohman, 1986). Males who later became alcoholic also had weaker interpersonal ties, ranging from being less considerate and less accepting of dependency to having a greater likelihood of leaving home early (IOM, 1989).
Cloninger (1987) has proposed an association between severe alcohol-related difficulties (in the type II alcoholism discussed earlier) and personality characteristics of high levels of novelty seeking and low levels of survival dependence and harm avoidance. These associations are all the more intriguing because the two disorders—alcohol abuse and dependence and antisocial personality disorder—probably have separate genetics.
Psychological factors such as low adaptability continue to influence alcohol use later in the life span. The probability of continued drinking and the eventual onset of alcohol abuse is higher if an individual is unable to develop alternative and more adaptive ways of coping with immediate situational demands, such as leaving home, changes in employment or marital status, retirement, or death of a spouse (IOM, 1989). In essence, the major determinants of problematic drinking may occur when the levels of external demand or strain are high and the individual is unable to cope with the stresses. The individual has high expectations that alcohol will produce the desired results, and he or she minimizes or denies the long-term negative consequences.
Factors external to the individual and arising in the broad social environment also affect the level of use and abuse of alcohol. The contextual factors that are strong predictors of use include community use patterns (Robins, 1984) and particularly peer group behavior (Barnes and Welte, 1986). Low socioeconomic status (Murray, Richards, Luepker, and Johnson, 1987) and neighborhood disorganization (Sampson, 1985) also contribute to increased risk for alcohol problems. Contextual factors also include the availability of alcohol, such as legality, enforcement, cost, and taxes (Hawkins, Catalano, and Miller, 1992). “Contrary to the prevalent view that prohibition failed, there is substantial evidence that it reduced alcohol consumption substantially ” (Goldstein and Kalant, 1990, p. 1515). Beginning with Cook and Tauchen (1982), a series of studies have suggested that increasing taxes decreases consumption. Levy and Sheflin (1985) showed that a 1 percent tax increase decreased consumption by 0.5 percent. Of the contextual factors, laws controlling availability and taxes controlling price are the simplest to change.
Psychosocial Aspects of Parental Alcoholism
Parental alcoholism is associated with a constellation of other risk factors, and it is these factors plus the alcoholism itself that lead to poor outcomes in children—of which alcohol abuse is only one (see Box 6.2).
Although much investigation has focused on identifying and assessing the magnitude of various risk factors involved in alcohol use, less is known about factors that may protect individuals from abusing alcohol.
Children of Parents with Alcohol Abuse and Dependence: Multiple Psychosocial Risk Factors for Their Development
Children growing up in families in which one or both parents are alcoholics face a wide range of problems (von Knorring, 1991 ). First of all, many attitudes, beliefs, and expectations concerning alcohol are formed early in life. Parental alcoholism adds pressures that may promote alcohol abuse. Children of alcoholics typically have early first-hand knowledge of alcohol; although many young children can identify various alcoholic beverages, researchers have found that there is a significant association between this ability and the level of drinking in the child's home. Some family dynamics reinforce the parent's abusive drinking, and children observe this and may internalize similar family norms. Studies have suggested that inadequate parenting—including lax supervision, an absence of parental demands, lack of parental interest or affection, and, most frequently, inadequate contact—is associated with increased risk of alcoholism (Zucker and Fitzgerald, 1991). It is not known whether this finding would hold if the study had controlled for other parental psychopathology, such as antisocial personality disorder, drug abuse, or depression.
Parental alcoholism also is associated with conflict and dysfunction in the family (Schulsinger, Knop, Goodwin, Teasdale, and Mikkelsen, 1986; Moos and Billings, 1982). Alcoholic families are less cohesive, less organized, less oriented toward intellectual or cultural pursuits, and more conflict-ridden (Clair and Genest, 1987). Children of alcoholics may have an increased risk of being neglected or abused (Zucker and Fitzgerald, 1991; Tarter et al., 1984; Lund and Landesman-Dwyer, 1979), but the evidence is not substantial. Children raised under such volatile circumstances may well be deficient in their socialization, and, also, a strong association between parental alcoholism and conduct disorder has been demonstrated (Steinhausen, Gobel, and Nestler, 1984).
Certain children in alcoholic families appear to be at particularly high risk. Children who have not experienced the cohesive impact of traditional family rituals during periods in which there is severe parental drinking are more likely to develop alcohol problems than are children from alcoholic families that have been able to maintain their rituals, such as those centering on dinner time, holidays, and vacations. In addition, boys with alcoholic fathers were more likely to become alcoholics themselves if the mother seemed to accept her husband's intoxicated behavior and to hold him in high esteem. These findings suggest that one developmental path to alcoholism may stem, in part, from family acceptance of an alcoholic parent 's intoxicated behavior (IOM, 1989).
Positive Group Norms
Membership in structured, goal-directed peer groups that do not abuse alcohol may protect teenagers against adolescent substance abuse. The element that appears to be critical is a group norm that does not expect or approve of substance use (Hawkins, Catalano, and Miller, 1992).
Brook and colleagues identified two protective factors related to attachment that reduce risk for adolescent drug use (not alcohol use specifically) (Brook, Brook, Gordon, Whiteman, and Cohen, 1990). The first was a strong attachment, or bond, between parent and adolescent and the second was a strong attachment between adolescent and father, which potentiated the positive effects of other protective factors, such as positive maternal characteristics.
Genetic Factors Modifying Expression of the Disorder
There are four clearly delineated polymorphic genetic loci that appear to modify the expression of alcoholism. This is more detailed information on genetic factors than is available for any mental disorder other than Alzheimer's disease. These loci include three regions that are responsible for isozymes that catalyze the oxidation of acetaldehyde (the oxidation product of alcohol) and the region that encodes the dopamine D2 receptor. The three loci encoding alcohol-metabolizing enzymes all can lead to an increase in the level of acetaldehyde following alcohol ingestion. Raised blood aldehyde levels are the basis of the flush reaction experienced by those carrying the appropriate genes. This reaction involves sweating, facial flushing, nausea, dizziness, and a feeling of faintness and is much more prevalent in Asian populations (Heizer, Canino, Yeh, Bland, Lee, Hwu, and Newman, 1990). Studies on Chinese, Japanese, and Korean populations show that these have between 30 and 50 percent expression of one of two inactive forms of aldehyde dehydrogenase, which leads to the flush reaction. In general, those affected with the flush reaction have much less tendency to abuse alcohol. This provides evidence that genetic factors can modify alcohol consumption and affect the expression of alcoholism. These factors can be modified by environmental factors, as shown by a study of men in Korea, where alcohol abuse is as high as in the West (Lee, Kwak, Yamamoto, Rhee, Kim, Han et al., 1990). Even here, those with aldehyde dehydrogenase deficiency tend to drink less than their non-affected counterparts; however, their level of abuse remains high due to cultural factors and peer pressure. This provides an interesting example of the power of environmental factors to overcome the inherent protection from alcoholism afforded by biological systems leading to acetaldehyde production.
In the case of the dopamine D2 receptor, there is some limited evidence that the minor allele of the DRD2 gene on chromosome 11 is
associated with alcoholism (Blum et al., 1990). Although this allele is not linked to the manifestation of alcoholism, it may be associated with the severity of the disease (Cloninger, 1991). Thus there may be genetic factors that can modify the expression of alcoholism even though they are not directly linked to the etiology of the disorder.
Findings and Leads
Alcohol abuse and dependence are genetically influenced disorders, and quantification of genetic risk has begun. Studies examining psychosocial risk factors for the onset of alcohol abuse and dependence have often failed to control for family history of alcoholism or other mental disorders, especially antisocial personality disorder and depression. As psychosocial risk factor research improves, more will become known about the relative and attributable risks associated with specific factors and with clusters of factors. It appears likely that it is the accumulation of both genetic and psychosocial risk factors that increases the risk for alcohol abuse and dependence. In particular, six risk factors are strongly associated with the onset of alcohol problems:
Having a parent or other close biological relative with alcohol abuse or dependence. The mechanism may be genetic, psychosocial, or both.
Having biological markers that are highly associated with later onset of alcohol dependence: (1) a low P3 amplitude, which is a measure of a brain wave pattern (an electrophysiological marker); (2) a lower stimulated adenylyl cyclase activity or lower monoamine oxidase activity (a biochemical marker); and/or (3) a decreased sensitivity to the effects of alcohol.
Demonstrating antisocial behaviors or a combination of aggressiveness and shyness during childhood.
Having low adaptability and being unable to cope with immediate situational stresses, including adverse family conditions.
Being exposed to community, neighborhood, or peer group norms that foster alcohol use and abuse.
Having easy access to alcohol (resulting from low cost, low taxes, lenient laws, and/or minimal law enforcement).
Identification of high-risk populations should include these multiple risk factors whenever possible. Suitable preventive intervention trials could then be designed. For example, if individuals with biological markers could be identified before they use alcohol, they could be given information that might encourage them to abstain from alcohol. Also, without alcohol there would be, obviously, no alcohol abuse or depen-
dence. Therefore control of availability has been and will continue to be a powerful prevention tool.
Major depression represents a profound biological dysregulation. Abnormalities in neurotransmitter function, the structure of sleep as measured by EEG studies, and regulation of neurohormonal response have been well documented. These can result in disturbances in eating, sleeping, energy, and attention, irritability, and distortions about the future, self-worth, and even about the value of life and living itself.
Major depression can result both from genetic influences and from severe and impairing traumatic life events. Animal models have elegantly demonstrated that a condition resembling severe depression that occurs in rats can result both from genetic influences and from environmental trauma and stress (Henn, Johnson, and Edwards, 1985). Thus, in the search for risk and protective factors, both classes of influence and their interactions are examined. Research has often focused solely on the broader category of mood disorders. In this review, evidence regarding mood disorders is used only when evidence on major depression is not available. When the older term “affective disorder” from DSM-III was used in the original research, that term is used here.
Biological Risk Factors
In terms of genetic influences, an individual's risk for mood disorders becomes larger the larger the proportion of genes shared with a mood-disordered individual. Rates for mood disorders among monozygotic twins are about three times those for dizygotic twins. The rate of concordance for mood disorders for monozygotic twins is 0.50 for unipolar disorder (major depression) and 0.70 for bipolar disorder (Tsuang and Faraone, 1990). This emphasizes both the difference in heritability for unipolar and bipolar disorder and that environmental factors play a significant role. Studies of individuals with less severe forms of depression, that is, with symptoms that do not meet criteria for disorder, show considerably less heritability (Tsuang and Faraone, 1990).
Family Studies. Using family aggregation studies, estimates of lifetime morbidity risks in first-degree relatives of probands with major depres-
sion range from 0.18 to 0.30 for adults (Petersen, Compas, and BrooksGunn, 1992). Aggregated risk is generally higher in children than in adolescents and in adolescents than in adults. Rough estimates are about 0.50 for children and 0.35 for adolescents (Tsuang and Faraone, 1990). Thus the genetic loading for child and adolescent onset of major depression may be higher than that for adult onset. Current longitudinal studies suggest that early onset may be associated with more frequent episodes of major depression during childhood. Weissman and colleagues report that individuals with an onset of major depression prior to age 20 are more likely to have family members who are depressed than those whose first episode occurs after age 20 (Weissman, Gammon, John, Merikangas, Warner, Prusoff, and Sholomskas, 1987a). Although there is strong reason to support a genetic component to depression, the exact weight of genetic and psychosocial factors remains to be determined and the nature of the genetic transmission in depressive disorders remains to be elucidated. Segregation analyses have not been helpful in elucidating a mode of transmission in mood disorders.
Linkage Studies. There is important work in progress regarding the forms of heritability of mood disorders. Most research has focused on bipolar disorder, but there has been some work regarding major depression. For example, Neiswanger and co-workers studied three extended families with unipolar affective illness and excluded linkage of this disorder to certain loci on chromosome 11 (Neiswanger, Slaugenhaupt, Hughes, Frank, Frankel, McCarty et al., 1990). A previous report of linkage to this region (Egeland, Gerhard, Pauls, Sussex, Kidd, Allen et al., 1987) also proved wrong when previously unaffected family members developed the illness (Pauls, Gerhard, Lacy, Hostetter, Allen, Bland et al., 1991).
Disease and Medication
Major depression frequently occurs in association with medical disorders and the use of certain medications. These depressions presumably occur because of disruption in neurotransmitter function that accompanies the underlying biological processes. Severe infections; tumors; endocrine conditions, including Cushing's disease, Addison's disease, hypothyroidism, hyperthyroidism, and diabetes mellitus; the use of medications such as reserpine and other antihypertensive agents, oral contraceptives, and various anticonvulsives; and the presence of anemia, electrolyte abnormality, and various metabolic disorders all are associated with the appearance of major depression.
There is an association in children between brain injury and increased risk for mental disorders (Rutter, 1983). The mechanism involved in this association is poorly understood. However, it has long been observed that there is an association between various kinds of learning difficulties, in particular difficulties in learning to read, and subsequent problems with low self-esteem, which can predispose to depression.
Psychosocial Risk Factors
Severe and Traumatic Life Events
The presence of severe and traumatic events in an individual's life is associated with increased rates of major depression (Beardslee and Wheelock, in press; Coyne and Downey, 1991). Factors that have received the most attention include downward social mobility, loss of job, death of a spouse, child, or parent, divorce, and poverty. More recently, it has become clear that being the victim of child maltreatment carries with it a heavy risk for subsequent mental disorder including depression (Green, 1991). Although data are not definitive as yet, it is also likely that other severe traumas, such as being the victim of a violent crime or of a natural disaster, may predispose to depression (Coyne and Downey, 1991). In an examination of the connection between sexual assault and mental disorders in a community population, a strong association was found between history of assault and later onset of major depressive episodes (Burnam, Stein, Golding, Siegel, Sorenson, Forsythe, and Telles, 1988). There is an extensive literature to suggest that repeated negative experiences can lead to the development of a sense of helplessness, hopelessness, and low self-esteem, as well as to a sense of not being in control of one's surroundings. These overlapping conditions strongly predispose individuals to the development of depression (Petersen et al., 1992).
Whereas negative life circumstances, as described above, predispose to depression, the presence of close, intimate, supportive relationships appears to protect against it (Coyne and Downey, 1991). However, the nature of these relationships is complex. Perhaps the best model involves a major loss in childhood—the loss of a parent—and the development of subsequent depression. Brown and Harris (1989) have shown that adults who lost a parent in childhood and have become depressed not only have that risk factor, but also require a provoking agent in adulthood and the absence of good social support. In a series of
studies of inner-city women in London who had lost a parent in childhood, Brown and Harris (1989) demonstrated that those who did not have a close confiding relationship in adulthood and had unusually strong stressors developed depression. Those who had lost a parent in childhood but had good relationships and no such stressors did not develop depression. The authors also showed that the loss of care following the death of the parent was more important than the parental loss itself. Further studies established that lack of care in childhood following loss of a mother is associated with mood disturbance in adulthood. This influence is mediated by premarital pregnancy and marital dysfunction. Inadequate care increases the risk of early premarital pregnancy, which in turn increases the risk of marriage to an undependable partner. Marriage to such a partner, in addition to being low in intimacy, increases both the risk of serious life events like trouble with the law, threats of eviction, and poverty, and the risk of depression.
Accumulation of Stresses at a Time of Transition
Recent evidence in adolescent females indicates that the accumulation of stresses at a time of transition may place them at greater risk for developing depressive symptoms (Petersen et al., 1992). In trying to understand why the rates of disorder are so high in adolescent women, Petersen and colleagues have suggested that the combination of going through puberty and having a transition from one form of school to another (from primary to secondary school), along with a breakup of the family, form a constellation of risk factors that leads to increased rates of depression in this group. Clearly, the burdens of childrearing, when not adequately supported, predispose to depression (Weissman, Leif, and Bruce, 1987b). Downward social mobility and the lack of access to opportunities also can play a role in depression (Dohrenwend et al., 1992).
Although in general, the foregoing risk factors are well established, detailed prospective studies of the influence of various risk factors over time and the mitigating effects of other variables, for the most part, have not been conducted in large samples. Two notable exceptions are the Epidemiologic Catchment Area (ECA) study (Anthony and Petronis, 1991) and the Alameda County study (Kaplan, Roberts, Camacho, and Coyne, 1987). Neither examined mood disorder in relatives, genetic influences, or the effect of severe trauma. They did, however, examine a variety of other influences. These studies excluded individuals who
were depressed at the time of first assessment, so that these risk factors were for first onset of depression subsequent to first assessment. Using the ECA data base, the incidence of new cases of depression in a one-year period was assessed, and the factors from the first assessment that predicted the onset of new cases in that interval were examined. These factors dealt primarily with sociodemographic information. The major risk factors that predicted episodes of major depression were being female, being separated or divorced at initial assessment, and not having paid employment or a job with prestige. For less severe forms of depression, the effects of being separated or divorced and the diminished risk among working persons were also found.
In a follow-up study in the ECA catchment area, poverty was shown to have a profound impact on onset of new cases and thus to be a significant risk factor for depression (Bruce, Takeuchi, and Leaf, 1991). Using a general measure of mental disorder, 6 percent of all new cases of all types of mental disorder occurring in a six-month interval were the result of poverty. For depression specifically, 10 percent of new cases in that interval were attributed to poverty. By extrapolating from the sample at the New Haven site in the ECA study, Bruce and colleagues estimated that during the interval of the six-month interview period, 1,200 new episodes of major depression could be attributed to poverty (Bruce et al., 1991).
In a follow-up of approximately 7,000 Alameda County adults nine years after initial assessment, low education, presence of physical disability or other chronic medical conditions, poor perceived health, a strong sense of personal uncertainty, a move of residence, job loss, financial problems, and a sense of anomie and social isolation were all associated with increased risk for depressive symptoms at follow-up, while, interestingly, marital status was not (Kaplan et al., 1987).
Mental health services are underutilized by minority groups (Hough, Landsverk, Karno, Burnam, Timbers, Escobar, and Regier, 1987). This has implications for prevention. First, such groups may have a preference for preventive services that do not require that they identify themselves as psychiatric cases. Second, prevention programs should be organized so as not to make the mistake that treatment programs did, that is, to appear to be inaccessible or unacceptable to significant segments of the population, especially ethnic minorities.
Across the life span, factors including good intelligence, easy temperament, and the presence of a supportive adult have all been shown to protect against the expression of psychopathology, including depres-
sion. In certain individuals whose parents suffer from depression, resiliency in late adolescence is associated with good interpersonal relationships, a strong sense of self, and a clear understanding of self and of the parent's illness (Beardslee and Podorefsky, 1988). In fact, most studies show that during adolescence the majority of children of parents with mood disorder are functioning reasonably well. At any one point in time, complex interaction between risk and protective factors operates in children of depressed parents, and an understanding of these factors across the developmental course highlights opportunities for prevention (see Box 6.3).
Findings and Leads
Depression is a common disorder that is seriously impairing and has multiple etiologies. It is associated with a series of other disorders and conditions that predispose to poor outcome. In particular, five risk factors are likely to be associated with the onset of depression:
Having a parent or other close biological relative with a mood disorder. The mechanism may be genetic, psychosocial, or both.
Having a severe stressor such as a loss, divorce, marital separation, unemployment, job dissatisfaction, a physical disorder such as a chronic medical condition, a traumatic experience, or, in children, a learning disorder.
Having low self-esteem, a sense of low self-efficacy, and a sense of helplessness and hopelessness.
Living in poverty.
It is appropriate to consider the possibility of programs to prevent the emergence of depression because of the substantial knowledge base about depression, the frequency of the disorder, and the costs associated with it.
Approaches that have targeted the prevention of clinical depression in high-risk adults or the prevention of depressive symptoms for those at high risk because of a major loss have all shown some promise (see Chapter 7 for illustrations of numerous preventive intervention research programs on depression). Definitive evidence of the prevention of the initial episode of major depressive disorder is not available at this time. Problems have included lack of large enough sample sizes, lack of adequate follow-up, and lack of valid measurement of symptoms and disorders. The most successful efforts to date have been able to show reductions in depressive symptomatology in high-risk groups rather
Children of Parents with Mood Disorders: Opportunities for Prevention
Having a parent with a serious mood disorder is the single largest risk factor for initial onset of depression in childhood and adolescence and, because it involves both genetic and psychosocial risk factors, is among the largest risk factors for depression across the life span. A brief review of the literature on children of parents with depression is in order both to look at how this risk factor operates and to illuminate opportunities for prevention.
Documentation of the Risk Factor
For decades, it has been well established that severe mental disorder in parents is associated with increased rates of mental disorder in offspring. Recently, a series of rigorous empirical studies have been conducted using standard diagnostic instruments with the children of parents with serious mood disorders (Beardslee and Wheelock, in press; Downey and Coyne, 1990). The majority of these studies focused on parental major depression, but some focused on bipolar disorder, and therefore the more inclusive term mood disorder is used here. These studies are the result both of the recognition of childhood depression as a discrete entity and of the awareness that such children are themselves at heightened risk, particularly for depression. There is a clear consensus in the empirical research literature that children of parents with mood disorders fare much more poorly than subjects in comparison samples. A series of studies conducted by different investigators in different sites, but with similar designs, have conclusively established that the rates of adolescent depression in offspring of parents with mood disorders are at least several times higher than in children of parents with no disorder. These rates often reach 30 percent by the end of adolescence (Downey and Coyne, 1990). Children in these families also manifest impairments in adaptive and social functioning, as well as school and medical problems. Moreover, youngsters who experience depression or other serious psychopathology are largely unrecognized and untreated (Keller, Lavori, Beardslee, Wunder, and Ryan, 1991). These findings parallel findings of underrecognition and undertreatment of childhood disorders in epidemiological studies and studies of pediatric practice (Beardslee, Salt, Porterfield, Rothberg, van DeVelde, Swatling et al., 1993b). They also parallel the corresponding finding in adults that depression is underrecognized and undertreated. There is also substantial literature to indicate that children of parents with severe mood disorder are at considerable risk for a variety of poor developmental outcomes from birth to age five (Beardslee and Wheelock, in press; Downey and Coyne, 1990).
Most of the studies of the impact of parental mood disorder on children have been conducted using clinically referred parents. Extension of studies to nonreferred samples has demonstrated the same powerful effect of parental mood disorder on child outcome (Beardslee, Keller, Lavori, Staley, and Sacks, 1993a).
Parental Mood Disorders: A Constellation of Risk Factors
The strong association between parental mood disorder and poor child outcomes is not a simple relationship. Parental mood disorder is associated with a number of other risk factors, and it is this entire constellation, including parental mood disorder, that leads to poor outcomes in children. This has important implications both for understanding etiology and for fashioning preventive intervention approaches.
In children with a depressed parent, the risk of developing depressive symptoms or disorders is greatly heightened by the presence of other associated mental disorders in the parent, depressive disorder in both parents, greater chronicity and severity of the parental disorder, the presence of divorce, and disturbances in parenting (Beardslee and Wheelock, in press; Downey and Coyne, 1990). These factors suggest particular groups for targeting. Adults with mood disorder have high co-morbidity with other disorders, in particular anxiety disorders and substance abuse. Given the phenomenon of assortative mating (i.e., the tendency of people to select as mates people with the same or similar characteristics), there is a much higher than chance rate of depression in the spouse of an individual identified with mood disorder. Hence youngsters are likely to be exposed both psychosocially and genetically to depressive disorder in both parents. Moreover, there is a higher rate of divorce and marital dysfunction in individuals with mood disorder, and these are risk factors for psychopathology in children independent of depression. Finally, there is overwhelming evidence that severe depression, regardless of its cause, profoundly impairs interpersonal relationships and imposes a heavy interpersonal burden on the family.
There are numerous interactional studies examining the patterns of relationship between depressed mothers and their young children that demonstrate profound disturbances in parenting (Beardslee and Wheelock, in press). The two psychosocial factors that have received the most attention across a wide range of studies of children of parents with mood disorders are (1) interferences with the ability to parent and (2) the presence of severe marital discord and divorce (Rutter, 1990).
Need to Study Multiple Outcomes
It is important to frame outcomes for children in developmentally appropriate terms. Outcomes reflecting depression in children from birth to age five are not diagnosable depressive disorders but impairments in cognitive functioning, psychosocial development, and attention. Depressive symptoms exhibited by school-age children are more variable but often involve interpersonal relationships, some depressive symptomatology, and some mental disorders. From early adolescence on, impairments can be classed in terms of the major diagnostic categories in DSM-III-R. For depression in one parent, the outcomes are quite variable. Some children develop anxiety disorders, some have school problems, and some develop depressive symptoms or disorders. Thus, at least for children and adolescents, preventive interventions targeting a single risk factor need to consider not a single diagnosis but a range of outcomes and a range of diagnoses.
Preventive Intervention Research
Children of parents with mood disorders present a particular opportunity for prevention because the risk to them is well documented. Interventions must be informed by a knowledge of the specific developmental level of the child and also must involve parents and other caretakers. Interventions that enhance parenting skills, apply cognitive behavioral techniques used with adults (Muñoz, 1987), or promote understanding in adolescence are encouraging. Another approach helps parents focus on the future of the children, helps the children better understand the illness experience of the parent, and enhances resiliency in the children. Initial results of this approach to strengthening families in adversity have proved promising (Beardslee et al., 1993b).
than documenting prevention of onset of major depression. This area is one of the most promising for continued preventive intervention research.
Conduct disorder has the earliest average age of onset of the five illustrative disorders in this report. It is an important disorder on several accounts. It is the disorder most frequently referred to child psychiatric clinics. It is hard to treat. It has a significant level of persistence into adult life and is a precursor to many other dysfunctions that give rise to impairment in adult life, including alcoholism and schizophrenia (Robins, 1966). There are at least two subtypes of conduct disorder—early onset and adolescent onset.
Biological Risk Factors
The role of genetic influences in the development of conduct disorder has been difficult to sort out. The families in which conduct problems arise often are disorganized and have a parent who exhibits either antisocial behavior or substance abuse. Thus the problem clearly runs in families, but the families also create environments that may result in conduct problems. There have not been twin and adoption studies of conduct disorder as there have been for the other illustrative disorders. In part, this is because conduct disorder is a relatively new diagnosis, appearing in the DSM for the first time in 1968. However, estimates of heritability can be obtained from adults
with antisocial disorder. It is a safe assumption that the adults with these problems did exhibit conduct disorder in childhood, but they are not representative of the entire group of individuals who have conduct disorder, many of whom will not go on to show full-scale antisocial behavior or criminality. Adult twin studies have demonstrated higher concordance for monozygotic over dizygotic twins in criminal behavior (Christiansen, 1977a,b). The use of adopted-away samples is an even better way to approach the question, but these studies are limited. Cadoret, Cain, and Crowe (1983) studied several adopted samples and concluded that both genetic and environmental forces play a role in the expression of antisocial behavior. In a large-scale Danish study of criminality, Mednick, Gabrielli, and Hutchings (1984) came to a similar conclusion that a genetic predisposition played a role in the development of criminal behavior. In 1986, Mednick and co-workers reported that biological fathers and male adoptees have much higher rates of criminality than adoptive fathers (Mednick, Moffitt, Gabrielli, and Hutchings, 1986). More recently, DiLalla and Gottesman (1989) reported that a heritable contribution to adult criminality appears more clearly established than to conduct disorder and delinquency.
Some studies thus support a role for genetic factors, but the data are inconsistent, inconclusive, and suffer from instability of diagnosis and other methodological flaws.
It has been proposed that physiological abnormalities underlie the symptoms of impulsivity and the failure to inhibit aggressive behaviors. Earls (in press) has reviewed the potential physiological processes in conduct disorder that might be under a degree of genetic control, and thus in part might explain the heritability of antisocial behavior, assuming that such heritability proves accurate upon future investigations. The most well-replicated physiological influence is disturbance of the autonomic nervous system, demonstrated by low heart rate, decreased amplitude and slow recovery of skin conductance, and slow EEG wave activity. Other possible, but not well-studied, influences include central neurotransmitter systems, dietary or metabolic influences, the effects of gonadal hormones, abnormal levels of platelet monoamine oxidase, and low levels of plasma dopamine B hydroxylase. Rutter and Giller (1983) have suggested that the autonomic features support a biological basis for the reported reduced anxiety and impaired passive avoidance following punishment in antisocial individuals.
Conduct disorder has been repeatedly shown to be more common in boys than in girls. In the Isle of Wight studies (Rutter, Tizard, and Whitmore, 1970), the rate of conduct disorder, using a much broader definition than that in DSM-III-R, in 10- and 11-year-olds showed a boy:girl ratio of 3.8:1. Similarly, in the Ontario Child Health Study (Offord et al., 1987), the rates for boys and girls 6 to 11 years were 6.5 and 1.8 percent, respectively. In early adolescence the rate in boys (9.1 percent) was found to be almost four times the rate in girls (Offord and Boyle, 1988). However, in the same study it was found that the ratio of conduct disorder in 15- and 16-year-olds approached 1 because of the later onset of conduct disorder in girls (Offord and Waters, 1983). It is still not clear whether the different ratios at the earlier ages are due to constitutional differences reflected in behavioral differences (Earls, 1987) or to differences in socialization, resulting in different learning experiences and expectations for boys than girls. What is clear is that the difference in ratios between boys and girls occurs early. In studies of young children, the precursors of conduct disorder —early behavioral problems, including oppositional behavior—are also more likely to occur in boys than girls (Earls and Jung, 1987; Richman, Stevenson, and Graham, 1982).
Early Temperamental Difficulties
Temperament refers to those aspects of personality that show some consistency across time (Kazdin, 1992). Differences in temperament are based on individual characteristics such as activity level, responsiveness, consistency of mood, and social adaptability (Chess and Thomas, 1977). “Easy to manage” children are characterized by a happy disposition, adaptability to change, and a willingness to approach new stimuli. Children who are temperamentally difficult and have mentally ill parents are more than twice as likely as children with easy temperaments and mentally ill parents to be the target of parental anger and criticism (Rutter and Quinton, 1984). Children who are difficult are more likely to show later behavioral problems than children who are less difficult (Reitsma-Street, Offord, and Finch, 1985; Earls, 1981). Greenberg, Speltz, and DeKlyen (1993) point out that data from the Bloomington Longitudinal Study (Bates, Bayles, Bennet, Ridge, and Brown, 1991) show that mothers' reports of infant difficultness at six months and infant resistance to control at one year significantly predicted maternal reporting of externalizing behavior problems at ages 3, 6, and
8 years. The intermediate variable was coercive mother-child interaction during the preschool years. It is the combination of infant difficulty with family stress or dysfunction that has been found to contribute to later behavior problems (Maziade, Coté, Bernier, Boutin, and Thivierge, 1989). Conversely, easy temperament appears to act as a protective factor in these circumstances. Although these results are encouraging, the evidence for temperament as a risk or protective factor for conduct disorder is still incomplete.
There is considerable co-morbidity between attention deficit hyperactivity disorder (ADHD) and conduct disorder. In the Ontario Child Health Study, 40 percent of ADHD children in 1983 also showed symptoms of conduct disorder four years later (Offord, Boyle, Racine, Fleming, Cadman, Blum et al., 1992). The difference between those with both disorders and those who remained attention deficit disordered but did not develop co-morbid conduct disorder was the level of family functioning (Offord et al., 1992). Families who are able to provide a supportive, consistent environment with expectable limits presumably allow these children to develop enough prosocial skills that they can function reasonably well in school and with their peers.
Cognitive and Neuropsychological Deficits
There has been considerable debate as to whether conduct disorder precedes or follows from low intelligence, language dysfunction, or neuropsychological deficits. There is some evidence that cognitive and linguistic problems precede the behavior problems (White, Moffitt, and Silva, 1989; Beitchman, Nair, Clegg, Patel, Ferguson, Pressman, and Smith, 1986). It has been suggested that cognitive deficits, poor language comprehension, and impulsivity in aggressive children and adolescents may be related to dysfunctions in the left frontal lobe of the brain (Gorenstein, Mammato, and Sandy, 1989). The specific deficits that are seen include inability to plan, concentrate, rechannel potentially harmful behaviors, and learn from the negative consequences of behavior (Moffitt, 1993; Moffitt and Henry, 1991).
Cognitive deficits understandably lead to school underachievement, which has been consistently associated with conduct disorder. In the Isle of Wight study (Rutter et al., 1970), one third of the 10-and 11-year-olds who were severely delayed in reading showed evidence of conduct disorder, and, conversely, one third of the conduct disordered
children were at least two years delayed in their reading after allowing for IQ differences. These associations held even after controlling for family size and social class. There are four major hypotheses concerning the overlap between underachievement and conduct disorder: (1) underachievement leads to externalizing behavior, (2) externalizing behavior leads to underachievement, (3) hypotheses 1 and 2 occur simultaneously, and (4) underlying variables are the actual cause in both problems. All four hypotheses need further exploration to derive explanatory models with sufficient rigor, complexity, and validity to handle the diversity of causal factors (Hinshaw, 1992).
Chronic Ill Health
Children with chronic ill health, if they also have a functional physical limitation (any sensory, physical disorder, or disability that interferes with functioning), have been found to have three times the incidence of conduct disorder as healthy peers (Cadman, Boyle, Offord, Szatmari, Rae Grant, Crawford, and Byles, 1986). Children with chronic ill health without disability have been found to have twice the incidence of conduct disorder (Cadman et al., 1986). Chronic conditions affecting the central nervous system place the child at even higher rates of risk; children with central nervous system damage have five times the incidence of conduct disorder, according to studies by Rutter (1977) and Brown and colleagues (Brown, Chadwick, Shaffer, Rutter, and Traub, 1981). It is not known whether brain damage exerts its effect primarily through the presence of cognitive disability per se or through the resulting difficult temperament on the part of the infant.
Psychosocial Risk Factors
Precursor Symptoms in the Child
Identification of patterns of early precursor symptoms may lead to identification of children and adolescents who are at especially high risk for developing conduct disorder. Beginning at ages four to six, aggression predicts later delinquency (Loeber and Dishion, 1983). When aggression is combined with other behavioral characteristics, however, the predictive power increases. A combination of aggressiveness and shyness appears to be predictive of conduct disorder as well as drug abuse (Farrington and West, 1990; Moskowitz and Schwartzman, 1989; McCord, 1988a,b; Kellam, Brown, Rubin, and Einsminger, 1983). Farrington and colleagues from the Cambridge Study in Delinquent Devel-
opment found that there was a tendency for shyness to act as a protective factor against delinquency and crime for nonaggressive boys but as an aggravating factor for aggressive boys (Farrington, 1989, 1987; Farrington, Gallagher, Morley, St. Ledger, and West, 1985). Another pattern that may predict conduct disorder is the combination of aggressiveness with peer rejection (Andersson, Bergman, and Magnusson, 1989). Finally, early substance abuse correlates with adolescent onset of conduct disorder (Robins, 1980).
The number of symptoms appears to be a better indication of the potential for serious disorder than the pattern at any one point in time (Robins and Ratcliff, 1980; Robins and Wish, 1977). Likewise, the earlier the first symptoms appear, the higher the risk may be for subsequent conduct disorder, and early onset of the disorder has been consistently linked to poorer outcomes, including serious and chronic antisocial behavior (Farrington, Loeber, Elliott, Hawkins, Kandel, Klein et al., 1990; Loeber, Brinhaupt, and Green, 1990; Tolan, 1987; Loeber and Dishion, 1983; Robins, 1966).
The importance of parental psychopathology as a cause of conduct disorder has been addressed in numerous studies, but as mentioned earlier, the influences of nature versus nurture have not been sorted out. A review of studies conducted from 1975 to 1985 found that criminal and alcoholic parents have a greatly increased risk of having children with conduct disorder (West and Prinz, 1987). In a large longitudinal case comparison study of 518 single-parent and 502 two-parent families, Avison (1992) found that children with externalizing problems directed toward others had mothers who were likely to score more than twice as high on measures of psychological distress and were twice as likely to have experienced problems with alcohol or to have had a major depressive episode. The same study identified that maternal alcohol problems have the greatest effect on the behaviors of younger boys.
Other studies have found that maternal antisocial personality has a profound negative effect on a child (Frick, Lahey, Hartdagen, and Hynd, 1989; Lahey, Russo, Walker, and Piacentini, 1989). Alcoholism and antisocial personality disorder in the father, combined with low socioeconomic status, are highly correlated with conduct disorder in the child (Earls, Reich, Jung, and Cloninger, 1988). The mechanism may be primarily through the poor parenting environment provided or through a genetic component. Children of alcoholics appear to have an elevated rate of truancy, more contacts with the police, and more substance
abuse and are more likely to drop out of school (West and Prinz, 1987). In addition to the influence of parental behaviors and psychopathology, it has been found that there can be a potentiation of antisocial behavior among brothers (Jones, Offord, and Abrams, 1980). However, the presence of sisters in a family tends to suppress antisocial behavior (Reitsma-Street et al., 1985).
Weiss and Hechtman (1986) studied 75 young adults and 45 normal controls matched initially on age, gender, IQ, and socioeconomic status. At 10- and 15-year follow-up into adulthood, the 25 percent of hyperactive adolescents who demonstrated significant antisocial behavior had higher initial ratings of aggressive behavior and family psychopathology.
Marital discord in families has been persistently found to predict disruptive behavior problems in boys, especially in combination with maternal depression (Rutter and Giller, 1983). It is the extent of discord and overt conflict, regardless of whether parents are separated, that is associated with the risk for antisocial behavior (Hetherington, Cox, and Cox, 1982). Grych and Fincham (1991) recently reviewed studies of marital conflict and children's adjustment, concluding that 15 of 19 relevant studies support the association between parental discord and children's psychopathology. Some studies have documented this link more specifically for conduct disorder (Jouriles, Murphy, and O'Leary, 1989). Furthermore, the effects of witnessing marital violence have recently been shown to predispose boys to use violence as a means of conflict resolution (Jaffe, Hurley, and Wolfe, 1990).
Other dysfunctional parenting practices, especially harsh, erratic, and abusive forms of discipline, also predispose to the development of conduct disorder. Patterson, Reid, and their colleagues have carefully documented how aversive behavior on the part of both child and parent, combined with parental inconsistency, create negative reinforcement patterns in which child aggression and coercion (increasingly demanding interaction) are reinforced (Patterson, DeBarysh, and Ramsey, 1989; Patterson, Chamberlain, and Reid, 1982). The combination of inadequate supervision, parental criticism, harsh and inconsistent discipline, and rejecting attitudes toward the child have been described by Patterson, Reid and their colleagues to have a specific, independent association with antisocial behavior in children.
On the basis of studies by several investigators (Widom, 1989a,b; Carmen, Rieker, and Mills, 1987; Lane and Davis, 1987), Earls (in press) has concluded that there is a strong association between child maltreatment and delinquency and adult crime in later years. Dodge and colleagues found that children who had been physically abused in
infancy had clinically significant symptoms by the age of six but that not all of the children had aggressive symptoms (Dodge, Bates, and Pettit, 1990). Some symptoms, especially those of girls, were of an internalizing nature, directed inwards. Approximately 25 percent of the abused or neglected children became delinquent, a rate double that in nonabused controls. The antisocial behavior apparently begins very early. Children who have been physically abused tend to behave in more aggressive ways than children who have not (Cicchetti and Carlson, 1989; Widom, 1989a,b). Lewis (1992) described a lack of empathy in abused toddlers, which she suggested reflects their conditioned ability to insulate themselves from any stimuli that might evoke their own painful experiences. The long-term effects of physical abuse and neglect seem to be greatest among those who have aggressive parents and became aggressive themselves (McCord, 1983).
Community Risk Factors
Indicators of socioeconomic disadvantage, such as poverty, overcrowding, and poor housing, have been shown to be associated with an increased risk of childhood conduct problems (Hawkins, Catalano, and Miller, 1992). Socioeconomic disadvantage appears to have its effect due to the aggregation of risk factors, that is, the number of life stresses and daily hassles that inevitably have an impact on family interactions and relationships in a way that changes what Rutter has termed the “under the roof culture” of the family (including family cohesiveness, parental responsiveness, and limit setting) (Rutter, 1985a). This effect occurs predominantly in urban settings. Offord and colleagues found that low income was one of the most significant risk factors for the onset of conduct disorder, but it had its effect on children aged 4 to 11, not on adolescents (Offord, Alder, and Boyle, 1986). In an exceptionally lengthy risk study—a 30-year follow-up to measures taken in the first five years of life—Kolvin and co-workers demonstrated that low socioeconomic status of a child's family at age 5 is a powerful risk factor (Kolvin, Miller, Fleeting, and Kolvin, 1988). Of the 31 percent of males who committed either a juvenile or an adult offense, only 5 percent came from the higher socioeconomic groups, I and II, whereas 26 percent came from group III and 42 percent from groups IV and V.
Sociological studies have shown that urban areas typically have higher rates of delinquency. In Rutter's classic studies comparing children living in the Isle of Wight with those in inner London, it was found that the rates of conduct disorder were twice as high in London. Within cities with high crime rates, there is marked variation by
neighborhood (Sampson, 1985), with rates varying by a factor as large as five (Rutter and Giller, 1983). High-delinquency neighborhoods are those areas in which there is social disintegration with a high rate of social problems, including high rates of adult crime, substance abuse, infant mortality, low birthweight, and child maltreatment.
In socially disorganized communities a significant decline in the proportion of older, long-time male residents leads to an increase in youths becoming members of delinquent gangs. Having an antisocial peer group plays a part in the acquisition and maintenance of aggressive behavior. Some reports support the idea that if antisocial youth leave an antisocial peer group and join a more prosocial group their level of antisocial behavior may diminish (Osborn and West, 1980; Knight and West, 1975). Despite the risk effects that tend to congregate in large urban areas, certain high schools, which emphasize academic achievement and personal responsibility and reward prosocial behavior, have been found to reduce the risk of antisocial behavior in their students (Rutter, Maughan, Mortimore, Ouston, and Smith, 1979). On the other hand, evidence suggests that being apprehended by the police escalates antisocial behavior in youth with conduct disorder, possibly because contact with law enforcement may lead to increased antiauthoritarian attitudes (Offord, 1989).
Accumulation of Risk Factors
Studies have consistently confirmed that as the number of adverse conditions accumulates, the risk of conduct disorder increases proportionately (Blantz, Schmidt, and Esser, 1991; Rutter, 1978). Moffitt (1990) reported that the presence of family adversity—including low education, psychiatric illness, substance abuse, and criminality in the parent; marital distress and family violence; and poverty and overcrowding —at age 5 was a significant predictor of teenage delinquency in children who showed hyperactivity and disruptive behavior problems in early childhood. The correlates of conduct disorder reported in the Ontario Child Health Study (Offord et al., 1992) indicate that the three most significant risk factors exerting independent effects on conduct disorder were family dysfunction (relative odds = 3.1), parental mental disorder (relative odds = 2.2), and low income. Low income had its effect on children aged 4 to 11 years (relative odds = 3.7) but not on adolescents. Farrington (1991) found that inadequate parental discipline and school failure, combined with economic disadvantage and family criminality, predicted juvenile convictions.
Greenberg, Speltz, and DeKlyen (1993) have suggested that there are
four domains of risk that are necessarily interrelated to produce early-onset conduct disorder. These are (1) contributions from the child's organic, biological difficulties (such as difficult temperament and abnormal psychophysiology); (2) factors in the family ecology and family adversity, disruption, and stress; (3) ineffective parental management and socialization; and (4) problems in early parent-child relations (such as insecure attachment in infancy and the preschool years).
It appears that it is the transactional interaction between factors in the child (such as genetic and temperamental factors) and factors in the family environment (any factor that produces a lack of responsivity in the primary caretaker) that produces aggressiveness in early childhood. Aggressive children are apt to be rejected by parents, peers, and teachers. This sets up further negative interaction cycles.
Just as the accumulation of risk factors influences outcomes in childhood, it also influences outcomes further on in the life cycle. A 25-year follow-up study of children with attention deficit hyperactivity disorder by Hechtman has suggested that a combination of measures influence outcome in adulthood (Hechtman, 1991; Weiss and Hechtman, 1986). These include (1) individual personal characteristics (such as IQ, health, and temperament); (2) family parameters (such as socioeconomic status, family composition, mental health of family members, emotional climate of the home, and childrearing practices); and (3) the larger social and physical environment.
The protective factors that reduce the chance that a child at risk will develop conduct disorder include good intelligence; easy disposition; an ability to get along well with parents, siblings, teachers, and peers; an ability to do well in school; having friends; being competent in non-school skill areas (Rae Grant, Thomas, Offord, and Boyle, 1989); and having a good relationship with at least one parent and with other important adults (Werner and Smith, 1992).
The presence of a positive warm bond between parent and child in early childhood can lead to greater compliance and reciprocity. This good relationship allows the child to empathize with another person 's affective state, and, according to Minde (1992), is an essential prerequisite for prosocial behavior. In contrast, aggressive children tend to misperceive frustration in others as hostility directed toward them, and then respond aggressively (Dodge, 1980). Involvement in extracurricular activities for which recognition is received (Rae Grant et al., 1989), the support of other significant adults in the community (Werner and
Smith, 1992), prosocial peer groups, and good schools that foster academic success, responsibility, and self-discipline (Rutter et al., 1979) all are associated with a diminished risk of conduct disorder and more favorable outcomes, even for adolescents living in high-risk situations. Hawkins and colleagues have emphasized the role of social bonding, which refers to attachment, commitment, and adherence to the values of others (Hawkins and Lam, 1987; Hawkins and Weis, 1985). This occurs in the contexts of family, school, and peer relationships.
Good schools have been found to have a profound protective effect on students at the secondary level. Rutter et al. (1979) has described these as emphasizing academic work, reinforcing good work and behavior, providing good working conditions for students, having consistent teacher expectancies, making teachers available to deal with problems, and according responsibility to students.
Findings and Leads
Much still remains unknown about conduct disorder, including its subtypes, the risk factors involved in its onset, and the protective factors in the child, family, and community that lead to more favorable outcomes. Both prospective, longitudinal studies that begin early in life and well-designed efforts at prevention are needed for progress to occur (Tonry, Ohlin, and Farrington, 1990).
It is the accumulation of risk factors and the interaction among them rather than any specific risk factor that is important in the onset of conduct disorder. The transactional interaction between the individual child and his or her environment over time is the ecological crucible in which the pathways to the development of a range of positive or negative childhood and adult outcomes are forged. During the early years of development, the family environment is of greater importance. As children develop and move outside the family, influences from peers, the school, and the community assume increasing importance and should be targeted for intervention studies. Preventive intervention programs must address these multifactorial risks across social settings. Knowledge will grow from research on the relative and attributable risks associated with single risk factors as well as clusters of risk factors.
The lack of twin and adoption studies in conduct disorder is a major research gap. Such data could contribute toward understanding the roles of genetic as well as environmental influences.
Because early onset has been consistently linked with poorer outcomes, preventive interventions should increasingly focus on the youngest age groups possible, especially preschoolers.
The transition from antisocial behaviors in adolescence to similar behaviors in adulthood especially warrants careful longitudinal study. The range of outcomes should include both psychiatric and nonpsychiatric adult dysfunctions in order to elucidate the various pathways during this transitional period (Earls, in press). Studies of those individuals who do not carry over their antisocial behaviors into adulthood are warranted, for they could lead to clues about protective factors and possibly preventive interventions.
RISK AND PROTECTIVE FACTORS COMMON TO MANY DISORDERS
It has become evident that even though some risk factors may be specific to a particular disorder, other risk factors are common to many disorders. A continuing emphasis solely on the identification of risk factors unique to specific mental disorders is not likely to be productive. The low incidence of some mental disorders, such as schizophrenia, makes predictions based on the occurrence of presumed risk factors especially difficult. Instead, there may be greater value in clarifying the role of those risk factors that appear to be common to many mental disorders, especially in view of the frequent co-morbidity of these disorders.
Individual risk factors during childhood can lead to a state of vulnerability in which other risk factors may have more effect. For example, a prematurely born, low-birthweight baby may be more vulnerable than a full-term, healthy sibling in a suboptimal family environment (see Box 6.4 for a description of low birthweight as a general risk factor). Similarly, a child may be vulnerable to parent-child interaction difficulties by reason of a difficult temperament, a chronic physical illness, neurophysiological deficits, or below-average intelligence. Low IQ is associated with several mental disorders. Research also has shown links between early language disabilities and the later development of severe behavior disorders (Dattilo and Camarata, 1991; Camarata, Hughes, and Ruhl, 1988; Carr and Durand, 1985; Donnellan, Anderson, and Mesaros, 1984). Gender is another important genetic factor (Rutter, 1979). In the prenatal period and first 10 years of life, boys are more likely than girls to be vulnerable to both physical and psychosocial stressors. In the second decade, girls appear to be more vulnerable to psychosocial stressors, and in early adulthood men once again appear to be more vulnerable (Werner and Smith, 1992).
Factors in the family that constitute significant risk factors for increased childhood psychopathology include severe marital discord, social disadvantage, overcrowding or large family size, paternal crimi-
Low Birthweight as a General Risk Factor
The vulnerability of low-birthweight children to a range of poor health outcomes including suboptimal intelligence has long been identified and has been recently reexamined in a large-scale study that included 676 low-birthweight children (under 2,500 grams) (McGauhey, Starfield, Alexander, and Ensminger, 1991). Twenty-five percent of the normal-birthweight children versus 36 percent of the low-birthweight children lived in a high-risk social environment, defined as stressful life events and a cumulative social environment risk index of ongoing stressful life conditions. Low-birthweight children were consistently more likely to have worse outcomes when exposed to a high-risk social environment than similar normal-birthweight children. However, low-birthweight children were not more likely than normal-birthweight children to have poor health outcomes in either a low- or moderate-risk social environment. Low-birthweight children were found to be consistently more likely to have poor outcomes in the presence of a high-risk social environment; thus a high-risk social environment doubled the risk of school failure and behavior problems for normal-birthweight children but quadrupled these risks for low-birthweight children (McGauhey et al., 1991).
Outcomes for very low birthweight infants (under 1,500 grams) are even more problematic. These infants are at risk not only because of their prematurity but also because of the complications of this state and the potential attachment problems associated with a long stay in an intensive neonatal care unit. Transactional interaction with family factors in this group remains an important topic for research.
nality, maternal mental disorder, and admission into the care of the local authorities, that is, child welfare services (Rutter, 1979). Community factors that impinge on children include social disadvantage, particularly the experience of being part of a welfare family. This is not simply due to income levels; with income controlled, rates of impairment have been found to be significantly higher for children from low-income welfare families than for children from low-income nonwelfare families (Offord et al., 1987). Living in subsidized housing (Rutter, 1981) and living in an area that has a high rate of community disorganization have also been found to increase the risk for mental disorders in childhood. Community institutions such as schools can either enhance or detract from intellectual and social growth and development and thus can function as a community risk or protective environment for children and adolescents (Rutter et al., 1979).
Although protective factor research has made major advances, it is less well developed than risk factor research, and several conceptual and methodological issues remain inadequately resolved (Luthar, 1993).
There is evidence, however, that a core set of individual characteristics and sources of support can buffer the effects of both biological and psychosocial risk factors during childhood.
Positive temperament, above-average intelligence, and social competence can contribute to individual resilience (Rutter, 1985b; Rutter et al., 1970). Children who are easygoing and responsive call forth the best from their parents and from peers, teachers, and other adults. Above-average intelligence may allow a child not only to do well in school but also to develop problem-solving skills and a sense of perspective and psychological differentiation from the family or community, fostering the growth of the autonomy and independence necessary for optimal adult functioning. Social competence includes the ability to get along with others. In adolescence, having a sense of coherence and an internal locus of control orientation (that is, a personal sense of being able to take charge of one's life) has been cited as a protective factor (O'Grady and Metz, 1987).
Smaller family structure, that is, not more than four children in the family and spacing of more than two years between siblings, has been found to be protective (Werner and Smith, 1992). In early childhood, having a close relationship with a parent who is responsive and accepting is very important (see Box 6.5 for a description of the quality of interaction with parents as a general protective factor). For older children, supportive parents, good sibling relationships, and adequate rule setting by parents have been found to be protective (Werner and Smith, 1982). A supportive relationship with one parent was found to provide a substantial protective effect for children living in severely discordant, unhappy homes (Rutter, 1985b).
Protective community factors include the relationships that children develop outside the family, with peers, significant other adults, and any available external support system such as church, youth groups, school, and recreational activities, all of which build competence and provide children with success (Jones and Offord, 1989; Werner, 1989; Werner and Smith, 1982). Good secondary schools positively affect academic achievement and, subsequently, vocational outcome. They also reduce the rates of truancy, school dropout, and juvenile court appearances for children in disadvantaged areas (Rutter, 1979).
In the Kauai Longitudinal Study, three clusters of protective factors differentiated the resilient group from other high-risk youth who developed serious and persistent problems in childhood and adolescence (Werner and Smith, 1992). These were (1) at least average intelligence and temperamental attributes that elicit positive responses from family members and strangers; (2) good relationships with parents or parent
Quality of Interaction with Parents as a General Protective Factor
There is consistent evidence that the nature and quality of children 's interaction with their parents affect their school performance, social competence, and interpersonal behaviors (Amato, 1989; Dornbusch, 1989). Behavior problems in the preschool years appear to vary with the extent to which parents are emotionally available to respond to their children's needs (Gotlib and Avison, 1993; Lee and Gotlib, 1991). Adequate parents are generally sensitive to their children 's cues in relation to their developmental needs (Rutter, 1989). Emde (1989) has suggested that this sensitivity includes both physiological and psychological regulation of the infant's needs. Empathic responsiveness facilitates the sharing of feelings and expressions of positive social behaviors (Easterbrooke and Emde, 1988). Minde (1991) emphasized that a further parental activity related to sensitive responsiveness is the function of discipline. Normal parents encourage self-control in a child by regulating the expression of feelings. Bowlby and others have convincingly shown that the quality of the tie or attachment between parent and infant plays an important part in the overall social and emotional functioning of a child (Bowlby, 1988).
The quality of the early mother-child relationship may be affected by a number of variables, including the mother's own experience in childhood (Main and Hesse, 1990) and the presence of mental disorders (especially depression). Psychiatrically disturbed parents are generally more preoccupied with themselves and thus are less responsive to their children (Minde, 1991).
A close relationship between the child and parents during the first five years of life is especially important because primary attachment relationships are developed during this period. Children who experience multiple changes in parental figures are therefore at risk for psychosocial problems.
substitutes, which encourage trust, autonomy, and initiative; and (3) an external support system that rewards competence and provides a sense of coherence. Resilient children were reported to grow into competent, confident, and caring adults.
In general, protective factors in adulthood fall into two broad groupings —(1) those that arise from the buffering effects of social support available to the individual and (2) personality factors or personal characteristics that affect the individual's ability to cope with stress (O'Grady and Metz, 1987).
MODELS FOR UNDERSTANDING RISK AND PROTECTIVE FACTOR INTERACTION
Understanding that risk and protective factors are common to many disorders is only a first step. It is also essential to understand that these
factors do not function in isolation; instead, there exists a dynamic interaction among them that undergoes modification and change throughout an individual's life span.
Three possible models for the ways in which risk and protective factors interact to produce competence in children are the compensatory model, the challenge model, and the protective model—all adapted from Garmezy, Masten, and Tellegen (1984).
In the compensatory model, risk factors, including genetic vulnerability and stresses, combine additively and can potentiate each other. Usually, it is the aggregation of risk factors rather than presence of any single risk factor that impairs development. This is not to say that all risk factors have equal weight; they probably do not. For example, genetic vulnerability may account for more of the attributable risk for schizophrenia than any other risk factor. However, generally, multiple risks potentiate each other. Sameroff (1987) found that children reared in families with seven or more risk factors scored 30 IQ points below children from families with no risk factors. Infancy risk factors appear to be magnified synergistically when family environments in childhood are negative or when a child is subjected to stressful life events (O'Grady and Metz, 1987).
It is evident that adverse conditions in a child's environment do not necessarily produce adverse outcomes. However, it is becoming increasingly clear that a combination of risk factors in the child and risk factors in the family environment, particularly if these are multiple, predispose the individual to negative outcomes. Rutter and Quinton (1977) suggested that a fourfold increase in the amount of stress in childhood produced a 24-fold increase in the incidence of later mental disorder. Studies have consistently demonstrated a relationship between the number and severity of life events and behavior problems. Findings for adults are similar, but research findings are less plentiful (O'Grady, 1983).
The challenge model describes a curvilinear relationship in which stress as a risk factor enhances competence as long as it is not excessive. This phenomenon has been described as one of “steeling ” or “inoculation” (Werner and Smith, 1982; Anthony, 1974). Murphy and Moriarty (1976) have suggested that successive, moderately challenging experiences strengthen coping capacities. The protective model suggests that protective factors modulate or buffer the impact of risk factors by, for instance, improving coping, adaptation, and competence building.
The concept of causal or etiological chains is helpful in understanding risk and protective factor interaction. Robins (1970) first described this concept as a process in which one event calls forth another in a chain that leads to an outcome. For example, consider a causal chain involving a mother and her infant:
Depressed mother → unresponsive parenting by the mother → lack of language stimulation by the mother during the child's early years → language delay in the child → learning difficulties in the child → cognitive disorder in the child.
Robins suggested that one could intervene at any point along the causal chain. Intervening at the weakest link, however, might be the most productive strategy. For example, an intervention could be aimed at improving parental responsiveness by treating the mother 's depression or by providing another responsive adult in the environment to interact with the infant. In some ways, this chain is too simplistic; for example, it could continue snowballing for many years, and it does not take into account that several chains can be operating simultaneously.
Sameroff (1987) modified Robins's concept of unidirectional causal chains to include a temporal framework that is bidirectional, emphasizing reciprocal interactions between the child and the environment. In other words, how things turn out is a complex result of the interaction between the child and the family environment early in life and the child and the peer, school, and community environment in later childhood. The patterns of interaction between the child's personal attributes and risk and protective factors in the family, school, and community environments are not linear, but are interwoven—like the threads in a Jacquard tapestry—in patterns of increasing complexity. Initially, parents develop a pattern of interaction with their infants that is dependent on many factors, including their own childhood experiences, marital relationships, and the quality of their social support systems. Factors related to the child may include gender, health status, physical maturity, and temperament. Infants change the nature of their parents ' responses to them, and thus the interactions change. Parents in turn have an impact on their children. Research on child maltreatment has provided illustrations of this more complex conceptualization of causal chains (see Box 6.6).
As they grow older, children carry the patterns of interaction and expectation learned in the family environment into their relationships with other adults and peers. These interactions will mold further relationship experiences and be molded by them, changing the developmental trajectory in positive or negative directions.
Things go wrong when the family environment is not able to meet the needs of the child, either because the child is too impaired or temperamentally difficult or because the parents lack responsiveness owing to their own lack of nurturing, mental disorder, or overwhelming environmental distress. Sameroff and Chandler (1975) have described this as the “continuum of the caretaking casualty”; at one end of this continuum is
Research on child maltreatment was stimulated in the early 1960s by reports of the “battered child” syndrome in the medical literature (Kempe, Silverman, Steele, Droegemueller, and Silver, 1962). Since that time, research studies in this field have generally focused on four types of child maltreatment: physical abuse, sexual abuse, emotional maltreatment, and child neglect.
Child maltreatment serves as a useful illustration of the complexities associated with identifying and addressing risk and protective factors in an etiological chain encompassing both social problems and mental disorders. It is both a social problem, with its own set of risk and protective factors, and a risk factor in itself for several mental disorders.
Although several key variables or risk factors have been associated with child maltreatment, such as poverty, a parental history of abusive experiences, and parental psychopathology, research on the causes of child abuse and neglect suggests that no single variable can adequately explain the origins of child maltreatment. The results of etiological studies are often conflicting, and the predictive power of single or combined variables, such as the individual characteristics of the parent, child, or environment alone, is limited. For example, although a strong association has been shown between poverty and child abuse, the relationship is complex—most poor parents clearly are not abusive, and poverty alone is not a sufficient or even a necessary antecedent for child maltreatment.
Models of child maltreatment have evolved from isolated cause-and-effect models to approaches that consider multiple pathways and interactive effects among factors that contribute to child maltreatment. Recognizing the importance of situational factors has led to the development of contemporary multicausal interactive models that emphasize the sociocultural context of child maltreatment. Child maltreatment is now described less as an individual disorder or psychological disturbance, and more as a symptom of an extreme disturbance of childrearing, often within a context of other serious family problems, such as alcoholism or antisocial behavior (Wolfe, 1991; Burgess, 1979; Starr, 1979). Although studies of abusive and nonabusive parents have not detected significant personality differences, research on the interactions of abusive and nonabusive family processes has yielded important distinctions. Abusive parents have unrealistic expectations of their children, tend to view their own children's behavior as extremely stressful, and view themselves as inadequate or incompetent parents (Wolfe, 1991).
The information in this box is based in part on Understanding Child Abuse and Neglect (CBASSE, 1993).
Child Maltreatment as a Risk Factor for Mental Disorders
Although research has suggested a relationship between child abuse and neglect and a variety of psychosocial and mental disorders, considerable uncertainty and debate remain about the effects of child victimization on children, adolescents, and adults. For example, the majority of children who are abused do not show signs of extreme disturbance. The consequences of abuse or neglect may not become apparent until the child becomes an adolescent or an adult, and thus the connections between the experience of abuse and the short- or long-term consequences may be diffuse and uncertain.
In addition, it is often difficult to separate the experience of child victimization from other traumatic experiences that may affect the life of a child. Child maltreatment often occurs within a family context or social environment characterized by multiple problems, including poverty, violence, substance abuse, and unemployment, and the process of distinguishing the consequences of behaviors that are associated directly with the experience of child maltreatment from those that result from other social disorders and family dysfunctions is a challenging task. For example, several studies suggest that the child's experience of witnessing violence toward siblings or parents may be as harmful as the experience of victimization itself (Faller, 1988; Rosenberg, 1987; Rosenbaum and O'Leary, 1981).
Studies of physical child abuse and child neglect consistently highlight physical aggression and antisocial behavior among the outcomes associated with these forms of child maltreatment (Kaufman and Cicchetti, 1989; Walker, Downey, and Bergman, 1989; Rohrbeck and Twentyman, 1986; Hoffman-Plotkin and Twentyman, 1984; Salzinger, Kaplan, Pelcovitz, Samit, and Kreiger, 1984; Perry, Doran, and Wells, 1983). Evidence from longitudinal studies indicates continued problems of aggression and anger (Egeland and Stroufe, 1981 b) and the development of conduct disorder (Rogeness, Amrung, Macedo, Harris, and Fisher, 1986). Maltreated children also appear to be less competent that their peers in social interactions (Strauss and Gelles, 1990; Howes and Espinosa, 1985). In physically abused children, lack of social competence may be manifest in withdrawal or avoidance (Kaufman and Cicchetti, 1989), whereas in other children, it appears as fear, anger, or aggression (Main and George, 1985).
The consequences of neglect can be especially severe and powerful in the early stages of child development. Drotar (1992) notes that maternal detachment and lack of availability may harm the development of bonding and attachment between child and parent, affecting the neglected child's emotional state, expectations of adult availability, problem solving, social relationships, and ability to cope with new or stressful situations (Aber and Allen, 1987; Main and George, 1985).
A prospective study of mothers who were psychologically unavailable to their infants compared their children to physically abused, neglected, verbally rejected, and control group children from the same high-risk sample (Egeland and Stroufe, 1981a). The results indicated that children in all maltreatment groups functioned poorly and their functioning deteriorated over time (Erickson, Egeland, and Pianta, 1989). Nearly all the children in this study whose mothers were psychologically unavailable were anxiously attached at 18
months of age, and these children demonstrated a nearly 40-point decline in performance on the Bayley Scales of Infant Development between 9 and 24 months.
Clinical samples of maltreated children have reported a high incidence of suicide attempts and self-mutilation (Green, 1978). Comparison studies of physically abused and nonphysically abused children have indicated heightened levels of depression, hopelessness, and lower self-esteem (Allen and Tarnowski, 1989; Kazdin, Moser, Colbus, and Bell, 1985) and greater emotional difficulties in older children (Kinard, 1982, 1980). Kaufman (1991) found that a disproportionate number of maltreated children met diagnostic criteria for one of the major mood disorders.
Inappropriate sexual behavior, such as frequent and overt self-stimulation, inappropriate sexual overtures toward other children and adults, and play and fantasy with sexual content, are the most commonly studied symptoms in studies that compare sexually abused children to children in control groups (Kendall-Tackett, Williams, and Finkelhor, 1993). Although sexually inappropriate behavior would seem relatively specific to sexual abuse, Deblinger and colleagues compared reports of inappropriate sexual behaviors across groups of children who experienced different forms of maltreatment and found approximately the same percentage of sexually inappropriate behavior in physically abused (17 percent) as in sexually abused children (18 percent) (Deblinger, McLeer, Atkins, Ralphe, and Foa, 1989). Kendall-Tackett et al. (1993) have found that sexually abused children were more symptomatic than their nonabused counterparts in terms of fear, nightmares, post-traumatic stress disorder (PTSD), withdrawn behavior, neurotic mental illness, cruelty, delinquency, sexually inappropriate behavior, regressive behavior, and other general problem behaviors. Estimates of sexually abused children diagnosed as meeting the DSM-III-R criteria for PTSD range from 21 percent (Deblinger et al., 1989) to 48 percent (McLeer, Deblinger, Atkins, Foa, and Ralphe, 1988).
The majority of abused children do not become delinquent, and the majority of delinquents were not abused as children. Prospective studies estimate the incidence of delinquency in adolescents who have been abused or neglected to be about 20 to 30 percent (Widom, 1989a). There have been numerous retrospective studies linking childhood maltreatment, especially sexual abuse, to specific forms of adult psychopathology, including mood disturbance, post-traumatic stress, self-injurious behavior, substance abuse, somatization, eating disorders, multiple personality disorder, and interpersonal violence. As with all retrospective studies, the validity of recall information is of questionable value.
Prevention of Child Maltreatment
Most programs to prevent child maltreatment have lacked methodological rigor, and their findings are equivocal. However, two research programs —the Prenatal/Early Infancy Project in Elmira, New York (see Chapter 7 and Chapter 11 ) and the Children and Youth Program (Hardy and Streett, 1989) have met with significant success and have demonstrated a reduction in child maltreatment.
an adaptive family environment that can meet the needs of the organically damaged or temperamentally difficult infant, and at the other end is the disordered family environment that cannot meet the needs of the least distressed, most healthy, normal, temperamentally easy newborn. In between are the majority of average environments that provide “good enough” parenting.
In discussing the ways in which early events might be linked to later outcomes, Rutter (1989) emphasized that not only continuities but also discontinuities are found between events in childhood and subsequent adult outcomes. Some risk pathways turn into more adaptive routes because of adventitious happenings. For example, a child from a dysfunctional family who is physically abused and then placed in a foster home has started on a life course of negative events. However, a continuous negative cycle is not predetermined; the course could be altered by an especially good relationship with the foster parents. This relationship could produce a discontinuity in the life course that had been expected prior to placement. Rutter (1989) has demonstrated that children at risk early in life who subsequently had good school experiences were three times more likely to show planning in their choice of life career or marital partner than those who had poor school experiences. Similarly, for women earlier at risk because of institutional experiences, the presence of marital support was found to lead to good social functioning and good parenting, in contrast with those who did not receive good marital support (Quinton and Rutter, 1988).
Werner and Smith (1982) have suggested that the interaction of risk and protective factors is a balance between the power of the person and the power of the social and physical environment. A balance is necessary throughout life, although different factors vary in importance at different developmental stages. These authors suggested that constitutional factors are more important during infancy and childhood and interpersonal factors are more important during adolescence. However, certain genetic vulnerabilities may not be potentiated until later in the life span. For example, schizophrenia usually appears in later adolescence, and Alzheimer's disease appears late in life. Adaptation at all ages appears in large part to be a function of the individual's ability to elicit predominately positive responses from others in his or her environment.
MAJOR FINDINGS AND PROMISING LEADS
Mental health outcomes depend on the interactions of risk and protective factors in the child, the family, and the wider environment. The nature, timing, severity, and length of particular risk factors and the
gender, age, and cultural identity of the individual are all key variables in determining mental health outcomes.
It appears that most risk and protective factors, other than genetic factors, are not specific to a single disorder. Much remains to be learned about both risk and protective factors and their interaction. Therefore, at this time the most fruitful approach for preventive interventions may be to use a risk reduction model that includes the enhancement of protective factors and to aim at clusters or constellations of risk and protective factors. Markers can be used to identify high-risk populations, but the interventions will be aimed at those causal and malleable risk factors that appear to have a role in the expression of several mental disorders. Identification of relative and attributable risks associated with various clusters of risk factors could greatly facilitate preventive intervention research.
Risk factors, including markers, should always be reviewed in relation to their rate of occurrence in the normal population. A given risk factor may not be unique to those individuals who will eventually develop a mental disorder. It may be quite prevalent in normal populations and thus will not—by itself—be especially useful in identifying individuals at risk. For example, increased cerebral ventricular size occurs in many individuals with schizophrenia, but it also occurs in about 4 percent of persons without the disorder. Screening a general population for ventricular size would identify more nonschizophrenics than preschizophrenics. A similar lack of specificity would probably result from screening for many, if not most, other risk factors—such as aggressiveness, poverty, and life stress—in general populations. Thus these factors are best used in combinations. It is the accumulation of risk factors, with appropriate weighting of the relative importance of each factor, that will yield the targets with the most potential for prevention of later onset of mental disorder(s).
The task in preventive interventions is to decrease risk and/or increase protection in the individual, the family environment, and the wider environment with which the individual comes into contact. But not all risk factors need to be reduced. Even reducing some in a multirisk situation is likely to result in more advantageous outcomes. Because of developmental changes, the timing of the reduction of risk may be even more critical than the number of risk factors addressed. Conversely, if the number of protective factors can be increased in the individual, family, and community, then resilience is likely to be increased and the disorder may be avoided.
General risk factors may lend themselves to universal preventive interventions consonant with broad community mental health efforts
that focus on public education and social welfare. Risk factors specific to a particular group of people can be addressed in selective preventive interventions. Individuals with early behavioral symptoms or markers are potential recipients of indicated preventive interventions. Risk reduction would seem to be a promising approach for prevention. The question that remains is whether it is being widely and successfully used. This issue is addressed in Chapter 7, which reviews illustrative preventive intervention research programs.
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