Mohammed T. Abou-Saleh

376 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYIn affective disorders, the average concordance rate for bipolardisorders in monozygotic twins was 60%, while the concordancerate in dizygotic twins was 12% 8 . The five-fold greater rate ofconcordance strongly indicates the importance of genetic factorsin the familial aggregation. For major depressive disorders, therole of genes is much weaker. Two recent twin studies 9,10 foundthat the relative risk for monozygotic twins was 1.9, while the riskfor dizygotic twins was 1.2. Both findings of heritability werestatistically significant.Adoption StudiesAdoption studies provide a powerful method of evaluating geneticand environmental contributions to the familial aggregation ofdisease. In these cases, adopted children have a genetic relationshipwith their biological family, but share the primaryenvironmental relationship with their adopted family. Thus, ifgenes are responsible for the familial transmission of a disorder,then the risk for the adopted child should more closely match therisk of the biological family. However, if environmental factorsare more responsible, the relative risk of the adopted child wouldmatch the risk of the adoptive family.In affective disorders, five studies have reviewed adoption andincidence of affective illnesses 11 . Two of these studies havedemonstrated strong genetic influences, while the others show amore variable response. One adoption study 12 suggested certainenvironmental influences, especially parental loss and parentalalcoholism, as predictors of depression.Genetic Markers and Linkage StudiesThe most specific studies for genetic involvement are geneticmarker and linkage studies. Genetic markers are specific areas onthe chromosome where laboratory procedures may differentiateindividuals on the composition of DNA at that location. They areused to identify where a specific gene may be on a chromosome.Linkage refers to the nearness of two or more genes or markers ona chromosome. Linkage studies are based on the principle that asthe genetic distance decreases, the probability that they will beinherited increases.A number of gene loci for affective illness have been proposedthrough linkage work, but the results have been disappointinglyinconsistent, and a number of the most striking findings haveproven controversial 13 . One possible exception is a small subset ofbipolar disorders that may be X-linked 11,14 . Recent investigationsin an ethnically homogeneous American Amish populationinitially suggested linkage to a marker on chromosome 11 15 .Unfortunately, more recent work has cast doubt on thisconclusion 16 and has prompted greater caution generally in theinterpretation of the linkage results in psychiatry.LATE-LIFE AFFECTIVE DISORDERSJust as affective disorders in early and middle life are quiteheterogeneous, late-life mood disorders are also a heterogeneousentity. However, it is unclear whether late-life affective disorderscomprise the same notions of heterogeneity as those in early andmiddle life. In late-life mood disorders, two groups of patients areusually differentiated: those who had an early-onset of illness andcontinue to have symptoms or episodes in their later life, andthose who had a late-onset of illness (usually defined as a firstonset after the age of 60 years).Mendlewicz 17 and other researchers have suggested that the ageof onset is an important clinical variable in the genetic study ofaffective illness. When differentiated by age of onset, late-onsetdepressive disorders have qualities that suggest they may begenetically different from early-onset forms. These characteristicsinclude the non-conformity of affective disorders to expectedgenetic models and clinical differences observed between late- andearly-onset depression.Most genetic models propose that strong genetic influences aremost often found in the most severe forms of an illness and in theearly expressions of the illness. However, late-onset affectiveillness syndromes are typically among the severest and mostrefractory to treatment 18,19 . Older patients with affective disorderswho require hospitalization tend to have a slower resolution ofsymptoms and a longer duration of hospitalization than youngeradult patients 20 . Further, patients with late-onset depression andbipolar disorders have less familial aggregation of mood disordersthan those with the early-onset affective disorders. This findinghas been extensively validated in many studies 21–26 . Late-onsetmood disorders are also less likely to display the gender disparity 21present in early-onset mood disorders.Clinically, patients with late-onset mood disorders tend to haveincreased impairment on neuropsychological testing and higherrates of incident dementia noted at follow-up 27 . While inadequatesupport appears particularly difficult among middle-aged patients,stressful life events appear to pose the greater risk of pooroutcomes among geriatric patients 28 .Gatz et al. 29 studied the characteristics of depression in a sampleof elderly reared-apart and reared-together Swedish twins. Theyfound evidence of only limited heritability (16%). In contrast astudy 30 of a sample of Danish twins 75 years of age and olderfound that depression symptomatology is moderately heritable inlate life (approximately 35%). However, both studies consistentlyimplicated environmental factors as the major source of variancein depression symptoms among the elderly.GENETICS OF LATE-LIFE AFFECTIVE DISORDERSHow can one understand the differences noted above, and howare they important for the genetic study of late-life mooddisorders? Two explanations have been proposed for the agerelatedvariation in genetic influence for affective illnesses:multifactorial inheritance and increased phenocopy expressionwith age. Multifactorial inheritance (also called polygenicinheritance) suggests that inheritance patterns are a result of acombination between multiple interacting genes and environmentalfactors. Examples of traits that have multifactorialinheritance include stature, intelligence and blood pressure 17 .According to the multifactorial theory, the onset of an affectivedisorder results from the additive effects of several genetic andenvironment factors. This concept is graphically illustrated inFigure 69.1. The horizontal axis represents the level of geneticpredisposition, while the vertical axis represents the level ofenvironmental risk. Thus, the more factors present (the number ofimplicated genes or environmental events that contribute to anaffective illness), the more likely an individual would develop anaffective illness and the more severe that illness would be. Onecould also assume that early-onset illnesses probably result fromgreater genetic loading, while late-onset illnesses may have lessgenetic loading but increased occurrence of environmental eventswith age.The second explanation, increased phenocopies, illustrates thelimited specificity of the affective disorders diagnosis. Bothbipolar disorder and major depressive disorder are syndromediagnoses, that is, the diagnosis is based on the presence of acollection of observed symptoms (phenotype) rather than anetiological cause. In this theory, late-onset affective illness is acollection of phenocopies. Phenocopies are illnesses with a