Mohammed T. Abou-Saleh

GENETICS OF AFFECTIVE DISORDERS 377Environmental risk factorsBACGenetic predispositionFull disorderSpectrum conditionsSubclinicaldisordersNeurobiologicabnormalitiesFigure 69.1 How genes and environment lead to illness. Adapted fromFaraone et al. 31characteristic phenotype but different underlying causes.Hypothyroidism is an example of a phenocopy. Individuals withhypothyroidism may meet major depression criteria, but theyrequire quite different treatment.It should be noted that the two explanations postulated for theobserved differences in age-related affective disorders are notmutually exclusive. We have already noted that affective disordersare heterogeneous. Figure 69.2 demonstrates two dimensions ofheterogeneity—clinical and causal. Clinical heterogeneity occurswhen more than one clinical condition can occur by the samecause. Causal heterogeneity occurs when two or more causes canindependently produce the same clinical syndrome 31 . In Figure69.2 the small circle at the top represents all patients who have thefull disorder (in this case, bipolar disorder or major depressivedisorder). The larger circle demonstrates three outcomes attributedto disease genes: ‘‘full disorder’’, ‘‘spectrum conditions’’ and‘‘symptom-free’’. Some individuals with the disease genes willdevelop the full disorder. Others will not meet criteria for the fulldisorder, but will show abnormalities and trends toward thedisorder. These are called ‘‘spectrum conditions’’. Finally, someindividuals will remain symptom-free despite carrying the samedisease genes.The small circle at the top of Figure 69.2 also shows that not allpatients who have the full disorder have the disease genes. Thissubgroup represents those patients with phenocopies of the fulldisorder. They have an illness that looks like a genetic disorderbut it is not caused by genes, at least not the same disease genes.It has long been known that depressive syndromes are verycommon in neurological disorders such as Parkinson’s disease,Alzheimer’s disease and stroke. More recently, researchers 32,33have proposed a subtype of depression called ‘‘vascular depression’’,based on the presence of white and gray matter changesobserved on magnetic resonance imaging (MRI) scans. Thesechanges are frequently seen as patients age, and both the patternand intensity of lesions appear to have a direct relationship tomajor depressive episodes (and possibly bipolar disorder). Thissubtype is differentiated from other depressive types by demonstratinga constellation of depressive symptoms, increasedincidence of apathy, psychomotor retardation, cognitive impairment,functional disability and a decreased incidence of familialaffective disorders. If this is shown to be true, then the age-relatedvariation in late-life affective disorders may be explained byincreasing phenocopies in older adults who have late-onsetaffective disorders. Patients with early-onset affective disorders(which would include elderly patients with previous diagnosis ofaffective disorders) may be more likely to have a genetic cause.As research like this sharpens our understanding of disease, the‘‘heterogenous’’ group of affective disorders will be differentiatedinto various subtypes, each with a more specifically definedcourse, prognosis and treatment. Each new subtype will alsosuggest new ways that genes and the environment may contributeto the expression of the illness. For example, current research isexamining how other ‘‘disease genes’’ may cause variousphenocopies. One of the major complications of Alzheimer’sdisease is the development of a major depressive disorder.Research has suggested that the presence of one of the ApoEalleles, which has been implicated in Alzheimer’s disease and isgenetically determined, may predispose patients to the developmentof major depression 34,35 . Other researchers have not foundthis finding to be consistent 36–38 . However, the implication is clear.Environmental and genetic patterns in late-onset affective disordersare emerging that are different from patterns seen in earlyonsetdisease.Full disorderFigure 69.2Faraone 11Spectrum conditionsSymptom freePhenocopiesDiseasegenesCausal and clinical heterogeneity. Adapted from Tsuang andREFERENCES1. Morton NE. Outline of Genetic Epidemiology. Basel: S Karger, 1982.2. Gershon ES, Mark A, Cohen N et al. Transmitted factors in themorbid risk of affective disorders: a controlled study. J Psychiat Res1975; 12: 283.3. Tsuang MT, Winokur G, Crowe RR. 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