Neuropsychological deficits in major depression reflect genetic/familial risk more than clinical history: a monozygotic discordant twin-pair study

Abstract

Neuropsychological deficits have been associated with major depression (MD) and persist in some individuals even after symptom remission. However, it is unclear if the deficits are a consequence of MD or are pre-existing and reflect MD vulnerability. We addressed this issue by studying 117 twins from monozygotic (MZ) pairs discordant for lifetime history of DSM-III-R defined MD and 41 twins from MZ pairs in which neither twin had experienced MD. Our assessment included a structured clinical interview and measures from the WMS-III and WAIS-III. The "unaffected" twins from discordant pairs showed the same pattern of performance as their affected cotwins on measures of attention, working memory, verbal memory, and visuo-spatial processing. Compared to twins from pairs with no MD history, twins in discordant pairs had lower performance in the domains of attention, memory, visuo-spatial processing, and general knowledge. However, after adjusting for sex and age, the groups differed only on attention and general knowledge. The similar performance of twins in pairs discordant for MD suggests that familial risk for MD has a greater influence on neuropsychological functioning than individual MD history. Findings of impairment in individuals euthymic for MD are more consistent with pre-existing deficits than scarring effects of MD.

Keywords: Cognitive functioning; Genetics; Major depression; Neuropsychological impairment; Risk factors; Scarring effects; Twins.

Figure 1. Expected Patterns of Deficits in Discordant Cotwin-Control Studies Under Alternative Models for the Etiological Relation between MD and Neuropsychological Deficits

MD History Model: Deficits are associated with clinical history of MD, Probands but not unaffected Cotwins show deficits relative to Controls; Family History Model: Deficits are associated with family history of MD, Probands and unaffected Cotwins show equivalent deficits relative to Controls; Family + MD History Model: Deficits are associated with both sources, as Cotwins and Probands show deficits arising from familial vulnerability and Probands have additional deficits associated with clinical history of MD.

Figure 2. Within Pair Differences (Proband - Cotwin) on Neuropsychological Measures Based on Discordant Twin Pairs

Scores are in SD-units and based on complete MZ pairs with confirmed discordance for MD. DSS=Digit Symbol Substitution; LNS=Letter Number Sequencing; BD=Block Design; VPA-I=Verbal Paired Associates Initial Recall; VPA-D=Verbal Paired Associates Delayed Recall; VO=Vocabulary. Sample Sizes (pairs): DSS=25, LNS=37, BD=26, VPA-I=39, VPA-D=37, VO=39.

Figure 3. Discordant Proband and Cotwin Neuropsychological Performance Relative to Control Group

Group scores are in z-score units and plotted relative to control group means and standard deviations. DSS=Digit Symbol Substitution; LNS=Letter Number Sequencing; BD=Block Design; VPA-I=Verbal Paired Associates Initial Recall; VPA-D=Verbal Paired Associates Delayed Recall; VO=Vocabulary.