Family Risk for Depression Tied to Cognitive Impairment

Family members of people with depression consistently performed worse on cognitive tests than people with no family history of mental illness, a meta-analysis showed.

Across 54 studies, first-degree relatives of people with major depressive disorder (MDD) performed worse than controls across most measures of cognition, reported Barbara Pavlova, PhD, of Dalhousie University in Halifax, Nova Scotia, and co-authors in JAMA Psychiatry.

This finding may mean that cognitive impairment is part of familial disposition to depression, Pavlova said. While it’s well established that people with major depressive disorder show cognitive impairment even in remission, it’s not clear whether the impairment is related to the illness or treatment, or part of a preexisting vulnerability, she noted.

“The distinction between the two alternatives matters: the former explanation would lead to search for different treatments, but the latter alternative informs causation and prevention,” Pavlova told MedPage Today.

“Looking at unaffected relatives is a good way of distinguishing between causes and consequences, but because relatives only share part of their genes, the size of the difference is smaller than in those who have depression themselves,” she added. “This is why it was necessary to bring together data from many studies to answer what may appear to be a simple question.”

In this meta-analysis, Pavlova and her group analyzed data from 8,468 individuals (3,246 first-degree relatives of people with major depressive disorder and 5,222 controls) from 54 non-overlapping studies from 1980 to 2018, looking only at studies with participants who were ages 69 years and younger. Controls had no first-degree relatives diagnosed with major depressive disorder, bipolar disorder, or schizophrenia. The average age of relatives with major depressive disorder was 15.38 years and 57.68% were female; the average age of controls was 14.70 years and 55.93% were female.

For each cognitive test, the researchers computed the standardized mean differences (SMD) between the first-degree relatives of people with major depressive disorder and controls. Study characteristics were not significantly associated with between-group differences, and there was no evidence of publication bias.

Based on the 54 studies, the overall cognitive performance of first-degree relatives of individuals with major depressive disorder was worse than controls (SMD −0.19, 95% CI−0.27 to −0.11, P<0.001) with moderate heterogeneity between studies. This small SMD between first-degree relatives of people with MDD and controls emerged in nearly all cognitive domains:

• Full-scale IQ: SMD −0.19
• Verbal intelligence: SMD −0.29
• Perceptual intelligence: SMD −0.23
• Memory: SMD −0.20
• Academic performance: SMD −0.40
• Language: SMD −0.29

There are several reasons why first-degree relatives of people with major depressive disorder may have impaired cognitive performance, including genetic and social factors, Pavlova and colleagues noted.

It’s also possible cognitive impairment could result from subclinical depressive symptoms, or “parental depression could negatively affect cognitive development through environmental influences such as home environment or parenting style,” observed Jonathan Roiser, PhD, of the University College London in England, and co-authors in an accompanying editorial.

While twin studies have shown that both depression and cognitive ability are influenced by genetics, other research suggests the causal nature between cognition and depression remains ambiguous, Roiser and colleagues wrote: “More sophisticated (but logistically challenging) genetically informed designs, for example adoption studies or children of twins studies, may provide clearer insights. Molecular genetics, with larger samples and better understanding of the genetic architecture of depression, may also help.”

If a causal role is established, “this could pave the way for novel interventions based on cognitive enhancement (either psychological or pharmacological), which could be particularly valuable given that cognitive impairment in depression is a risk factor for poor treatment outcome,” they added.

Pavlova and co-authors noted several limitations to their study. They could not assess several potential confounding characteristics due to the nature of the studies, nor control for mild forms of psychopathology in relatives of people with major depressive disorder. Because this was a meta-analysis of cross-sectional data, the findings could not determine a causal relationship between cognitive impairment and depression.

The authors included only studies with clinically validated measures for diagnosing depression, which maximized specificity but potentially may have missed relevant data, the editorialists added.