CME Author: Vicki Brower
Study Authors: Lynn E. MacKenzie, Rudolf Ulmer, et al.
Target Audience and Goal Statement:
Psychiatrists, psychologists, and family medicine specialists
The goal was to compare cognitive performance between individuals with, and without, close relatives with a history of major depressive disorder (MDD).
- Do first-degree relatives of individuals with major depression have cognitive impairment?
- Can causation be demonstrated regarding cognitive impairment and depression, or just an association between the two?
Study Synopsis and Perspective:
A meta-analysis of 54 studies indicated that first-degree family members of people with MDD consistently performed worse on cognitive tests than individuals with no family history of depression, who served as controls. The family members were not themselves considered to be depressed.
It is well established that people with MDD show cognitive impairment even in remission from depression, but it is not clear whether the cognitive impairment is related to the illness (preceding it or a result of MDD) or treatment, or part of a preexisting vulnerability, according to study researcher Barbara Pavlova, PhD, of Dalhousie University in Halifax, Nova Scotia, and her co-authors, whose study appeared in JAMA Psychiatry.
“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. The latter finding may mean that cognitive impairment is part of familial disposition to depression, Pavlova said.
Regarding her team’s methodology, Pavlova said, “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. This is why it was necessary to bring together data from many studies to answer what may appear to be a simple question,” she said.
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 MDD, 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 5 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
“Across multiple measures of cognitive ability in more than 8000 individuals, we found evidence of slightly but robustly impaired cognition in first-degree relatives of people with MDD compared with those with no family history of severe mental illness,” the authors summarized.
This study may be the first systematic review and meta-analysis of cognitive performance in first-degree relatives of individuals with MDD, authors stated.
Source References: JAMA Psychiatry DOI:10.1001/jamapsychiatry.2018.3672; JAMA Psychiatry editorial DOI:10.1001/jamapsychiatry.2018.3631
Study Highlights: Explanation of Findings
When first-degree relatives of individuals with MDD were compared with controls, the former performed significantly worse in the following domains of cognition: full-scale IQ, verbal intelligence perceptual intelligence, memory, academic performance, and language.
There are several reasons why first-degree relatives of people with major depressive disorder may have impaired cognitive performance, including genetic and social factors associated with the risk of MDD, Pavlova and colleagues noted. Recent large-scale genetic studies have mapped the genetic risk of depression to several dozen loci in genes that play significant roles in neuronal development, synaptic function, and plasticity, the authors wrote.
Another possibility is that cognitive impairment in relatives of patients with MDD could be affected by environmental factors, such as poverty and low socioeconomic status, which may run in families along with depression, and can affect family members who do not themselves develop depression. Related to this is research that shows that mothers with MDD show decreased shared attention and vocalization with their infants and toddlers, and that children of mothers with serious depression speak less often to their mothers, compared with controls, the study authors write. These factors could negatively impact children’s cognition. However, the authors assert that “results of sensitivity analyses restricted to samples in which relatives and controls were tightly matched on socioeconomic status together with sensitivity analyses restricted to offspring suggest that a genetic mechanism is a more likely determinant of cognitive deficits in unaffected relatives.”
They concluded that in light of recent genetic studies, their results suggest “that a slight reduction in general cognitive ability is part of the familial risk for depression and is likely mediated through genetically influenced neurodevelopmental mechanisms.”
Authors of an accompanying editorial appear to agree, at least in part. MDD in relatives 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. While twins studies have shown that both depression and cognitive ability are influenced by genetics, other research suggests that a causal relationship 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,” they added.
If cognitive impairment does cause depression, “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,” Roiser and colleagues wrote.
The study’s authors noted that the large number of independent samples is one strength of their research, as was their inclusion criteria of a validated clinical interview and confirmation of no severe mental illness in the first-degree relatives of the control cohort.
Pavlova and co-authors also 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. Finally, they stressed the need for longitudinal research which would include follow-up throughout the typical onset period of adolescence and early adulthood, and well-screened control groups without family history of severe mental illness.
The editorial writers observed that authors included only studies with clinically validated measures for diagnosing depression, which maximized specificity, but potentially may have missed relevant data.
Ultimately, because this was a meta-analysis of cross-sectional data, their findings did not determine that a causal relationship exists between cognitive impairment and depression.
Judy George wrote the original study for MedPage Today