Review
A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder

https://doi.org/10.1016/j.jad.2011.10.023Get rights and content

Abstract

Background

Recurrent-episode Major Depressive Disorder (MDD) is associated with a number of neuropsychological deficits. To date, less is known about whether these are present in the first-episode. The current aim was to systematically evaluate the literature on first-episode MDD to determine whether cognition may be a feasible target for early identification and intervention.

Methods

Electronic database searches were conducted to examine neuropsychological studies in adults (mean age greater than 18 years old) with a first-episode of MDD. Effect sizes were pooled by cognitive domain. Using meta-regression techniques, demographic and clinical factors potentially influencing heterogeneity of neuropsychological outcome were also investigated.

Results

The 15 independent samples reviewed yielded data for 644 patients with a mean age of 39.36 years (SD = 10.21). Significant cognitive deficits were identified (small to medium effect sizes) for psychomotor speed, attention, visual learning and memory, and all aspects of executive functioning. Symptom remission, inpatient status, antidepressant use, age and educational attainment, each significantly contributed to heterogeneity in effect sizes in at least one cognitive domain.

Limitations

Reviewed studies were limited by small sample sizes and often did not report important demographic and clinical characteristics of patients.

Conclusions

The current meta-analysis was the first to systematically demonstrate reduced neuropsychological functioning in first-episode MDD. Psychomotor speed and memory functioning were associated with clinical state, whereas attention and executive functioning were more likely trait-markers. Demographic factors were also associated with heterogeneity across studies. Overall, cognitive deficits appear to be feasible early markers and targets for early intervention in MDD.

Introduction

A single episode of Major Depressive Disorder (MDD) is defined as a minimum of five symptoms present during the same two-week period, including lowered mood and/or loss of pleasure and associated symptoms such as feelings of worthlessness and suicidal ideation (American Psychiatric Association, 2000). Symptoms also need to be accompanied by clinically significant distress or functional impairment. MDD is predicted to have the second largest disease burden by 2020 (Murray and Lopez, 1997). In a large Australian sample of over 10,000 participants, 3.2% met diagnostic criteria for MDD in a given month (Wilhelm et al., 2003). More than 60% of an American sample of 48 MDD patients rated their social or occupational functioning as significantly, severely, or “totally” impaired (Jaeger et al., 2006).

Diagnosis and treatment of MDD have traditionally focussed on mood symptoms. However, neuropsychological dysfunction is often present in the disorder and has been shown to contribute independently to poor functional outcome (Jaeger et al., 2006). For example, information processing, memory, and verbal fluency deficits were found to be predictive of poor academic, occupational and daily functioning in MDD. Thus, identifying and treating cognitive deficits may prove to be an important avenue in reducing functional decline. For the purposes of the current study, the terms ‘cognitive’ and ‘neuropsychological’ functioning will be used interchangeably.

Between 50% and 75% of individuals diagnosed with MDD experience more than one clinically significant episode in their lifetime (McClintock et al., 2010), with recurrence rates increasing proportionally with the number of subsequent episodes (Angst, 1999, Mueller et al., 1999, Solomon et al., 1997) and subsequent episodes reducing the effectiveness of antidepressant medication (Kaymaz et al., 2008). Moreover, cognitive impairments in MDD are associated with higher rates of relapse and recurrence (Fossati et al., 2002, Majer et al., 2004) due to a number of underlying mechanisms. For example, cognitive inflexibility may reduce the effectiveness of cognitive restructuring in psychotherapy. Thus, identifying and treating cognitive deficits in MDD may be particularly critical earlier on in the disease process prior to the cumulative effects of illness chronicity (Hickie et al., 2005, Sheline et al., 1999). Early identification and intervention assumes that intervening at the early stages of a disorder will be more effective than targeting chronic illnesses, since first-episode disorders are thought to be less entrenched (Hetrick et al., 2008, McGorry et al., 2006). As such, response to treatments in the earlier stages tends to be more favourable. Indeed, there is research to suggest that psychological treatments, such as psychotherapy, earlier in life and at earlier stages of illness reduces the rate of recurrence in depressive episodes (Clarke et al., 1999, Jarrett et al., 2001). Taken together, cognition may be an important target for early identification and intervention in MDD, which may contribute not only to reducing functional decline, but potentially to reducing the chances of chronic relapse and recurrence.

Despite the benefits and importance of early detection, most studies investigating cognitive functioning in MDD have focussed on patients with a history of more than one episode of depression, as exemplified by a number of reviews (Austin et al., 2001, Castaneda et al., 2008b, Clark et al., 2009, McDermott and Ebmeier, 2009, Zakzanis et al., 1999). Deficits have typically been identified in the areas of psychomotor speed, attention, learning and memory, and executive functioning. In addition, brain regions thought to subserve these functions have also been found to be abnormal (Clark et al., 2009, Lorenzetti et al., 2009). It is less clear whether cognitive deficits in recurrent MDD are independent or a consequence of mood state. For example, executive functioning has been shown to both improve (Biringer et al., 2005) and persist (Paelecke-Habermann et al., 2005) following remission of depressive symptoms. Other variables indicative of burden of illness, such as duration of illness, have also been shown to negatively correlate with cognitive functioning in MDD (Elgamal et al., 2010). There is also data to suggest that antidepressant use is associated with better cognitive functioning (Constant et al., 2005, Kamph-Sherf et al., 2004). Thus, the nature of how clinical characteristics contribute to cognitive dysfunction remains vital to the interpretation of neuropsychological variables in MDD (Palmer et al., 2009). This is further complicated by evidence suggesting that cognitive dysfunction is also linked to demographic characteristics (Austin et al., 2001, Grant et al., 2001, Hill et al., 2004, Naismith et al., 2003, Porter et al., 2007, Withall et al., 2010). For example, a recent study demonstrated that premorbid intelligence and educational attainment were positively associated with neuropsychological functioning in MDD (Elgamal et al., 2010). Stratification of look-up tables in the published normative literature also indicates that age tends to be associated with neuropsychological performance. Thus, it is clear that a number of demographic and clinical factors are likely to obscure the interpretation of cognitive data in MDD research, although it is not, as yet, entirely certain how each of these variables relate to the cognitive functions currently reviewed in the literature.

There have been fewer studies investigating the neuropsychological functioning of patients with a first-episode of MDD. This is despite evidence suggesting that neuropsychological dysfunction may already be present before an individual meets full diagnostic criteria for MDD. For instance, memory impairments have been identified in those at risk of developing the disorder (Burt et al., 1995, Mannie et al., 2009). Further suggestions of cognitive dysfunction in first-episode MDD include findings of neurobiological changes at this early stage, similar to those found in recurrent MDD. Specifically, hippocampal atrophy and enlargement of the amygdala (Frodl et al., 2002a, Frodl et al., 2002b, Kronmüller et al., 2008, Zou et al., 2010), gray matter changes in the temporal lobes (Bora et al., 2011), and white matter abnormalities, particularly in cortico-subcortical circuits (Ma et al., 2007, Zhu et al., 2011), have been demonstrated in first-episode MDD samples. Thus, regions identified as abnormal in recurrent MDD may be associated with changes at the first-episode of MDD or even preceding clinical onset. These findings support the notion that neuropsychological functioning, associated with these regions, may already be abnormal at this early stage.

The aim of the current study was to systematically review the literature on the neuropsychological functioning of first-episode MDD to determine whether cognition may be a plausible target for early identification and intervention in this population. Meta-analytic techniques were used to determine the magnitude of cognitive dysfunction. Given the heterogeneity of demographic and clinical characteristics in MDD research, the current study also used meta-regression techniques to investigate potential moderators of cognitive dysfunction. It was hypothesised that patients will show significant deficits in cognitive functions typically detected in recurrent-episode MDD, although to a lesser extent. That is, significant reductions in psychomotor speed, attention and working memory, learning and memory, and executive functioning were expected in first-episode MDD patients. Furthermore, demographic factors were expected to explain heterogeneity in cognition, such that higher premorbid intelligence and educational attainment in patients relative to healthy controls were predicted to correlate with better neuropsychological performance. Difference in age between patients and controls was also predicted to be associated with the level of cognitive performance. In regards to clinical variables, remission of depressive symptoms and antidepressant use were expected to correlate with better neuropsychological functioning, whereas younger age of onset, inpatient status, and psychiatric comorbidity, were predicted to be associated with poorer cognitive outcome.

Section snippets

Search criteria

Searches of peer-reviewed empirical studies between 1990 and February 2011 were conducted in PubMed and PsycInfo databases. The start date of 1990 was chosen as this was the first time the current construct of “major depression” was in wide-use in the scientific literature (Kemp et al., 2010). Various combinations of search terms were used (first, single, episode, unipolar, depress*, neuropsycholog*, neurocognitive, cognitive, impairment, deficit, functioning). Reference lists of articles

Included studies

Electronic database searches yielded 27 articles that met the inclusion criteria, with an additional study obtained from the reference lists. Of these articles, 10 studies were excluded on the basis of not controlling for the effects of recurrent episodes, 4 studies for demonstrating that recurrence influenced neuropsychological performance without reporting results for first-episode MDD patients separately, and one study for not including a healthy comparison group (control). In total, 13

Discussion

The main aim of the current review was to systematically review the literature on the neuropsychology of first-episode MDD in order to determine whether cognition may be a potential target in early identification and intervention of MDD. Thirteen studies were reviewed in total, which contributed to fifteen independent samples, representing a diverse range of countries. Eight of these studies also included recurrent-episode MDD patients, although each had individually demonstrated that

Role of funding source

None.

Conflict of interest

None.

Acknowledgements

None.

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