Cognitive deficits and the role of antidepressant treatment

A review of antidepressant treatment effects on cognitive deficits in MDD is beyond the scope of this chapter, but in general antidepressant treatments tend to ameliorate, but not reverse, cognitive deficits in patients with MDD. For example, despite symptomatic remission in patients with MDD, during SSRI (selective serotonin reuptake inhibitor) treatment, cognitive deficits persisted (Herrera-Guzmán et al., 2010). In a study of elderly patients with MDD, treatment with duloxetine resulted in significant improvement relative to placebo on a composite cognitive score with both verbal learning and recall (Raskin et al., 2007). A recent study on the new agent vortioxetine, a serotonergic antidepressant with 5-HT7 antagonistic properties, found it to have a positive effect on cognitive performance after correction for depressive symptomatology (McIntyre, Lophaven, & Olsen, 2014).

Cognitive deficits as an epiphenomenon in MDD

The term “epiphenomenon” in medicine implies that a symptom is concurrent, but not causally contributory to a disease. Accordingly, epiphenomenalism holds that our actions have purely physical causes (e.g. neurophysiological changes in the brain), while our intention, desire, or volition to act does not cause our actions, but is itself caused by the physical consequences of our actions. Mental events are thus viewed as completely dependent on physical functions and, as such, have no independent existence or causal efficacy; “like the bell of a clock that has no role in keeping the time, consciousness has no role in determining behavior” (Huxley, 1874).

Proponents of this hypothesis argue that neuropsychological deficits are simply epiphenomena of age, poor motivation, inattention, or response bias. This is termed the “effort-automatic hypothesis.” While cognition refers to processes such as memory and attention by engaging cortical regions, emotions are states elicited by rewards and punishment and are thought to engage subcortical regions (Pessoa, 2008). Cognition is a necessary precondition for emotion; emotions influence how we think and interpret events and are the result of cognitive processes but they also have an impact on cognition itself (Lazarus, 1984). There is no doubt that cognition and emotion are interlinked but the question for the epiphenomenon argument of cognition in MDD is how much of a role emotion plays, and to what degree emotion is a state as opposed to a more permanent trait effect. Two phenomena can co-occur and have no causal relationships, as one is only the epiphenomenon of the other. Therefore, psychomotor retardation, poor attention, and other cognitive processes could be associated features of a mood disorder, concurrent with sadness, without being part of the central process (because they are also generated in the same brain areas). The Pessoa review claiming that “emotion is a cognition” is interesting because it addresses both concepts at the same level, facilitating the analyses of their respective roles. Indeed, it is “intuitive” that they are different (we subjectively “feel” emotions, not cognitions) but emotions seem to have all the characteristics of cognition when they are analyzed at the brain circuitry level, with high connections (hubs) with other brain areas. The endophenotype studies in MDD involve specific cognitive tasks that are always connected to emotions, and show that they are usually more sensitive to such negative messages (affective bias rather than cognitive bias). This dysfunctional inhibition of negative information may be a trait characteristic that interferes with the processing of neutral information and that may increase the risk of developing MDD. Some studies have suggested that it is the emotional valence of the task rather than a neutrally mediated cognitive element of the task that best explains poorer performance of MDD patients relative to HCs (Gotlib & Joormann, 2010; Disner et al., 2011).

There has been support for the role of environmental experience on structural brain development with one hypothesis being that impairments in early maternal nurturing contribute to enhanced and maladaptive stress reactivity and increased risk for MDD. The association between the small size of the hippocampus and very early risk factors of MDD (such as early sexual abuse) orientate toward interesting pathways of risk factors. In two such studies, early maternal support exerted a positive influence on hippocampal development in children without MDD but not in children with MDD (Luby et al., 2012); moreover, hippocampal loss was found in children exposed to early maltreatment (Teicher, Anderson, & Polcari, 2012). Therefore, exposure to early stress in humans can lead to abnormal anatomical structures (potentially through the cortisol axis and abnormal neuroplasticity and neurogenesis capacities), which might predispose to future depressive episodes.

There are reports that cognitive impairment resolves with treatment or that the length of the depressive episodes (indicating a state factor) rather than the number of depressive episodes is important. In one study, relatives and remitted MDD patients performed at the level of HCs on the California Verbal Learning Test, suggesting that verbal learning at least may be a state rather than a trait marker for MDD. In a large community-based sample of more than 8,000 MDD patients, severity of illness was associated with improved cognitive performance at baseline. With regard to the follow-up of the remitted group, the number and length of past depressive episodes were the most important predictors of improved cognitive performance, suggesting that both state and trait effects may be important at different stages of the illness (Gorwood, Corruble, Falissard, & Goodwin, 2008). A meta-analysis conducted in 14 studies of currently depressed patients examined the correlation between depression severity and neuropsychological performance, noting that depression severity was related to reduced cognitive performance across the domains of episodic memory, executive function, and processing speed, but not semantic or visuospatial memory (McDermott & Ebmeier, 2009).

Pessoa also makes the case that current knowledge of brain function and connectivity, which divides the brain into cognitive and affective regions, is inherently problematic. His concern is that affective and cognitive brain regions are indistinct from each other and therefore brain regions viewed as “cognitive” may also be involved in “emotional” brain circuitry (Pessoa, 2008). Evidence for cognitive/emotional integration in the DLPFC is shown in a working memory study where activity in the DLPFC was modulated by the valence of the picture, with pleasant pictures enhancing activity and unpleasant pictures decreasing activity compared with neutral stimuli (Perlstein, Elbert, & Stenger, 2002).

Cognitive dysfunction in psychiatric illness could be viewed as a “transnosographic scar” as it is prevalent across many disorders without a unique marker for any particular disorder. Schizophrenia is characterized by a broad pattern of cognitive deficits, from attention and working memory to social cognition and language. Impairments in bipolar disorder, which shares certain genetic risk factors with schizophrenia, are similar but generally less severe. In MDD, cognitive impairment is persistent and strongly related to disability, with recovery inversely correlated with the severity of deficits (Millan et al., 2012).

Although psychiatric disorders have a moderate to high heritability, genetic risk factors are numerous, only have a small effect, and show low penetrance; taken together, it is difficult to identify genetic risk factors for cognitive dysfunction in psychiatric disorders. Even within each disorder there is considerable heterogeneity among individuals, with regard to both causation and characteristics. “Correlated” does not necessarily imply “causal,” so that even if a genetic defect is associated with a psychiatric disorder, it does not necessarily indicate a role in the induction of cognitive impairment. In addition to genetic factors, environmental factors, such as excessive stress, are risk factors for impaired cognitive function. Stress is mediated through excessive activation of the hypothalamic–pituitary–adrenal (HPA) axis with resultant compromise in cognition. Prenatal and childhood stress triggers long-term changes in adolescence and adulthood, involving impaired cognitive function and an increased risk of MDD and other psychiatric disorders. These delayed effects of stress appear to reflect structural and functional changes in cortico-limbic circuits. For example, in women suffering from MDD, cognitive impairment was related to a history of early childhood adversity and reduced hippocampal volume (Millan et al., 2012).

As discussed above, there may be other valid sociobiological reasons for cognitive deficits in MDD at different stages of the illness. In contrast, some consider that there is only modest evidence to support an association between MDD and an attentional bias toward negative material. Although potentially susceptible to response biases, evidence for a negative interpretation bias in MDD also comes from studies using emotion recognition tasks. Patients with MDD have been found to be both slower and less accurate than HCs in recognizing neutral emotions (Leppänen, Milders, Bell, Terriere, & Hietanen, 2004; Gollan, Pane, McCloskey, & Coccaro, 2008).

In addition, patients with MDD often misinterpret neutral faces as sad, a bias that has been found to persist following symptom remission (Leppänen et al., 2004). Other investigators have observed that patients with MDD exhibit difficulties in the identification of subtle positive emotion (Surguladze et al., 2004; Joormann & Gotlib, 2006), with such difficulties also documented in remission samples (LeMoult, Joormann, Sherdell, Wright, & Gotlib, 2009), and also observed in individuals at high risk for depression (Gotlib & Joormann, 2010), suggesting that biases in the interpretation of facial emotion represent a risk factor for the onset of a depressive episode (Foland-Ross & Gotlib 2012). Remitted and non-medicated MDD patients had bilateral amygdala response in association with a negative recall bias following a sad mood induction which was not observed in the patients without sad mood induction or in HCs (Ramel et al., 2007). Beck’s cognitive model predicts the presence of abnormal “hot processing” in MDD (negative emotional biases) on the basis of negative expectations. These negative expectations, which include dysfunctional attitudes and negative attributional styles that can lead to maladaptive thought processes characteristic of MDD, such as negative automatic thoughts and rumination, can be considered a form of ‘‘top-down’’ hot cognition. They are the targets of psychological interventions such as cognitive therapy, which could be conceptualized as training depressed individuals to exert cold cognitive control over their top-down negative biases, for example through working memory, inhibition, and problem-solving (Roiser & Sahakian, 2013).

Conclusion

Throughout this chapter, we have described the cognitive deficits in MDD at different stages of the illness including at-risk, first episode, recurrent episodes, remission, and at follow-up. The sum of this evidence has allowed some to conclude that cognitive deficits can be considered trait markers of MDD (Beblo et al., 1999; Austin, Mitchell, & Goodwin, 2001). While verbal measures of memory and fluency appear to be sensitive to the clinically depressed state, executive functioning and attention seem to be more trait-related domains (Douglas & Porter, 2009). It is conceivable that different subtypes of MDD display different patterns of cognitive impairment. Cognitive impairment in MDD has been associated with higher rates of relapse and recurrence (Majer et al., 2004; Sumner, Griffith, & Mineka, 2010), reinforcing the idea that neurocognitive abnormalities could constitute markers of acquired vulnerability. Nevertheless, not all studies have confirmed the hypothesis of a direct link between past depressive episodes and cognitive impairment (for a review see Hasselbalch et al., 2012). If one considers the weight of past episodes on neurocognitive abnormalities, which requires large samples to be detected, these negative studies have had more limited statistical power, due to their particularly small sample sizes. Another source of heterogeneity in the results arises from the fact that the studies have investigated various aspects of neurocognitive deficits that might not systematically overlap.

If the endophenotype is shown to be specific to MDD and not to be present in other disorders, its identification would supplement current psychiatric diagnoses based on clinical symptomatology. This MDD endophenotype could then be used as an aid in identifying persons who are at elevated risk for developing the illness and preventative or treatment strategies could be implemented. It would assist in the identification of a biological subtype of this illness, predicting the clinical course of the illness, allow for individualized treatment, and predict therapeutic response. This brain-based endophenotype for MDD would then be tested in clinical MDD samples to develop a predictive algorithm, providing greater diagnostic and therapeutic clarity for this disorder (Peterson & Weissman, 2011). Developing treatment strategies specifically targeting cognitive impairment in MDD could help advance the standard and future individualization of patient care (Papakostas, 2014).