Antypa, N.
Citation
Antypa, N. (2011, June 21). Cognitive vulnerability to depression : genetic and environmental influences. Retrieved from https://hdl.handle.net/1887/17719
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General Introduction
“With great effort I eat, walk and talk. There is no meaning in anything any more. My appetite has committed suicide and my creativity has drowned. The only thing active in me is thinking: thoughts race in my head as if there is a negativity prize for the worst one. I don’t remember the last time that I got out of bed with energy… And melancholy has become my cosy friend, always by my side. The time passes like a movie, in which I don’t want to play, and not even watch…” A.B.
A person that experiences low mood or anhedonia (the inability to gain pleasure from otherwise pleasurable experiences) along with a collection of negative symptoms such as, changes in sleep or appetite, fatigue, feelings of worthlessness, difficulty to concentrate or thoughts of death is considered to suffer from depression. In the fields of contemporary psychology and psychiatry, a depression diagnosis is based on the criteria for a Major Depressive Episode, as described by the Diagnostic and Statistical Manual of Mental Disorders-IV (1994) (Table 1).
According to the World Health Organization, depression is the leading cause of disability as measured by Years Lived with Disability and was the fourth leading
contributor to the global burden of disease in 2000. Today, depression is already the 2nd cause of global burden of disease in the age category 15-44 years for both sexes
combined. By the year 2020, depression is projected to reach 2nd place of the ranking calculated for all ages and for both sexes (WHO, 2010).
Once depressed, always depressed? A person that has suffered from a clinical
depression is very likely to experience recovery from this debilitating state (either through treatment or time). Unfortunately, depression will probably come back to haunt this person sooner or later. About 50% of recovered depressed individuals will experience another major depression episode within two years after remission, and about 80% will relapse within 15 years (Mueller et al., 1999). In spite of the dramatic increase in treatments, no decrease in recurrence rates has been observed. The underlying vulnerability to depression is mostly left uncovered.
Table 1. Diagnostic criteria for Major Depressive Episode according to the DSM-IV A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
(1) depressed mood most of the day, nearly every day, as indicated by either subjective report (eg. feels sad or empty) or observation made by others (eg. appears tearful).
(2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others).
(3) significant weight loss when not dieting or weight gain (eg. a change of more than 5%
of body weight in a month), or increase or decrease in appetite nearly everyday.
(4) insomnia or hypersomnia nearly everyday
(5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
(6) fatigue or loss of energy nearly every day
(7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
(8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The symptoms are not due to the direct psychological effects of a substance (eg. a drug of abuse, a medication) or a general medical condition.
Cognitive Vulnerability to depression
Depression is an idiopathic disorder with a diverse etiology (Krishnan & Nestler, 2008). There are various possible causes, which are mostly considered as risk factors, such as stressful life events (Kessler, 1997) chronic health diseases like cancer or hypothyroidism (Evans et al., 2005), and genetic predisposition (Kendler & Prescott, 1999; McGuffin et al., 1996).
However, the causal formula that may trigger the first episode of depression is rarely the same one that will trigger the next one. For example, adverse life events play a greater role in the initial than in recurrent episodes of depression (Monroe & Harkness, 2005). The chronic nature of depression is unlikely to be attributed to psychosocial stress, which is thought to be important in cueing the first episode, but not recurrence.
The reason for this observation was described by Post (1992) as “behavioral
sensitization” or “kindling effect”, meaning that the person develops a neurobiological response that evolves over time as a function of recurrent depressive episodes. From a cognitive science perspective:
“Vulnerability to depressive relapse/recurrence is determined by the increased risk of particular negative patterns of information processing being activated in depressed states. […]the likelihood of cognitive patterns being activated is dependent on the frequency of past usage, and increased reliance on these patterns of processing makes it easier for their future activation to be achieved on the basis of increasingly minimal cues.” (Segal et al., 1996; page 371).
(i) Cognitive reactivity
Along these lines, Teasdale’s differential activation hypothesis (1988) assumes that during a depressive episode an association between depressed mood and negative thinking patterns is formed such that subsequent low mood will re-activate the negative thinking patterns. The reactivation of such dormant cognitive styles poses the individual at risk for falling again into a full episode of depression. The ease with which such maladaptive cognitions are triggered by non-pathological low mood is referred to as cognitive reactivity (Ingram et al., 1998; Lau et al., 2004). This approach is different to traditional cognitive theories of depression that emphasize core dysfunctional beliefs and attitudes at any given moment as vulnerability factors (eg. Beck, 1967). Experimental studies incorporating sad mood inductions have consistently demonstrated that formerly depressed patients have higher cognitive reactivity compared to never-depressed individuals under a low mood, whereas the two groups don’t differ prior to the mood induction (Miranda et al., 1998; Segal et al., 1999;
Van der Does, 2002). These studies show that there is some residual deficit in individuals with history of depression that is only measurable when their mood is challenged. Segal et al., (2006; 1999) showed in two studies that after treatment with either cognitive behavioural therapy or antidepressant medication, remitted depressed patients with higher cognitive reactivity under low mood, have higher risk of relapse. Cognitive reactivity is one form of cognitive vulnerability to depression, depicting the association between maladaptive cognitions and sad mood.
(ii) Emotional Information Processing
Biases in information processing have been hypothesized to play a role in the onset and maintenance of depression (Leppanen, 2006). Attention, appraisal and other kinds of processing of environmental stimuli are of fundamental importance, since this is
the way the brain decides what matters to it (Harmer et al., 2009). Accumulating evidence through experimental research has shown that cognitive processes, such as memory, learning, attention, motor function and decision-making are affected in depressed patients (Austin et al., 2001).
Recent research has indicated that depressed patients do not show a broad impairment in the processing of neutral information, but mood-congruent biases are observed when processing emotion-relevant information. For example, depressed individuals show a selective memory for negative material, mostly seen in explicit memory paradigms (Matt et al., 1992).
Depressed patients also show a differential processing of recognizing human facial emotions. They are more likely to classify ambiguous facial expressions as negative (Bouhuys et al., 1999; Gur et al., 1992; Surguladze et al., 2004). This tendency was predictive of future depressive relapse (Hale, 1998; Bouhuys et al., 1999), but non- predictive results have also been found (see Johnson et al., 2007). It is yet unknown whether there is a general bias in the processing of negative facial emotional expressions in depression, or whether this bias is specific to certain emotions. Most research has shown that depressed patients are more likely to show a preferential processing of sad emotional expressions, or show difficulty in the identification of happy facial emotions (Gotlib et al., 2004; Gur et al., 1992; Surguladze et al., 2004; Suslow et al., 2004).
Such biased patterns of information processing may also persist into the euthymic phase. Formerly depressed participants (as well as currently depressed) selectively attended to sad faces compared to healthy controls (Joormann & Gotlib, 2007). After a mood induction, individuals with history of recurrent depression had more difficulty identifying happy facial expressions (LeMoult et al., 2009).
Furthermore, experimental manipulations of the neurotransmitter serotonin seem to affect such aspects of emotional cognitive functioning. Commonly used techniques involve administration of a serotonergic antidepressant (for one/few days) or tryptophan depletion (the temporary lowering of serotonin in the brain). Such manipulations affect the recognition of emotional faces, such as fearful and happy expressions, both in healthy volunteers (Harmer, Bhagwagar et al., 2003; Harmer, Rogers et al., 2003; Harmer et al., 2004; Hayward et al., 2005) and in remitted depressed patients (Merens et al., 2008).
Furthermore, depressed patients perform worse on tasks measuring attention and response inhibition with affective words. Depressed patients were less likely or slower to react to positive words in comparison to negative words than healthy participants
(Erickson et al., 2005). Tryptophan depletion in healthy participants also increases response times to happy words (Murphy et al., 2002).
Impaired decision-making is also implicated in depression (Rahman et al., 2001).
Decision-making is characterized by a choice that one has to make by considering the possible rewards (expected value) associated with that option. In the laboratory such choices are often measured using a gambling task. Depressed patients show impaired decision-making behaviour in such a task by having slower deliberation times and fail to accumulate as many points as healthy controls (Murphy et al., 2001). Research in healthy samples also shows that decision-making behaviour can be modulated by tryptophan depletion (Rogers et al., 1999; Rogers et al., 2003).
Cognitive Vulnerability as an “Endophenotype”
Vulnerability markers that are inherent to the depressive disorder have been proposed as “intermediate phenotypes” or “endophenotypes”: they fill the gap between the gene and the elusive disease process (Gottesman & Gould, 2003). A direct link between gene(s) and depression (operationalized as a DSM-IV diagnosis) seems highly implausible. No gene has been found to singularly code for any psychiatric disorder so far (Hasler et al., 2004), largely due to the heterogeneous nature of such disorders.
Endophenotypes can be measured on clinical, cognitive, neurophysiological, neuroanatomical, biochemical or neuropsychological levels (including self-report measures) (Gottesman & Gould, 2003). To qualify as a potential endophenotype, the following criteria have to be fulfilled:
The endophenotype:
(a) is associated with illness in the population (b) is heritable
(c) is state-independent (manifests in an individual whether or not illness is active) (d) co-segregates with illness within families
The assumption is that gene effects on endophenotypes may be more readily measurable than gene effects on complex phenotypes. The endophenotype may be detectable in carriers of risk alleles even if carriers do not show all the clinical diagnostic symptoms (Meyer-Lindenberg & Weinberger, 2006). Many risk gene associations to endophenotypes are observed also in healthy individuals. In depression, an increasing
amount of research has focused on a specific candidate gene: the serotonin transporter gene (SLC6A4), which is a key regulator of serotonergic neurotransmission (Heils et al., 1996). A polymorphism in the promoter region of this gene (5-HTTLPR) has two variants: short allele (s) carriers have reduced transcriptional efficiency of serotonin compared with individuals with two copies of the long allele (ll) (Heils et al., 1996). More recently, an A/G single nucleotide polymorphism (rs25531) within 5-HTTLPR has been described (Wendland et al., 2006). The G allele within the l variant (LG) shows lower 5- HTT mRNA expression, similar to the s allele (Hu et al., 2006). A relatively consistent association between 5-HTTLPR and activity in the amygdala and subgenual cingulated region has been found (Pezawas et al., 2005), constituting such neurobiological circuits as successful endophenotypes.
Depression is known to be partly heritable, with a heritability estimate of 37%
from twin studies (Sullivan et al., 2000). This means that the environment plays a key role in the expression of this disorder. It is more likely that genes interact with environmental influences to set off behavioural phenotypic disorders like depression. Gene-
environment interaction research provides a potential pathway of understanding why individuals respond differently to environmental influences. When the effect that an environmental stimulus can have on an individual is dependent on genotypic variation then a gene-environment interaction occurs.
Gene-environment interactions on depression diagnosis have shown promising (Caspi et al., 2003) but inconsistent results (Risch et al., 2009; Uher & McGuffin, 2008).
Similar research with the personality trait “neuroticism” as an endophenotype of depression is also inconclusive (Munafo et al., 2009). Failures to find consistent results may be due to the heterogeneity of the (endo)phenotype and the environment (life events) (Lotrich & Lenze, 2009). Consequently, more specific endophenotypic measures of depression are warranted.
Research Aims
On the whole, we observe that vulnerability to depression can be conceptualized as a latent endogenous process explained by genetic, biological, cognitive and
psychological variables (Ingram & Siegle, 2009). The aim of this thesis was twofold. In the first part, the role of cognitive reactivity and emotional information processing as vulnerability factors / endophenotypes of depression were investigated. In the second
part, effects of experimental manipulations on emotional cognition and cognitive reactivity were examined.
A note on the assessment of Cognitive reactivity (CR)
CR has been traditionally assessed in the lab by the use of a sad mood induction along with administration of the Dysfunctional Attitude Scale (DAS) (Weissman, 1979) before and after this procedure. However, some drawbacks to this method have been pointed out (Van der Does, 2002). Firstly, the sad mood induction procedure is complex allowing assessment of CR only in lab settings. Secondly, about 25% of participants fail to
respond to it with sad mood (Martin, 1990). Thirdly, the DAS is administered both before and after the mood induction; that is twice in 7 minutes. Consequently, a questionnaire was developed to overcome these problems - The Leiden Index of Depression Sensitivity (LEIDS-R) (Van der Does 2002; 2003). This questionnaire asks participants to imagine themselves at times when they felt down or when they were in a low mood and then fill in the questionnaire. Whereas the DAS is comprised of items like
“You can only be happy if you are good-looking, rich and smart”, the LEIDS is comprised of conditional items “When in a sad mood, I more often think about how my life could have been different”. The LEIDS-R has six subscales that cover different cognitive domains:
Rumination, Hopelessness/Suicidality, Control/Perfectionism, Aggression, Risk- Aversion, and Acceptance/Coping. The scale can differentiate between previously depressed and never depressed individuals (Van der Does, 2002; Van der Does, 2005;
Merens et al., 2005). It is also related to thought suppression (Van der Does, 2005) and to participants’ response to tryptophan depletion (Booij & Van der Does, 2007).
Independent research groups using the LEIDS-R have shown that CR scores predict depression history over and above rumination (Moulds et al., 2008) and that CR may mediate effect of Mindfulness Based Cognitive Therapy (Raes et al., 2009).
Part A: Cognitive vulnerability to depression and endophenotypes
In the first part of this thesis, the role of CR (using the LEIDS-R) is further investigated in the context of depression vulnerability. One of the most stable symptoms that a person suffers from across depressive episodes is suicidal ideation (Lewinsohn et al., 2003; Williams et al., 2006) or suicidal behaviour (Oquendo et al., 2004). The role of cognitive reactivity in recurrent depression has been recently studied within the context
of suicidality. It is suggested that suicidal ideation arises as part of the negative thinking patterns during the first episodes and an association is formed between depressed mood and suicidal thoughts such that future mood fluctuations may re-activate such thinking (Lau et al., 2004). One study examines whether there is a specific CR profile for a subtype of individuals that have suffered from suicidal tendencies during their depression.
Furthermore, the plausibility of CR as an endophenotype of depression was investigated. In another study, the relationship between genetic variation on the
serotonin transporter gene and childhood adversity (a gene-environment interaction) was examined on CR. A gene-environment interaction was also tested for the personality trait of neuroticism and depression diagnosis as comparable (endo)phenotypes.
In that study, facial emotion perception was also examined as a plausible endophenotype. Biases in the perception of emotional face expressions can influence social and emotional adaptation (Ohman, 2002) and in this way may contribute to the development or maintenance of depression. There is preliminary evidence that there is a relationship between facial emotion recognition and the 5-HTTLPR (eg. Beevers et al., 2007, 2009). The aim was to further investigate the association of this candidate gene with facial emotion perception as a neuropsychological endophenotype and to explore the possible moderating role of stressful life events and gender.
Part B: Modifying cognitive vulnerability to depression
As previously mentioned, biases in emotional cognition can be seen in healthy, as well as in groups at risk for depression, by the use of experimental manipulations such tryptophan depletion or antidepressant administration. For example, one week of
antidepressant administration (citalopram or reboxetine) in healthy participants produced biases that are in the opposite direction of those seen in depressed patients (Harmer et al., 2004). Both drugs decreased the recognition of fearful facial emotional expressions while mood remained unaffected. Although a considerable amount of research has explored antidepressant effects on cognitive functioning (Harmer et al., 2009), little research exists on how alternative treatment approaches, such as omega-3 fatty acid supplementation, may affect cognition. During the last decade, there has been an increasing amount of literature on the effects of omega-3 fatty acid supplementation on mood or symptom improvement in depressed individuals, showing moderate beneficial
effects (Appleton et al., 2010, for a meta-analysis). However, similar to antidepressant effects, subjective improvement of mood may not be always detectable after short-term treatment with omega-3 fatty acids, whereas effects on cognitive functioning may appear.
In the second part, this thesis aims to explore the effects of omega-3 fatty acid supplementation on emotional cognition, cognitive reactivity and mood state. Firstly, in a challenge study involving healthy volunteers, effects of omega-3 fatty acids compared to placebo were investigated on the abovementioned outcomes. Secondly, in a randomized placebo-controlled trial, effects of omega-3 were examined on the emotional information processing (primary outcome) and mood (secondary outcome) of recovered depressed individuals, a group at risk of subsequent depression.
Outline of this thesis
In Chapter 2, the different aspects of CR are compared between recovered depressed participants with/without history of suicidality during their prior depression.
The CR profiles of suicide ideators and attempters are elucidated. In Chapter 3, a gene- environment interaction (5-HTTLPR and childhood maltreatment) was explored on CR, on Neuroticism and on depression diagnosis. In Chapter 4, the relationship between 5- HTTLPR and facial emotion perception was investigated. Interactions with both recent and early life adversity as well as gender were also examined on this endophenotype. In Chapter 5, the effects of omega-3 fatty acid supplements on mood state and cognition of healthy individuals are reported. Chapter 6 presents the results of a randomized placebo-controlled trial on the effects of omega-3 supplementation on cognition and mood of recovered depressed individuals. Chapter 7 contains a summary and integration of the main findings, methodological considerations, clinical implications and future directions in the field.
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