Cognitive Functioning in Major Depression – A Summary

The aim of the present paper is to summarize the research during the past decade regarding cognitive functioning in Major Depressive Disorder (MDD). Cognitive impairment in the acute phase of illness has been frequently reported. The findings are shown in different cognitive domains, such as executive functions, attention, memory and psychomotor speed. Fewer reports have investigated cognitive functioning in MDD in longitudinal studies. Some longitudinal reports show that the impairment observed in the acute phase of illness may be long lasting despite symptom reduction and recovery. However, findings regarding cognitive functioning in depression are divergent. Factors that might contribute to the divergent findings, such as depression subtype, severity and comorbidity are discussed. Clinical implications and focus of future research directions is highlighted.In conclusion, depression is associated with cognitive impairment in the acute phase of illness, and some reports indicate that this impairment might be long lasting despite symptom reduction and recovery.


INTRODUCTION
MDD is the most prevalent of all mental disorders with an estimated life prevalence as high as 13.5-21.2% (Kessler and Walters, 1998;Turner and Gil, 2002;Kessler et al., 2005). Moreover, at any time as many as 5% of the population suffers from depression (Murphy et al., 2000). Together with schizophrenia, depression is responsible for 60% of all suicides worldwide and is predicted to be the second largest cause of disability in year 2020, for all ages and both genders (World Health Organization, [WHO], 2009). Regarding course of recovery it has been reported that only 20% of MDD patients recover and remain continuously well, while as many as 20% estimates to either commit suicide or always be incapacitated. The remaining 60% will recover but have further episodes (Hollon and Shelton, 2001).
Historically, MDD was seen as an episodic disorder but recent fi ndings have indicated that developing a chronic course of the disease has been underestimated (Rush, 2001). MDD is associated with a high relapse risk, found to be highest during the fi rst year after a depressive episode (Mueller et al., 1999). Moreover, 50% of depressed patients experience a relapse within 2 years after their fi rst episode, and 80% will experience more than one depressive episode during their life course (Mueller et al., 1999).
Due to the presented magnitude of this disorder, consequences are signifi cant both at an individual level and for society. Disability in life functioning is a serious feature concerning Major Depressive Disorder (MDD) and a number of studies suggests that MDD is associated with signifi cant disability and poorer quality of life (see review Papakostas et al., 2004). Numerous MDD patients experience that maintaining job performance at an acceptable level is diffi cult or impossible. Many have problems in fully participating in social and/or family life, and further they have problems in meeting other expectations from the society.
Although depression traditionally is seen as affective in nature, the last decades research have shown that depression is associated with a considerably and important disturbance in cognitive functioning. (Den Hartog et al., 2003;Markela-Lerenc et al., 2006;Gohier et al., 2009), problem solving and planning (Naismith et al., 2003), mental fl exibility (Naismith et al., 2003;Airaksinen et al., 2004), verbal fl uency (Reiches andNeu, 2000;Ravnkilde et al., 2002) decision making (Chamberlain and Sahakian, 2006) and working memory (Egeland et al., 2003b;Naismith et al., 2003;Rose and Ebmeier, 2006;Taylor Tavares et al., 2007), or the ability to inhibit one source of information and at the same time facilitate processing of another source of information (Hugdahl et al., 2009) (Table 1). More specifi cally it has been suggested that the inability to shift mental set is the most prominent EF impairment in MDD patients (Austin et al., 2001). Opposed to these fi ndings, others have reported MDD patients to show normal performances in multiple aspects of EF (Grant et al., 2001;Landrø et al., 2001;Vythilingam et al., 2004;Stordal et al., 2005).
In sum, several studies have during the last decade presented fi rm evidence of EF impairment in the acute phase of depression, however factors contributing to the various impairment described in the literature must be indentifi ed in a larger degree.

ATTENTION DEFICITS IN THE ACUTE PHASE OF ILLNESS
Several recent studies have reported MDD patients to show defi cits on a variety of attention related tasks (Cohen et al., 2001;Landrø et al., 2001;Koetsier et al., 2002;Liu, et al., 2002;Ravnkilde et al., 2002;Hammar et al., 2003a;Porter et al., 2003;Lampe et al., 2004;Keilp et al., 2008;Simons et al., 2009) though the nature of the impairment is diffi cult to defi ne as various studies investigate different aspects of this concept. Moreover, attention is closely related to other cognitive domains, especially psychomotor speed and EF. It has been suggested that attention can be divided into processing speed, selective attention and automatic processing; selective attention being a part of EF (Brebion et al., 2000;Egeland et al., 2003a), thus a frontal lobe function (Landrø et al., 2001). It has been shown that MDD patients are impaired on effortful attention related tasks, whereas normal performance is shown on automatic processing (Hammar, 2003;Hammar et al., 2003a).
It has been found that MDD patients show impairment on speeded measures however; remain unimpaired on selective attention (Pardo et al., 2006). Further, there have been studies reporting no impairment in attention in mild to moderate MDD patients (Grant et al., 2001) or MDD patients (Harvey et al., 2004;Lampe et al., 2004). The divergent results reported in the domain of attention have been suggested to be caused by a too simple attention model that does not differentiate between processing speed on the one hand, and the ability to select relevant stimuli and resist distraction on the other (Egeland et al., 2003a).
In sum, impairment in attention related tasks is frequently reported in the acute phase of MDD. An important discussion is whether specifi c aspects of attention are more vulnerable, and what impact these attention defi cits have for daily life functioning, treatment and recovery in this patient group.

MEMORY DEFICITS IN THE ACUTE PHASE OF ILLNESS
The cognitive domain of memory has been closely related to MDD. Memory is a complex concept involving several different processes. Consequently, various neuropsychological methods are used when different memory processes are investigated. Studies investigating memory have for instance distinguished between episodic and semantic memory, implicit and explicit memory and immediate and delayed memory, the latter being further divided into free and cued recall. Moreover, visual memory has usually been separated from verbal memory (Moscovitch, 1992).
Numerous studies have reported an association between MDD and memory impairments (Landrø et al., 2001;Fossati et al., 2002;Ravnkilde et al., 2002;Egeland et al., 2003b;Porter et al., 2003;Airaksinen et al., 2004;Campbell and MacQueen, 2004;Vythilingam et al., 2004;Matthews et al., 2008) (Table 2) however, the relationship is not clear. Studies have found MDD patients to be impaired in both verbal and visual memory (Reischies and Neu, 2000;Naismith et al., 2003), verbal delayed memory and verbal percent retention, however not in immediate verbal memory or visual memory (Vythilingam et al., 2004). Somewhat opposed to this, some have found immediate and delayed visuo-spatial memory to be impaired whilst immediate and long-term verbal declarative memory was preserved (Porter et al., 2003). Wang et al. (2006) found no impairment in fi rst ever or recurrent depressed young adults compared to controls in verbal memory. Findings have also shown normal performance on tasks assessing verbal short-term memory and nonverbal long-term memory, whilst verbal working and long-term memory are impaired (Landrø et al., 2001). In contrast there are studies reporting primarily no impairment in MDD patients on tasks assessing memory (Grant et al., 2001;Barch et al., 2003;Den Hartog et al., 2003;Harvey et al., 2004).
In conclusion, memory impairment is frequently reported in the acute phase of MDD, however the nature and the mechanisms behind this impairment is somewhat unclear.

NEUROPSYCHOLOGICAL PROFILE IN THE ACUTE PHASE
Despite numerous of studies investigating cognitive functioning in MDD there is no agreement upon a conclusive neuropsychological profi le characterizing depression. However, three hypotheses have been postulated in order to explain the cognitive impairment in this disorder. First, a global-diffuse hypothesis, which states that MDD patients show a generally lowered cognitive profi le, suggesting a global-diffuse impairment on a range of cognitive domains (Veiel,   Although cognitive impairment in the acute phase of MDD is well documented, the knowledge of how the impairments develop in a long-term perspective is scant. A major question, with implications for our understanding of MDD, is whether cognitive impairment manifested during periods of depression is long lasting or improves during remission and recovery.

DEPRESSION AND LONG-LASTING COGNITIVE IMPAIRMENT -A NEW FIELD OF INTEREST
A common understanding early in the literature and in clinical practice has been that cognitive impairment restores as depression heals. This assumption has been questioned the last decade. The association between cognitive function and MDD in a long-term perspective has seldom been investigated, thus longitudinal studies on this topic are few and results are divergent. Knowledge in this area is therefore limited, and there are still numerous questions regarding how cognitive functioning evolves in relation to symptom reduction and remission (Figure 1).
Of the longitudinal studies existing on this fi eld several indicates that cognitive impairment seen during episodes of illness, also persists during episodes of symptom reduction (Hammar et al., 2003b;Airakinsen et al., 2006) and even in remission (Reischies and Neu, 2000;Majer et al., 2004;Weiland-Fiedler et al., 2004;Neu et al., 2005;Paelecke-Habermann et al., 2005;Smith et al., 2006;Gruber et al., 2007;Nakano et al., 2008), although some studies report no such fi ndings (Koetsier et al., 2002;Biringer et al., 2005;Lahr et al., 2007). Other studies suggests that cognitive impairment worsens for every episode of depression (Brown et al., 1999;Sweeney et al., 2000) and that impairment observed in a nonsymptomatic phase is related to number of previous episodes of depression (Kessing, 1998). It is possible that prolonged cognitive impairment holds true for sub groups of depressed samples, thus not all patients are characterized by long-lasting impairment. Hammar et al. (2003b) found that depressed patients showed impaired cognitive performance on cognitive demanding tasks (effortful processing) when symptomatic and that the impairment prevails after 6 months, despite signifi cant improvement in the depression symptoms.
In contrast a 2-year follow-up study reported a correlation between improvement in depressive symptoms and improvement in EF, suggesting that depression related changes in EF are reversible upon remission . However, MDD patients failed to improve to the level of controls at follow-up on some EF measures, and the observed improvement in the depressed patient group could be due to a general training effect which was not controlled for because of missing control group at follow up. Gualtieri et al. (2006) found that MDD patients who are successfully treated with newer antidepressants are better cognitively than untreated patients. However, the performance was still worse than healthy controls. 1997; Landrø et al., 2001). Secondly, a hypothesis of specifi c cognitive impairment, suggesting that MDD is associated with pronounced impairment within specifi c cognitive domains, foremost in EF and memory (Austin et al., 2001;Elliott, 2002). Thirdly, regardless of domain the cognitive effort hypothesis claims that MDD patients show impairment on effortful tasks whereas they show normal functioning on automatic tasks. Automatic processing is considered to be stimulus-driven, whilst effortful processing requires attention and cognitive capacity, and is also defi ned as an instruction-driven process (Hasher and Zacks, 1979;Hammar et al., 2003a).
The research over the past decade show diversity in fi ndings; no single cognitive function has been found that characterizes all depressed patients, and not all patients are impaired in the same degree. However, there is fi rm evidence that depressed patients as a group are characterized by cognitive impairment in the acute phase. Diversity among fi ndings might be explained by different methodological issues, such as inclusion of patients with different severity or subtypes of depression: in example bipolar disorder, fi rst episode of major depression, recurrent episodes, depression with psychotic features, dysthymia, in patients versus out patients etc. In addition studies investigate different age groups, apply a variety of neuropsychological tests, and have different inclusion and exclusion criterion in example regarding medications and substance abuse. Co morbid disorders may play an important role in explaining diversity in fi ndings across studies (Baune et al., 2009) in particular co morbid anxiety (see review Levin et al., 2007). When these factors are mixed within studies, it is diffi cult to subtract the core of the neuropsychological impairment in depression. In example, there is strong reason to believe that fi rst ever depressed patients might show a different cognitive profi le than recurrent depressed patients. It can be diffi cult to determine whether a person is experiencing a fi rst ever depressive episode, thus a throughout diagnostic screening should be a part of inclusion. All these factors might infl uence results and cause diffi culties in agreement upon a neuropsychological profi le that characterize depression in the acute phase of illness. It is highly likely that different subgroups of depressed samples show different patterns of impairment. In addition, Scheurich et al. (2008) have suggested that the cognitive impairment associated with depression can be infl uenced by motivational aspects. Such knowledge would further be of importance for the treatment course of depression.

Aspect of impairment References in the acute phase
Verbal memory Naismith et al. (2003); Reischies and Neu (2000) Visual memory Naismith et al. (2003); Reischies and Neu (2000) Verbal delayed memory Vythilingam et al. (2004) Visuo-spatial memory Porter et al. (2003) Verbal working memory Landrø et al. (2001) Verbal long term memory Landrø et al. (2001) Regarding the relation between MDD and long-term cognitive functioning two different hypotheses have been proposed. Based on earlier fi ndings the fi rst hypothesis suggests that cognitive impairment sustains despite symptom reduction (Martinez-Aran et al., 2000;Reischies and Neu, 2000;Austin et al., 2001;Hammar et al., 2003b). The second hypothesis states that multiple depressive episodes further deteriorate cognitive impairment (Sweeney et al., 2000). There is, however, increasing indications in the recent literature that symptom reduction in depressions is not followed by cognitive improvement to a similar degree.

IMPAIRMENT IN DAILY LIFE FUNCTIONING
Depression is associated with impairment in daily life functioning (see review Papakostas et al., 2004). Several studies have investigated how depression affects daily life functioning in the acute phase of illness, thus the knowledge on this fi eld is rather conclusive. Studies have shown that MDD affects several aspects of work performance, including productivity, task focus and days absent caused by sickness (Wang et al., 2004;Adler et al., 2006). A central aspect of life functioning is family and social relations, again shown to be impaired in depressive patients, including household strain, social irritability, fi nancial strain, limitations in occupational functioning and poor health status (see review Papakostas et al., 2004).
Traditionally, mood symptoms have been used to explain this disability in life functioning in mood disorders. However fi ndings indicate that improvement in daily life functioning does not follow improvement in depression symptoms to a similar degree (Adler et al., 2006;Kennedy et al., 2007). Daily life functioning has been found to be impaired even in phases of remission of depression (Angermeyer et al., 2002;Jaeger et al., 2006). Different factors could explain why improvement in depressive symptoms is not followed by improvement in daily life functioning to a similar extent. Residual symptoms, comorbidity, misdiagnosis and long-lasting cognitive impairment could be important factors associated with long-lasting impairment in daily life functioning (Kennedy et al., 2007).
Studies have found that cognitive impairment play an important role in functional recovery from depression (Jaeger et al., 2006). This has also been reported regarding bipolar disorder (Martinez-Aran et al., 2007).
The lack of knowledge on this fi eld regarding the possible impact long-lasting cognitive impairment represents for daily life functioning in this patient group is strikingly. And there is only few studies investigating this question. This possible relationship has enormous clinical implications.

CLINICAL IMPLICATIONS
Remitted MDD patients are often expected to function at a premorbid level. However, this might not be a rightful expectation if cognitive functioning and daily life functioning is impaired in a long time course after depression. The results of this expectation may lead to frustration, low self esteem, low coping, and feelings of worthlessness for the individual involved, and in a worst case enhance the risk of relapse. Patients cognitive functioning and the impact this has on daily life functioning should be a focus in ongoing treatment. Impaired cognitive functioning affects family life, school performance, work performance and social Although several questions remain to be answered, the literature clearly indicates that depressed patients as a group is subject to neuropsychological impairment that may persist despite symptom reduction and remission, see "II" in Figure 1. Following this, another important question rises: How does long-lasting impairment in cognitive functioning affect daily life functioning in depressed individuals? well described inclusion and exclusion criterion. This would make comparison across studies more precise, thus possibly answer the question of divergent fi ndings.
Future research will have the possibility to clarify questions regarding the impact cognitive functioning in MDD patients have on life functioning in a long-term course. It is important to make clear this relationship because of the impact this might have on recovery, treatment course and outcome of the disease. Improving cognitive functioning, in example trough cognitive rehabilitation, might show crucial for work performance and occupational life in this patient group and also help patients in the therapeutic process. Identifying risk factors for relapses and new episode is of great importance in order to reduce the burden of MDD worldwide.

CONCLUDING REMARKS
During the past decade much research has focused on cognitive function in MDD, and impairment in cognitive functioning in the acute phase of illness is well documented. Less is known about the course of this impairment and several questions remain unanswered. Some studies report the impairment observed in the acute phase to be long lasting, and also persistent in phases of remission. However, there are contradictory fi ndings on this fi eld which might indicate that this holds true in subgroups of depressed patients, thus not describe all MDD patients. In particular there is a lack of studies investigating these questions in fi rst ever depressed samples, and longitudinal studies following patients over several years. There is a need for studies investigating cognitive functioning in well defi ned homogenous patient groups longitudinally in the future.
life. Cognitive training and rehabilitation could prove important in treating depression in the long-term course, and help prevent relapse. And important challenge is to unite research and practice, and it is of great importance that the possible long-lasting cognitive impairment associated with depression is debated in clinical settings.

FUTURE STUDIES
Cognitive impairment may be an enduring component of a chronic depression (Kennedy et al., 2007). It is evident that increased focus on longitudinal studies is necessary if the relation between MDD and cognitive function shall be further explored and understood, this mainly to improve rehabilitation conditions and prevent relapses. One of the main questions that must be further investigated is if long-lasting cognitive impairment is a risk factor for relapse episodes. If so, will cognitive training and rehabilitation be possible treatments in order to prevent new episodes. These types of questions are in today's literature still unsolved.
Moreover, MDD patients in general are a heterogeneous group and there is reason to believe that the degree of cognitive impairment is related to clinical factors such as numbers of previous episodes, duration, onset as well as treatment factors like effects of medications and hospitalization. There are many distinct combinations of symptoms that would qualify for a diagnosis. Thus, this implicates that future studies must aim to include homogenous patient groups and differ between factors such as degree of severity as well as between fi rst episode patients, patients with recurrent episodes, bipolar diagnosis etc. Following this, an important challenge for future studies is homogenous patient groups with