Cognitive Impairment in Major Depressive Disorder

About Cognitive Impairment and Depression

Depression is one of the most common and burdensome psychiatric disorders worldwide, with an estimated 5% of the population affected.

The condition is characterized by episodes of depressed mood that are frequently recurrent. Depressive disorder can also be chronic if episodes are prolonged without resolution, or persistent where depression continues for 2 or more years.

Although episodes of isolated low mood are common, when low mood is accompanied by other features which limit quality of life, it is referred to as Major Depressive Disorder (MDD).

MDD can be mild, moderate, or severe, and various subtypes are recognized: anxious; atypical; catatonic (marked reduction in movement); melancholic; mixed features; peripartum (following childbirth); psychotic; and seasonal (triggered by changing seasons).

MDD is a complex disease and symptoms are often grouped as emotional, physical and cognitive. It is understood that the greater the number and severity of symptoms, the greater the likelihood of impacts on day-to-day life (known as functional impairment).

Figure 1. Key symptoms for major depressive disorder (MDD). For a diagnosis of MDD, individuals need to present with 5 or more of any of the above symptoms and one of either depressed mood or inability to feel pleasure. The greater the number and severity of symptoms, the greater the impact on the individual’s ability to function normally. Adapted from Malhi et al. (2018) 1
While cognitive symptoms (related to the ability to think clearly and with a good memory) were often overlooked in the treatment of depression, they are now considered vital components of the disease requiring therapy to improve overall quality of life.

People with depression often experience impairment in cognitive function in several domains, including ability to make decisions, making decisions quickly (processing speed), ability to focus attention, to learn new information, to understand and follow instructions (executive function), and memory not only before and during depressive episodes but also after remission of mood symptoms.

Although various classes of antidepressant medication are in use, studies have failed to show a clear difference in efficacy between classes, except where disease is severe2. Consequently, antidepressant classes are generally administered based on their side-effect profile and tolerability, and not based on the patient symptom profile.

Almost all existing antidepressants target increasing the chemicals in the brain which are responsible for communication between nerve cells. Furthermore, barely any breakthroughs in the optimization of MDD treatment outcomes have been made over the past several decades despite considerable global efforts.

The Actinogen phase 2 depression trial has closed recruitment

Cognitive impairment is a prominent feature that remains poorly managed

Cognitive impairment is often an ongoing symptom, with one study indicating that cognitive impairment may persist in up to 44% of patients considered to be in remission of the depressive episode3.

Evidence indicates that cognitive impairment can also compound and become progressively worse with subsequent depressive episodes and may also be associated with increased risks of relapse and of developing dementia4. Cognitive dysfunction in MDD is thereby a source of ongoing functional impairment and reduced quality of life for patients5.

Despite this, treating cognitive impairment in MDD has been largely overlooked in the development of new drugs, with most focusing solely on improving mood symptoms.

Cognition remains an unmet medical need for drug development.

Strong scientific rationale for targeting brain cortisol in the treatment of depression

Cortisol is an essential hormone that is produced mainly in the adrenal gland, just above the kidney. It helps manage the body’s response to stress (both mental and physical).

Cortisol production in the adrenal gland is controlled by two parts of the brain, the hypothalamus and the pituitary gland.  The hypothalamus detects stress by receiving input from other parts of the brain. In response, the pituitary gland secretes a hormone which stimulates cortisol production in the adrenal gland.

As cortisol increases in the blood, it is detected by the hypothalamus and signals to stop further production of cortisol. Alterations of the HPA axis and cortisol, such as chronically elevated cortisol or disturbed daily cortisol secretion rhythm, have been studied in relation to MDD for decades and are the most consistent biological features found to be associated with depression.

Many studies have found that cortisol concentrations in plasma and cerebrospinal fluid were elevated in MDD.

Persistent HPA-axis dysfunction after treatment in MDD has also been associated with poorer clinical prognosis, cognitive impairment, treatment failure, and an increased risk of relapse. Higher cortisol levels at baseline predict poorer treatment outcomes and a greater persistence of clinical symptoms post-treatment6.

Depression is also a common symptom of Cushing’s syndrome, where there is an excess production of cortisol, with up to 80% of Cushing’s patients also experiencing depression7, further highlighting the association of chronically elevated cortisol and depression.

Based on these observations, researchers have pursued compounds that modify HPA-axis function for the treatment of depression. Generally, these medications were designed to either reduce the production of cortisol in the adrenal glands or to prevent cortisol from binding to its receptor.

The effects of these medications on cognition in MDD have not been thoroughly investigated in these studies. When combined, results from these clinical trials show that reducing cortisol improves depression. Although none of the treatments studied were suitable for routine clinical use, the principle was proven.

Given the strong scientific rationale, Xanamem’s unique mechanism of action is a promising therapeutic strategy in MDD. By targeting cortisol production in brain cells to improve cognitive function in people with MDD, Xanamem may improve cognitive function and in turn functional outcomes for these patients.

  1. Malhi, G.S. and J.J. Mann, Depression. The Lancet, 2018. 392(10161): p. 2299-2312.
  2. Rush, A.J., Unipolar major depression in adults: Choosing initial treatment. 2020, UpToDate
  3. Conradi, H.J., J. Ormel, and P. de Jonge, Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med, 2011. 41(6): p. 1165-74

  4. Gorwood, P., et al., Toxic effects of depression on brain function: Impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. American Journal of Psychiatry, 2008. 165(6): p. 731-739

    Semkovska, M., et al., Cognitive function following a major depressive episode: a systematic review and meta-analysis. The Lancet Psychiatry, 2019. 6(10): p. 851-861.

  5. Jaeger, J., et al., Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res, 2006. 145(1): p. 39-48.

  6. Fischer, S., et al., Cortisol as a predictor of psychological therapy response in depressive disorders: systematic review and meta-analysis. Br J Psychiatry, 2017. 210(2): p. 105-109.

  7. Lin, T.Y., J. Hanna, and W.W. Ishak, Psychiatric symptoms in Cushing’s syndrome: A systematic review. Innovations in Clinical Neuroscience, 2020. 17(1-3): p. 30-35.

Publications

Effect of glucocorticoid and 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD1) in neurological and psychiatric disorders

Dodd S, Skvarc D R, Dean OM, Anderson A, Kotowicz M, Berk M 10 Feb 2022. Int J Neuropsychopharmacol. doi: 10.1093/ijnp/pyac014.

 

Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study

J. Conradi, J. Ormel and P. de Jonge 2011. Psychological Medicine, 41, 1165–1174.

 

Depression and Hypothalamic-Pituitary-Adrenal Activation: A Quantitative Summary of Four Decades of Research

Cinnamon Stetler, PhD, And Gregory E. Miller, PhD 2011. Psychosomatic Medicine 73:114–126.

 

Central CRH system in depression and anxiety — Evidence from clinical studies with CRH1 receptor antagonists

Florian Holsboer, Marcus Ising 2008. European Journal of Pharmacology 583, 350–357.

 

Depression

Malhi, G.S. and J.J. Mann 2018. The Lancet 392(10161): p. 2299-2312.

 

Unipolar major depression in adults: Choosing initial treatment

Rush, A.J 2020. UpToDate.

 

Toxic effects of depression on brain function: Impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients

Gorwood, P., et al., 2008. American Journal of Psychiatry 165(6): p. 731-739.

 

Cognitive function following a major depressive episode: a systematic review and meta-analysis

Semkovska, M., et al. 2019. The Lancet Psychiatry 6(10): p. 851-861.

 

Neurocognitive deficits and disability in major depressive disorder

Jaeger, J., et al. 2006. Psychiatry Res 145(1): p. 39-48.

 

Cortisol as a predictor of psychological therapy response in depressive disorders: systematic review and meta-analysis

Fischer, S., et al. 2017. Br J Psychiatry 210(2): p. 105-109.

 

Psychiatric symptoms in Cushing’s syndrome: A systematic review

Lin, T.Y., J. Hanna, and W.W. Ishak 2020. Innovations in Clinical Neuroscience 17(1-3): p. 30-35.

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