Depressive Cognitive Disorders

Etiology

The long-term persistence of inflammatory processes leads to cognitive deficits in depression.[9] It is presented in two different forms— ‘depressive cognitive disorders’ or the ‘Wernicke pseudodementia.’ The latter is considered a more severe form. 

Depression is the dominating cause of memory loss in the elderly population. Numerous factors contribute to the development of depressive cognitive disorders:

• Neurotransmitter hypothesis— The serotonin hypothesis formulates the basis of the treatment of major depressive disorder and the accompanying memory impairment. The serotonin 5-HT-1B receptor is proposed as a likely factor in the etiology of depressive disorders. The dysfunction of 5-HT-1B receptors is detected in the brains of depressive patients.[10]
• Neurological pathways— Memory and learning process is linked with an intricate circuitry that involves the amygdala and its associations with the structures in the frontal and temporal lobes: The medial temporal gyrus, prefrontal, and the anterior cingulate cortex. Major depressive disorder mainly affects these brain structures (specifically the amygdala and hippocampus), leading to deficits in memory and the verbal learning process.[11]
• Neuroendocrine factors— Researchers have found that hypercortisolemia attributed to depressive disorder is related to the degeneration of neurons in the hippocampus leading to cognitive impairment.
• Genetic factors— C9ORF72 repeats on chromosome 9 are found in patients suffering from depressive cognitive disorders. This has been earlier correlated with neurodegenerative dementia. This finding confirms the genetic association of depressive cognitive disorders.[12]
• Psychosocial and environmental factors— the interplay of various factors such as abuse (mental and physical) in the past, poor social support, loss of a job, negative life events, and substance abuse leads to increased stress and depression by altering the hypothalamic-pituitary axis, which eventually causes cognitive impairment.[13]

Epidemiology

The prevalence of a major depressive disorder in the elderly population varies between 30 and 45%. Out of these, 10 to 12% of the patients get admitted to an acute care setting, and 12% to 14% get admitted to a nursing home.[14] The cognitive impairment has been documented to be 85 to 94% of the time during an acute depressive episode and 39% to 44% of the time after recovery of the depressive episode.[3] On the other hand, neurodegenerative dementia is accompanied by depression in 15 to 23% of cases. Research shows 20% to 30% of executive function deficits in depressed individuals.[15]

Pathophysiology

The pathophysiology of depressive cognitive disorders is originated from the underlying neuropsychiatric disorder. Due to the overlapping signs and symptoms of depression and dementia, it becomes difficult to discern the exact pathology of cognitive impairment. Numerous cognitive deficits are found in late-onset depression. Among those, memory impairment (anterograde and retrograde) is extensively analyzed for the evaluation of cognitive distinctions in depressive disorder and dementia. Major depressive disorder depicts a multitude of deficits in the spheres of episodic memory, including explicit vocal and visual memory domains. The implicit memory functions are preserved. This memory impairment is secondary to the temporal lobe abnormality seen in a depressive disorder. Circadian rhythm disruption seen in depression has been theorized to contribute to cognitive decline.

Patients with neurodegenerative dementia exhibit a considerably more fast rate of forgetting as differed to depressed and normal people who forget data at a similar rate. Depressed individuals with memory impairment also tend to show less random variation in their responses. A clear-cut ‘unified theory’ for the cognitive impairment in depression has not been formulated, but research points to an encoding problem seen in these patients. A depressive disorder is associated with negative automatic thought (NAT) and rumination, which encroach into the consciousness affecting cognition.[16] Lack of natural instincts linked with motivation, impetus, action, concentration, and arousal seems to be associated with the presence of effort mandating cognitive impairment in depressive disorders.[15]

History and Physical

The assessment of depressive symptoms in dementia is confounded by numerous factors: overlapping symptoms, the issue of symptom continuation, communication problems in severe dementia, and reliability of caretaker opinions. A detailed history and a thorough mental status examination are required for adequate diagnosis.

Overlapping symptoms in history are decreased interest in pleasurable activities, altered sleep, decreased/increased appetite, increased/decreased psychomotor activity, difficulty concentrating, and decreased energy. The likelihood of a superimposed depression in neurocognitive dementia should be contemplated when the patient's symptoms, such as sleep alterations due to loss of diurnal rhythm or lack of motivation, become more serious over a short span of time. In severe dementia, a history of depressive symptoms may be hard to find secondary to aphasia. In such cases, the collection of history from the caregiver as well as detailed observation during the examination is required to formulate a diagnosis. Besides, sometimes patients with dementia have anosognosia (refusal of disability), which further complicates the reporting of symptoms suggestive of depression.

Collecting history from the caregiver can benefit, as well as complicate the diagnosis as they are themselves vulnerable to increased degrees of responsibility and sadness. The occurrence of depression in dementia has been strongly associated with the caretaker's burden and their own depression.

Clues in history that helps to diagnose depression are—

• Acute or subacute changes in symptoms
• Symptoms of hopelessness, helplessness, guilt, death wishes, and suicidal ideation. A detailed history should be taken to rule out active suicidal ideations, intent, or plans in any patient who expresses death wishes.
• In severe dementia, signs such as frequent moan, saddening appearance, sudden changes in psychomotor activity (agitation or retardation)
• Episodes of frequent screaming with depressive content, refusal to eat 
• Past history and family history of depression
• Prominent complaints of memory loss and related feelings of distress, recent and long-term memory equally affected with a complete absence of language disturbance.

In addition to history, a detailed mental status examination, neurocognitive tests, and laboratory tests are required to rule out other medical causes. Observing the patient's behavior during examination is very critical and important. Depressed people lack adequate motivation to finish the task, take additional time to accomplish the task, and document frequent attention or concentration problems. They are usually apathetic and easily diverted. Patients with depression often document memory difficulties and associated distress repeatedly. On the other hand, patients with dementia seem to be less distressed and familiar with the magnitude of their own cognitive deficiencies.

On further questioning during the mental status examination: Patients with depression either do not respond or will reply," I don't know," to questions pertaining to orientation, attention, concentration, memory, calculation, abstraction, and judgment.

Evaluation

In addition to history and mental status examination, laboratory testing to rule out other medical causes of cognitive deficits such as HIV, syphilis, vitamin B12, and folate deficiency, and paraneoplastic syndromes, etc., should be ordered. 

Neuropsychological tests— Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Wechsler Memory scale (WMS), clock drawing test, and Trail Making test are commonly used.[9] RBANS is a test that measures immediate and delayed memory, attention, language, and visuospatial skills. It was formulated for two primary applications: as a test for the diagnosis and description of dementia and as a tool for finding neurocognitive deficiencies in a mixture of disorders. WMS measures patients' performance on seven domains testing the auditory, visual, visual working, immediate, and delayed memory.[17]

Neuroimaging studies— Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT) are ordered to look for particular brain abnormalities seen in dementia.[5]

Rating Scales— The most commonly used scale for screening depression in dementia is the Cornell Scale for Depression in Dementia (CSDD). The CSDD is a 19-item instrument assimilating data from both patient and caretaker. It evaluates mood-related signs (Anxiety, sadness, anhedonia, irritability), behavioral disturbance (Agitation, retardation loss of interest), physical signs (Appetite and weight loss), cyclic functions (diurnal variation in symptoms), and ideational disturbance (Suicide, poor self-esteem, etc.). Scores greater than ten are associated with a probable diagnosis of a major depressive episode. Scores of more than 18 indicate a definite major depressive disorder.[18]

Treatment / Management

Pharmacological Treament

• Selective Serotonin Reuptake Inhibitor (SSRI)— Recent data approves serotonin reuptake inhibitors (SSRIs) as the first-line treatment for depression in dementia as cholinergic side effects (including cognitive impairment) have been less prominent with SSRIs. Adverse effects commonly seen in the elderly are decreased sodium levels, akathisia, markedly decreased appetite, and bradycardia. Other side effects include gastrointestinal discomfort (nausea, vomiting, loose stools), anxiety, and sleep abnormalities.

• Serotonin-norepinephrine reuptake inhibitors (SNRI)— These act as the next-line of treatment after SSRIs. It comprises venlafaxine, desvenlafaxine, and duloxetine. This class of drug is believed to be safe in older people. The commonly seen adverse effects are nausea, dizziness, insomnia, and constipation. [14]

• Tricyclic antidepressants (TCAs)— These drugs should be avoided in patients with cognitive impairment as these increase susceptibility to anticholinergic effects, including cognitive deficits, by blockage of muscarinic receptors.

• Zolmitriptan— It is a 5-HT-1B agonist found to be effective in the treatment for depression and associated cognitive impairment. It acts by modifying the serotonergic receptors. The adverse effects commonly seen in the elderly are numbness, tingling, and drowsiness. [10]

• Vortioxetine— It has a multimodal mechanism of action: agonist at 5-HT1A receptors, 5-HT1B partial agonist, and 5-HT3 receptor antagonist. Recent data confirm its effectiveness in the treatment of depression with cognitive deficits. Adverse effects are similar to SSRIs. [3]
(B3)

• Cholinesterase Inhibitors (Donepezil, galantamine, rivastigmine)— These medications have been found to ameliorate subsyndromal depression in patients with dementia. These have a positive effect on the behavioral symptoms of dementia in addition to the effect on improving cognition.[19]
(A1)

Non-Pharmacological Treament

• Electroconvulsive therapy (ECT)— It is safe and beneficial in depression and other disorders leading to cognitive deficits. ECT limits cognitive injury related to a major depressive disorder associated with dementia in the elderly. In depressed patients with dementia, it showed substantial refinements in both mood and cognition.  Though it causes confusion as a side effect, it could be decreased by reducing the frequency of administering ECT to one to two times weekly.[20]
(B3)

• Interpersonal/Behavioral Approaches— Both strategies are associated with considerable improvement in depressive symptoms in patients and their family members. Therapy of the caretaker is a critical factor in the treatment of the patient with depression associated with cognitive impairment.

• Healthy habits

1. Diet: Researchers have ascertained that people who follow a 'healthy' diet routine are less likely to be depressed.
2. Regular workout: Meditation and yoga are guarding against depressing disorders. A plausible reason seems to be the impact of everyday work out on brain-derived neurotrophic factor (BDNF).
3. Omega-3 fatty acids: It regulates the serotonergic and dopaminergic neurotransmitters, leading to mood regulation. It also has an anti-inflammatory effect.

Differential Diagnosis

• Major depressive disorder— Cognitive deficits, including memory impairment, are one of the core diagnostic symptoms in patients with depression.[21]

• Dementia— Neurodegenerative dementia is presented with the disruption of numerous cortical functions along with behavioral manifestations as the primary symptom. A thorough examination and cognitive testing should be performed before formulating the diagnosis.

• Late-onset bipolar disorder—Symptoms of bipolar disorder that may present as symptoms of a dementia process— decrease the need for sleep, easy distractibility, irritability, decreased energy, and decreased interest in pleasurable activities.[5]

• Delirium— secondary to drugs (withdrawal of alcohol, barbiturates, steroids), metabolic disturbance (hypo/hyperthyroidism, fluid-electrolyte imbalance), and infection (urinary tract infection, lung infection, meningitis, encephalitis).[17]

• Structural abnormalities (tumor, subdural hematoma, normal pressure hydrocephalus)— The onset of symptoms would be abrupt or acute, the patient would complain of headache in case of a tumor. On examination, shuffling gait will be found in the case of normal pressure hydrocephalus or Parkinson disease.

Prognosis

The prognosis of depressive cognitive disorders is controversial, with surveys documenting transformation to irreversible neurodegenerative dementia and additional reviews documenting no transformation. In the past, it came to be more obvious that depression correlated with cognitive deficits can be the prodromal phase of dementia. In this respect, current data reports depression to be related to a twofold heightened risk of transforming to irreversible dementia. Researchers have found that over an interval of 4 to 5 years, more than 70% of cases originally diagnosed with depression with cognitive impairment transformed into dementia, and 18% of these cases were originally found to have no changes in cognition.

Complications

Depressive cognitive disorders are related to a considerable amount of disability. It complicates management, exacerbates functional problems, and governs other adverse consequences.[22] It is associated with interference with life and activities due to prolonged hospitalization. Cases with coexisting depressive disorder and dementia seem to utilize health care and the nursing home facility at a considerably increased amount than cases with either disorder alone. Caretaker responsibility is heightened many folds when they have to care for patients who have both dementia and a depressive disorder. The additional important complication of depressive cognitive disorder is suicidal ideation. The percentage rises in aged separated or divorced white men. Social withdrawal and associated medical illness further enhance the risk. Depression with dementia furthermore increases the likelihood of medical co-morbidity in old age like cardiovascular illnesses, diabetes, stroke, etc.