Depressive Cognitive Disorders

Etiology

Depression is the dominant cause of memory loss in the older adult 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 individuals.[11]
• Neurological pathways: Memory and learning processes are 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 (particularly the amygdala and hippocampus), leading to deficits in memory and the verbal learning process.[12]
• 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 experiencing depressive cognitive disorders. This has been earlier correlated with neurodegenerative dementia; this finding confirms the genetic association of depressive cognitive disorders.[13]
• 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, adverse life events, and substance abuse, leads to increased stress and depression by altering the hypothalamic-pituitary axis, which eventually causes cognitive impairment.[14]

Epidemiology

The prevalence of major depressive disorder in the older adult population varies between 30% and 45%. Of these, 10% to 12% of patients are admitted to an acute care setting, and 12% to 14% are admitted to a nursing home.[15] Cognitive impairment has been documented to be present in 85% to 94% of the time during an acute depressive episode and in 39% to 44% of the time after recovery of the depressive episode.[4] On the other hand, neurodegenerative dementia is accompanied by depression in 15% to 23% of cases. Research results show a 20% to 30% prevalence of executive function deficits in depressed individuals.[16]

Pathophysiology

Depressive cognitive disorders originate from an 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 is associated with many 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 temporal lobe functional abnormalities seen in depressive disorders. Circadian rhythm disruption seen in depression has been theorized to contribute to cognitive decline.

Patients with neurodegenerative dementia exhibit a considerably faster rate of forgetting as compared 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 cognitive impairment in depression has not been formulated, but research points to an encoding issue seen in these patients. Depressive disorders are associated with automatic negative thoughts and rumination, which encroach on conscious thought and affect the encoding of memories.[17] Additionally, in depression, a decrease in motivation and concentration negatively impacts the effort applied to initial learning.[16]

History and Physical

Numerous factors confound the assessment of depressive symptoms in dementia: overlapping symptoms, the issue of symptom continuation, communication problems in severe dementia, and the reliability of caretaker opinions. A detailed history and 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 reduced energy.

The likelihood of a superimposed depression in neurocognitive dementia should be considered 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 period. In severe dementia, a history of depressive symptoms may be difficult to find secondary to aphasia. In such cases, the collection of history from the caregiver and a detailed examination are required to formulate a diagnosis. Furthermore, patients with dementia may have anosognosia (refusal of disability), which further complicates the reporting of symptoms suggestive of depression. Collecting history from the caregiver can benefit and complicate the diagnosis, as they are 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 suggest depression include:

• Acute or subacute changes in symptoms
• 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 moaning, a saddening appearance, and sudden changes in psychomotor activity (agitation or slowing)
• Episodes of frequent screaming with depressive content
• Refusal to eat 
• History and family history of depression
• Prominent complaints of memory loss and related feelings of distress, recent and long-term memory are equally affected, with a complete absence of language disturbance

In addition to history, a detailed mental status examination, neurocognitive testing, and laboratory testing are required to rule out other medical causes.

Evaluation

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

• Neuropsychological tests: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Wechsler Memory Scale (WMS), clock drawing test, and Trail Making test are commonly used.[18] 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 diagnosing and describing dementia and as a tool for finding neurocognitive deficiencies in a mixture of disorders. WMS measures patients' performance in 7 domains, testing the auditory, visual, visual working, and immediate and delayed memory.[19]
• Neuroimaging studies: Magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography are ordered to look for particular brain abnormalities in dementia.[8]
• Rating scale: 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 that assimilates data from both a patient and their caretaker. This rating scale evaluates mood-related signs (anxiety, sadness, anhedonia, irritability), behavioral disturbance (psychomotor changes, loss of interest), physical signs (appetite and weight changes), cyclic functions (diurnal variation in symptoms), and ideational disturbance (suicide, poor self-esteem). Scores greater than 10 are associated with a probable diagnosis of a major depressive episode. Scores of more than 18 indicate a definite major depressive disorder.[20]

Treatment / Management

Pharmacological Treatments

• Selective serotonin reuptake inhibitors (SSRIs): Recent data suggest SSRIs as the first-line treatment for depression in dementia, as cholinergic adverse effects (including cognitive impairment) have been less prominent with SSRIs. Adverse effects commonly seen in older adults are decreased sodium levels, akathisia, markedly reduced appetite, and bradycardia. Other adverse effects include gastrointestinal discomfort (nausea, vomiting, loose stools), anxiety, and sleep abnormalities.
• Serotonin-norepinephrine reuptake inhibitors (SNRIs): Venlafaxine, desvenlafaxine, and duloxetine act as the following line of treatment after SSRIs. This class of drug is believed to be safe in older adults. The commonly seen adverse effects are nausea, dizziness, insomnia, and constipation.[15]
• Tricyclic antidepressants: These drugs should be avoided in patients with cognitive impairment as they increase susceptibility to anticholinergic effects, including cognitive deficits, by blocking muscarinic receptors.
• Zolmitriptan: This drug is a 5-HT-1B agonist found to be effective in the treatment of depression and associated cognitive impairment, which acts by modifying the serotonergic receptors. The adverse effects commonly seen in older adults are numbness, tingling, and drowsiness.[11]
• Vortioxetine: This drug has a multimodal mechanism of action; it is an agonist at 5-HT1A receptors, a 5-HT1B partial agonist, and a 5-HT3 receptor antagonist. Recent data confirm its effectiveness for the treatment of depression with cognitive deficits. Adverse effects are similar to those of SSRIs.[4]
• 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 impact on improving cognition.[21]
(A1)

Non-Pharmacological Treatments

• Electroconvulsive therapy (ECT): This therapy 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 older adults. In depressed individuals with dementia, this therapy showed substantial refinements in both mood and cognition. Though it can cause confusion as an adverse effect, this therapy could be decreased by reducing the frequency of administering ECT to 1 to 2 times weekly.[22]
• 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.
(B3)

Lifestyle Interventions

• Diet: Researchers have ascertained that people who follow a 'healthy' diet routine, such as the Mediterranean diet, are less likely to be depressed.
• Regular exercise: Meditation and yoga can help guard against depressive disorders; additionally, regular moderate exercise is protective against the development of depression. A putative explanation is that exercise increases the production of brain-derived neurotrophic factor.

Differential Diagnosis

The differential diagnosis of depressive cognitive disorders includes the following:

• Major depressive disorder: Cognitive deficits, including memory impairment, are one of the core diagnostic symptoms in patients with depression.[23]
• 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 include decreased need for sleep, easy distractibility, irritability, decreased energy, and decreased interest in pleasurable activities.[8]
• 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).[19]
• Other neurologic pathologies: These include tumors, hematomas, and normal pressure hydrocephalus. Depending on the pathology, the course could range from acute to chronic and present with neurological symptoms specific to the primary condition.

Prognosis

The prognosis of depressive cognitive disorders is controversial, with mixed evidence for transformation to irreversible neurodegenerative dementia. Current data reports depression to be related to a 2-fold heightened risk of transforming to irreversible dementia. After over 4 to 5 years of observation, researchers have found that more than 70% of cases diagnosed initially with depression with cognitive impairment transformed into dementia, and 18% of these cases were found initially to have no changes in cognition.

Complications

Depressive cognitive disorders are related to a considerable amount of disability. This complicates management, exacerbates functional problems, and governs other adverse consequences.[24] This condition is associated with interference with life and activities due to prolonged hospitalization. Cases with coexisting depressive disorder and dementia seem to utilize healthcare and the nursing home facility at a considerably higher rate than cases with either disorder alone.

Caretaker responsibility is heightened when they care for patients who have both dementia and a depressive disorder. Another significant complication of depressive cognitive disorder is suicidal ideation. The prevalence of suicidal ideation is higher in older and separated/divorced white men. Social withdrawal and associated medical illness further enhance the risk. Depression with dementia furthermore increases the likelihood of medical comorbidity in older age, such as cardiovascular illnesses, diabetes, and stroke.