Cognition in Late Life Depression: Treatment Considerations

Opinion statement

Late life depression (LLD) frequently presents with cognitive impairment, and growing evidence suggests that these disease processes are “linked” in multiple ways. For some individuals, LLD may be a recurrence of a long-standing depressive illness, while for others it may be the leading symptom of a developing neuropathological disorder. Overall, studies investigating the relationship between treatment of LLD and improvement in cognitive functioning have yielded mixed results. Research suggests that a subset of individuals with LLD and cognitive dysfunction will experience an improvement in cognitive function after antidepressant treatment, though a significant proportion will continue to exhibit cognitive impairment following resolution of their depressive symptoms. From a treatment standpoint, it is critical to ensure that an individual's depressive symptoms have been treated to remission, measured by a standardized rating scale such as the Geriatric Depression Scale (GDS). SSRI or SNRI monotherapy is often effective, and may be enhanced by employing an evidence-based psychotherapy such as Problem Solving Therapy (PST) or Interpersonal Therapy (IPT), modified to accommodate cognitive impairments that may be present. With respect to specific treatment of cognitive dysfunction, cognitive augmentation or training strategies can be helpful for some patients, and may be explored in combination with treatment of the primary depressive episode. While the introduction of a cholinesterase inhibitor (e.g. donepezil) may be considered, the potential benefit (modest improvement in cognition and functioning) must be weighed against an increased risk for worsening or recurrent depression. Finally, lifestyle factors—such as aerobic exercise, follow-up with a primary care physician for management of co-morbid medical illnesses, and regular participation in stimulating activities (such as through a senior center)—are important and should be included as part of the overall treatment plan.

Introduction

Late life depression (LLD), defined as a major depressive episode occurring in an older adult (60 years or older), encompasses both late-onset cases, as well as early-onset cases that recur or continue into the later years of life. In the clinical setting, patients with LLD frequently present with cognitive complaints, and 20-50% of individuals with LLD are estimated to have cognitive impairment greater than that of age- and education-matched never-depressed control subjects [1, 2]. Cognitive deficits in LLD, which include impairments in episodic memory, speed of information processing, executive functioning, and visual-spatial ability [1-7], have been associated with increased rates of depression relapse, poor response to antidepressant treatment, and greater overall disability. Of the cognitive domains that are often affected, information processing speed and executive functioning appear particularly vulnerable, and several studies have reported that overall cognitive impairment associated with LLD appears to be predominantly mediated by slowed speed of information processing and/or working memory deficits.

From a diagnostic perspective, LLD is often under-reported, under-recognized, misdiagnosed, and under-treated [8], due in part to characteristics that set it apart from earlier-onset depression (i.e. depression that presents before age 60). Compared to younger adults, individuals with LLD are less likely to present with sadness or dysphoria [9] and are more likely to exhibit agitation or somatic symptoms such as gastrointestinal distress, insomnia, or fatigue [10]. In addition, while earlier-onset depression is more prevalent in women, such gender differences are greatly reduced in LLD [11]. LLD is also generally more chronic and difficult to treat to remission than earlier-onset depression, an observation that has been attributed in part to medical co-morbidity and co-occurring cognitive dysfunction [12]. For these reasons and others, LLD is associated with significant mortality, health care utilization, physical disability, and functional decline in older adults [13-15].

A complex relationship exists between the treatment of LLD and improvement (or resolution) of cognitive symptoms. Studies suggest that a subset of individuals with LLD and cognitive dysfunction may demonstrate an improvement in cognition after antidepressant treatment [16], though a significant proportion will continue to experience cognitive impairment following resolution of depressive symptoms [17-22]. Certain risk factors, including lower baseline cognition, older age, later age of depression onset, and greater vascular burden, have been associated with less cognitive improvement after antidepressant treatment [23]. In the following sections, we present an overview of current treatment options for the management of cognitive dysfunction in LLD.

Treatment

Diet and lifestyle

• Diet and lifestyle modifications may play a positive role in the management of older adults with depression and cognitive dysfunction. Healthcare providers should encourage:

  • An assessment by a dietician to ensure adequate caloric intake, evaluate the need for vitamin supplementation (especially for frail and medically-complex patients), and recommend dietary changes that may enhance vascular health (e.g. Mediterranean diet)
  • Driver skill assessment, with driving restrictions if appropriate [24, 25]
  • Family members and caregivers as active members of the treatment team
  • Regular follow-up with a primary care physician:

    • Cognitive and depressive burden are closely related to physical health. With this in mind, it is important that patients maintain close follow-up with a primary care physician who can facilitate guideline-based management of co-morbid medical conditions—such as diabetes, hypertension, and heart disease—that are known to have a deleterious effect on mood and cognition [26].
    • If available, a collaborative-care model is encouraged (e.g. a mental health “care-manager” partnering with a primary care practice). In addition to ensuring that patients receive regular mental health assessments, a “team-based” approach may help patients adhere to their treatment regimen [27].

Pharmacologic agents

• Antidepressant medications: For patients with LLD and impaired cognition, the first task is to ensure adequate treatment of the depressive episode, verified by ratings on a clinical scale with validity in older adults, such as the GDS [28].

  • When selecting antidepressant medications, the clinician should be aware that certain agents have the potential to impair cognition (such as agents with anticholinergic or sedative properties).
  • Tricyclic antidepressants (TCAs) have anticholinergic properties that impair cognition, and their use should be avoided in older adults, whenever possible [29] [Class IV]. Particularly challenging TCAs include amitriptyline, desipramine, imipramine, and nortriptyline.
  • Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs) are generally better tolerated than TCAs [30] and are associated with fewer cognitive side effects.
  • Whenever possible, psychotropic polypharmacy should be avoided in older adults, to minimize the potential for drug-drug interactions, compliance errors, and overall side effect burden [31].

• In the following section, we provide a brief review of antidepressant classes that are useful for treating LLD.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the preferred first-line pharmacotherapy agents for LLD. As a class, the SSRIs are not associated with poorer cognitive performance, and may even slightly improve cognition in individuals with minor depression [32]. Most clinical trials have demonstrated similar efficacy across the SSRI class, and for this reason individual agents are usually chosen based on side-effect profile and risk for drug-drug interactions [33]. While the details of specific agents are beyond the scope of this article, SSRIs that are often used to treat LLD include escitalopram, citalopram, and sertraline. In older adults, fluoxetine is usually avoided, due to its long half-life and multiple drug-drug interactions, and paroxetine is typically avoided due to its high anticholinergicity [34].

Standard dosage	Varies by agent [35]. To minimize side effects, starting dose should be half of that prescribed for a younger adult. Increase dose over 1 to 2 week intervals, with plan to reach therapeutic dosing within 4 weeks. While average therapeutic dose is typically lower than that of a younger adult, there is a fair amount of inter-individual variability, and some older adults will require doses that meet or exceed the average therapeutic dose for younger adults [34].
Contraindications	Relatively few, apart from recent or current treatment with agents that increase risk for serotonin syndrome. Monitor sodium level in patients with history of hyponatremia.
Main drug interactions	Must avoid simultaneous treatment with MAO inhibitors. Escitalopram, citalopram, and sertraline are considered “cleaner” SSRIs, with fewer drug-drug interactions. “Dirtier” SSRIs include fluoxetine, paroxetine, and fluvoxamine, due to greater potential for drug-drug interactions [34].
Main side effects	Nausea, diarrhea, insomnia, sexual dysfunction, agitation, restlessness, and daytime sedation, among others.
Special points	Special caution must be used with citalopram, given risk for QT prolongation among adults older than sixty. In this population, the maximum FDA-approved dose for citalopram is 20 mg/day. For all SSRIs in elderly, check sodium level one month after starting treatment, given risk for Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in the elderly.
Cost-effectiveness	Citalopram and sertraline are more cost-effective than escitalopram, due to availability of generic formulations.

Serotonin–norepinephrine reuptake inhibitors (SNRIs)

The SNRIs are typically used as second-line agents for the treatment of LLD, after failure to respond to two previous SSRI monotherapy trials. The SNRI class includes duloxetine, venlafaxine, desvenlafaxine, and milnacipran (not available in the United States). As a class, the SNRIs have a slightly greater side effect burden than the SSRIs, though are better tolerated than the older TCAs [36].

Standard dosage	Varies by agent [35]. To minimize side effects, starting dose should be half of that prescribed for a younger adult. Increase dose over 1 to 2 week intervals, with plan to reach therapeutic dosing within 4 weeks. While average therapeutic dose is typically lower than that of a younger adult, there is a fair amount of inter-individual variability, and some older adults will require doses that meet or exceed the average therapeutic dose for younger adults [34].
Contraindications	For venlafaxine: uncontrolled hypertension, hyponatremia.
Main drug interactions	For all SNRIs: simultaneous treatment with linezolid or an MAO-inhibiting agent. For duloxetine: avoid thioridazine due to CYP2D6 interaction. For desvenlafaxine: avoid axitinib due to CYP3A4 interaction [35].
Main side effects	Venlafaxine may cause noradrenergic side effects that include dry mouth, constipation, and tachycardia, as well as treatment-emergent hypertension. Abrupt discontinuation of venlafaxine may lead to symptoms such as nausea, chills, insomnia, irritability, and parasthesias. Duloxetine has lower risk for treatment-emergent hypertension, and fewer discontinuation symptoms when treatment is terminated, but may be associated with greater risk for liver enzyme abnormalities.
Special points	For individuals with normal hepatic metabolism, venlafaxine is primarily metabolized to O-desmethylvenlafaxine (ODV) by the enzyme CYP4502D6, and ODV plasma levels are normally two to three times higher than those of the parent drug. As a result, with the exception of patients who are “poor metabolizers” through the CYP450 2D6 system, patients who have been treated with venlafaxine have been treated (primarily) with desvenlafaxine.
Cost-effectiveness	The extended-release formulation of venlafaxine is considerably more expensive than the standard-release formulation, and its relatively small efficacy advantage has not been viewed as sufficient justification to offset its higher cost. Desvenlafaxine and duloxetine are not available in generic formulation, and are more expensive than standard-release venlafaxine.

Add-on pharmacotherapy for treatment of depression

For individuals who do not respond to SSRI or SNRI monotherapy, combination pharmacotherapy may be appropriate. Widely used combinations include the addition of an atypical antipsychotic (such as aripiprazole, risperidone, or olanzapine), bupropion (an activating antidepressant), or mirtazapine (a sedating antidepressant) to SSRI or SNRI monotherapy. Evidence-based psychotherapy (discussed below) should be used in conjunction with the above-noted pharmacotherapy strategies.

• Pharmacotherapy for cognitive enhancement: Pharmacologic augmentation with a cholinesterase inhibitor, such as donepezil, may improve cognition in certain individuals with LLD and cognitive dysfunction. As a “disease-modifying” drug, memantine has been shown to slow cognitive and functional deterioration in individuals with moderate to severe Alzheimer's disease, but this effect has not been demonstrated in individuals with milder cognitive dysfunction associated with LLD.

Donepezil

The benefits of donepezil—modest cognitive and functional enhancement and slowing of the dementia conversion rate—must be weighed against the risk of recurrence of major depression in those with mild cognitive impairment, the possible appearance of manic symptoms, and the potential to worsen suicidal ideation or behavior [37] [Class I].

Standard dosage	5 mg once daily; may increase to 10 mg once daily after 4-6 weeks; effective dosage range in clinical studies: 5-10 mg/day
Contraindications	No absolute contraindications
Main drug interactions	May increase serum concentration of succinylcholine, and caution is advised if these agents are used concurrently [35]
Main side effects	Insomnia and other sleep disorders (abnormal dreams, vivid dreams, nightmares), dose-related anorexia/weight loss, diarrhea, nausea, and/or vomiting; may cause bradycardia or heart block in some individuals, independent of their personal history of cardiac disease. Lower-weight patients (<55 kg) may experience more nausea, vomiting, and weight loss compared to higher-weight patients.
Special points	Considered to improve “cognitive symptoms” in Alzheimer's Disease, but not classified as a “disease-modifying” agent.
Cost-effectiveness	Expensive

Memantine

Memantine has been shown to slow cognitive and functional deterioration in individuals with moderate to severe Alzheimer's disease, but this effect has not been demonstrated in individuals with cognitive dysfunction associated with LLD. In addition, it has been proposed that memantine may exhibit antidepressant effects [38], though this has not been demonstrated in human studies [39].

Standard dosage	Begin 5 mg/day, and increase by 5 mg each week, to achieve target dose of 20 mg/day. Total daily doses >5 mg daily should be given in two divided doses.
Contraindications	No absolute contraindications, but caution is advised in patients with cardiovascular disease—clinical trial data suggests an increased incidence of cardiac failure, angina, bradycardia, and hypertension, compared with placebo. Also, use with caution in patients with severe hepatic impairment.
Main drug interactions	Monitor closely when prescribed with trimethoprim, sodium bicarbonate, or carbonic anhydrase inhibitors [35]
Main side effects	Generally well tolerated; may cause dizziness, confusion, headache, somnolence or fatigue, vomiting, weight loss, cough in some individuals.
Special points	Currently, the only “disease-modifying” pharmacologic agent for the treatment of Alzheimer's Disease.
Cost-effectiveness	Expensive

Psychotherapy

Psychotherapy, focused on depressive symptom reduction and overall rehabilitation, has been shown to improve global outcomes in patients with LLD, and can be provided in various settings, including outpatient clinics, senior centers, and day-hospital programs [40]. While it can be challenging to utilize traditional psychotherapeutic techniques with cognitively-impaired individuals, several evidence-based psychotherapies have been adapted for use in this population, including Problem Solving Therapy (PST) and Interpersonal Therapy (IPT). Brief Behavioral Treatment for Insomnia (BBTI), another psychotherapeutic intervention, utilizes behavioral techniques to treat sleep disturbances, which are highly prevalent in older adults with cognitive and affective disorders. While Cognitive Behavioral Therapy (CBT) is an effective and well-studied psychotherapy for adults with MDD, its utility in cognitively-impaired individuals with LLD is less clear, and we generally prefer treatment with PST, IPT, or BBTI, which may be more accessible for the older patient. If CBT is utilized for the treatment of LLD with cognitive dysfunction, modifications may be necessary [41].

Problem Solving Therapy (PST)

• PST focuses on “problem-solving” skills, and is particularly helpful for treating depressed older adults with impaired cognition. PST teaches individuals to mobilize their coping resources to approach self-identified problems and exert control over them [42]. PST directs the patient to select a “problem” that he or she would like to address, teaches a method for reviewing potential solutions, and provides a directed approach for implementing an appropriate solution. Patients are typically taught these skills over 5 weeks, and then continue to practice them (under the supervision of a therapist) for an additional 8-12 weeks.

• The ”problem solving method” consists of seven steps:

  • Problem orientation (how to recognize that a problem exists)
  • Problem definition (breaking the problem down into concrete components)
  • Goal setting (defining the preferred outcome)
  • Solution generation (brainstorming solutions to reach the preferred goal)
  • Decision making (selecting the most feasible and effective solution)
  • Implementation (planning when and how to use the solution)
  • Solution verification (evaluating the effectiveness of the solution).

• Alexopoulos and colleagues [43] designed a modified form of PST for depressed elders with executive dysfunction, in which therapists offer more structured and directed assistance during the first phase of treatment. As treatment progresses, therapists become less active and foster independent use of the problem solving method. Therapists also employ detailed action plans, which include calling the patient to “check in,” as well as involving caregivers in the treatment plan.

Interpersonal Psychotherapy (IPT)

• IPT is a structured, time-limited therapy that is effective for the treatment of LLD [44].

• In the initial phase of treatment, depressive symptoms are explored and psycho-education is provided; in doing so, the patient's depressive symptoms are linked to recent interpersonal stressors. In the early stages of treatment, the therapist will identify one of four “problem areas” as the focus of the therapy. Potential problem areas include: complicated grief, interpersonal conflict, role-transition, and interpersonal deficits. The patient is supported as he or she works on solutions to the problem area, and it is assumed that once the patient gains mastery over one problem area, this effect will generalize to other areas as well [45].

• IPT is well-liked by elderly patients, and has been shown to be superior to usual care in patients with moderate to severe depression [45].

Brief Behavioral Treatment for Insomnia (BBTI)

• Sleep disturbances are frequently co-morbid with affective and cognitive disorders in older adults, and are associated with reduced quality of life and greater overall disability [46].

• While hypnotic agents such as benzodiazepines are effective for the treatment of insomnia, safety concerns for their use in older adults include cognitive impairment and increased risk for falls and fractures [46].

• In addition to educating patients about the importance of healthy sleep, BBTI encourages the use of four primary behavioral interventions [46] [Class I]: reduced time in bed; get up at the same time every day, regardless of sleep duration; do not go to bed unless sleepy; and do not stay in bed unless asleep. These interventions are derived from sleep restriction and stimulus control techniques, and have well-documented efficacy.

Cognitive Training

• Cognitive training and augmentation techniques [47] can be broadly divided into “internal” and “external” strategies:

  • “Internal” strategies involve memory or cognitive training aimed at enhancing cognitive performance. In recent years, internet-based approaches have been developed, along with a growing body of academic literature that documents their potential efficacy. Although results vary according to the specific intervention, computerized cognitive skill training programs, on the whole, appear to positively impact cognitive performance [48], with greatest efficacy shown for the domains of memory and visual spatial ability, and least efficacy shown for the domains of attention and executive functioning [48].
  • “External” strategies involve the use of pre-arranged physical reminders, to serve as automatic cues in the patient's environment. Three types of physical reminders are recommended [49]:

    • Immediately writing things down on a “memory” notepad, calendar, or checklist. May be coupled with auditory or visual cues (e.g. an alarm that “rings” at specified times).
    • Placing reminders in prominent places that are in the patient's line of sight (such as on the bathroom mirror or the refrigerator).
    • Associating frequently-lost objects (such as keys, wallets, spectacles) with pre-established locations. The patient should practice the act of placing these objects in their designated locations.

Interventional procedures

• Electroconvulsive Therapy (ECT): ECT is a safe and effective treatment for LLD [50] [Class IV], and may be particularly useful for treating suicidal ideation and psychotic symptoms in depressed elders [51]. In healthy adult patients, ECT can result in transient cognitive side effects—such as reduced concentration, disorientation, and retrograde memory loss [50]—that typically resolve within 4-8 weeks [52]; in older adults, however, the cognitive effects of ECT are less clearly defined. Pre-treatment cognitive impairment is a strong predictor of co-occurring, and perhaps persistent, ECT-associated memory impairment [53]. Some reports have suggested that ECT does not cause long-term cognitive problems in older patients [54], though further study of this topic is warranted. From a clinical perspective, cognitive testing and monitoring must be performed before, during, and after treatment with ECT [50].

Standard procedure	May be provided in an inpatient or outpatient setting, though is usually started on an inpatient basis for older adult patients. Administered either unilaterally or bilaterally, up to three times per week. While frequency and number of treatments are determined by severity of illness, response, and tolerability, most patients will complete greater than ten treatments as part of an acute-phase ECT trial.
Contraindications	While there are no “absolute” contraindications to the use of ECT in older adults, the greatest risk appears to exist for patients who have had a stroke, especially in the past 6 months.
Complications	Nausea, headache, muscle aches, and risks associated with general anesthesia.
Cost-effectiveness	While expensive, studies have suggested that ECT may result in shorter overall inpatient psychiatric hospital stays for severely depressed elderly patients [51].

• Repetitive Transcranial magnetic stimulation (rTMS): rTMS appears to be a safe and well-tolerated treatment for treatment-resistant depression in older individuals [55]. Questions remain, however, with regards to its antidepressant efficacy. It appears that rTMS exhibits fewer deleterious cognitive side effects than ECT, and may even improve immediate memory in some patients [56]. For treatment-refractory depression in the elderly, ECT continues to be the “gold-standard” interventional procedure, though the benefits of rTMS—including lack of need for general anesthesia, ease of treating on an outpatient basis, and more favorable cognitive side effect profile—suggest that it will continue to be explored as an alternative to ECT over the coming years.

Standard procedure	Usually administered by stimulating the left dorsal lateral prefrontal cortex, 5 days/week over 4-6 weeks in an outpatient setting.
Contraindications	Contraindicated in individuals at increased risk for seizures, those with implanted metallic or cochlear implants, and individuals with other implanted electrical devices (such as pacemakers).
Complications	The most serious complication is generalized tonic-clonic seizures.
Special points	For treatment of LLD, rTMS appears to be less efficacious than ECT.
Cost-effectiveness	Expensive

Assistive devices

• As hearing or visual impairment may be mistaken for cognitive dysfunction, hearing should be assessed by an audiologist and vision should be assessed by an ophthalmologist or optometrist, with corrective actions implemented as necessary.

• We highly recommend the use of a pillbox to organize medications. The pillbox should be filled on a regular weekly or monthly schedule, preferably with the assistance of a caregiver.

Physical/speech therapy and exercise

• Physical and Occupational therapy

  • Physical therapists can assess the need for a wheelchair or walking aid, as well as recommend or guide the implementation of an exercise program.
  • Occupational therapists can evaluate the patient's home for safety, and assess the need for assistive devices.
• Exercise

  • Exercise has been shown to have antidepressant effects in the elderly [57], even in individuals who respond poorly to antidepressant medications [58].
  • Cardiovascular (i.e. aerobic) exercise may be particularly helpful, and has the potential to maintain or improve cognitive health and functioning in older adults [59].

Emerging therapies

• Deep brain stimulation (DBS)

  • In recent years, DBS has emerged as a useful treatment for certain movement disorders, and is being investigated for the treatment of other neuropsychiatric conditions, including depression and dementia. Several studies have investigated DBS for dementia, and have shown that DBS can influence neuronal activity within pathologic circuits associated with cognitive dysfunction [60] and potentially produce clinical benefits by enhancing the synthesis of nerve growth factors [61]. For treatment-resistant depression, DBS may be helpful in targeting white matter tracts adjacent to the subgenual cingulate gyrus, an area that is metabolically hyperactive in individuals with this disorder [62, 63].
  • DBS is a circuit-specific intervention that may have fewer cognitively-adverse effects than ECT, and could possibly even enhance cognition. It has been proposed that potential pro-cognitive effects of DBS may be enhanced by combining stimulation with another intervention, such as cognitive remediation [64].
• Vagal nerve stimulation (VNS)

  • Vagal nerve stimulation is currently used as an adjunctive intervention for refractory epilepsy and treatment-resistant depression. VNS requires a surgical procedure to attach an electrode around the vagal nerve, which is then connected to a pulse generator in the chest. While VNS is effective for the treatment of refractory epilepsy—especially in the pediatric population—and has been used for treatment-resistant depression, there is currently no data to support its use in LLD with cognitive dysfunction. Results of an open-label pilot trial suggest a positive effect of VNS on cognition in patients with Alzheimer's disease, though further studies are required [65].
• Magnetic seizure therapy (MST)

  • MST is a promising experimental therapy for depression [66], and involves the induction of a seizure through use of magnetic stimulation. MST is less invasive that ECT, and because magnetic fields are able to pass freely into the brain, MST is able to induce a more focal seizure compared with ECT. MST targets stimulation to the prefrontal cortex (a region of the brain that is thought to be critical for antidepressant response), and limits exposure to the hippocampus (a region of the brain that is important for memory). Therefore, MST holds the promise of retaining the efficacy of ECT while limiting side effect burden.