Clinical Supplement

Print Friendly 

Depression in the Elderly: The Unique Features Related to Diagnosis and Treatment

Moderator: Katherine Shear, MD; Section editor: David L. Ginsberg, MD; Discussants: Steven P. Roose, MD, Eric J. Lenze, MD, George S. Alexopoulos, MD; CME Reviewer: Eric Hollander, MD


Primary Psychiatry. 2006;12(8 suppl 7):1-16.



This CME activity is expired.


Funding for this symposium monograph supplement has been provided through an unrestricted educational grant by Forest Pharmaceuticals, Inc.


An expert panel review of clinical challenges in psychiatry



Statement of Need and Purpose:


The elderly population is growing at a rapid rate and currently constitutes >12% of the United States population. Depression, a heterogeneous disease often accompanied by significant medical and psychiatric comorbidity, is prevalent and underrecognized among the elderly. Detection of depressive symptoms in the elderly is complicated by high medical comorbidity, frequent use of multiple medications, and a tendency of some older adults to resist psychiatric evaluation. While an episode of depression can first present in late-life, it is more likely to be a recurrence of a disorder that began earlier in life or a continuation of a chronic form of depression.


Most older patients can tolerate and respond to acute treatment with serotonergic antidepressants, other psychotropic agents, or manual-based psychotherapy. Antidepressants, particularly serotonergic medications, are considered first-line treatment for major depressive disorder. Psychotherapy has also been found to be efficacious. However, outcomes under usual-care conditions remain poor. Since depression in the elderly often occurs in the context of ongoing medical conditions, treatment is often complicated due to the increased likelihood of drug interactions.


Despite the availability of safe and efficacious treatments, depression remains a significant healthcare issue for the elderly and is associated with functional decline, diminished quality of life, mortality from comorbid medical conditions or suicide, demands on caregivers, and increased service utilization. 


Learning Objectives:


•Recognize and differentiate late-onset depression and its relationship to vascular illness.


•Understand and implement an appropriate treatment strategy for comorbid depression and medical illness.


•Recognize bereavement-related depression and anxiety, including complicated grief, and understand the data related to treatment efficacy.


•Implement appropriate antidepressant and anxiolytic treatment strategies for comorbid depression and anxiety.


Target Audience:


This activity is designed to meet the educational needs of psychiatrists.


Disclosure of Off-Label Usage:


This continuing medical education activity may contain references to unlabeled or investigational uses of drugs or devices.


Accreditation Statement:


Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide Continuing Medical Education for physicians.


Mount Sinai School of Medicine designates this Continuing Medical Education activity for a maximum of 1.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

Faculty Affiliations and Disclosures:


Dr. Alexopoulos is professor of psychiatry at Weill Medical College of Cornell University, and director of Weill-Cornell Institute of Geriatric Psychiatry in White Plains, New York. He is a consultant to Forest; on the speaker’s bureaus of Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Janssen, and Pfizer; and receives grant/research support from Cephalon and Forest.


Dr. Lenze is assistant professor of psychiatry at the University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, in Pennsylvania. He has received grant/research support from Janssen and Pfizer.


Dr. Roose is professor of clinical psychiatry at the College of Physicians and Surgeons at Columbia University in New York City. He is a consultant to Forest and Wyeth; and receives grant/research support from Bristol-Myers Squibb, Forest, and Wyeth.

Dr. Shear is professor of Psychiatry at the University of Pittsburgh School of Medicine and director of the Panic, Anxiety, and Traumatic Grief program at Western Psychiatric Institute and Clinic, both in Pittsburgh, Pennsylvania.  She is a consultant to and on the speaker’s bureau of Pfizer; and receives grant/research support from Forest.




Depression affects 6.5 million of the 35 million Americans ≥65 years of age. While depression usually begins earlier in life and recurs periodically, it can present for the first time in people 80–90 years of age as well. Depression throughout the lifespan has a genetic/biological component but is also very much affected by social environmental factors. As people age, demographic factors, social support, and negative life events remain important to overall mental health, while physical illness and disability begin to take on a much more prominent role. Depression in the elderly is associated with impairment, dependency, disability, and significant distress for the individual and their family. This population is likely to present with concomitant cognitive dysfunction and medical illness, which can complicate the identification and treatment of psychiatric conditions. Bereavement is almost universal in late life and is sometimes a deterrent to appropriate diagnosis and treatment of depression. Physical frailty and diminishing social resources further complicate the treatment of depression in the elderly. Elderly individuals respond well to standard pharmacotherapy and psychotherapy treatments for depression. However, due to the high rate of relapse of depression in this population, continuous treatment is often warranted. This monograph will review depression in the elderly in the context of social disruptions, such as bereavement, caregiver strain, interpersonal conflict, role transitions, and social isolation; late-onset vascular depression and cognitive impairment; and physical illness including disability.




Katherine Shear, MD—Moderator

Bereavement-Related Depression in the Elderly


Recognition and Prevalence of Bereavement



Bereavement is a profound stressor that leads to some of the most intense psychological pain human beings can experience. Despite the fact that bereavement is very common in the psychiatric population, clinicians and researchers have paid little attention to it. Recognition of complicated grief versus normal grief is difficult because due to inadequate empirical evidence, there is no model to help clinicians distinguish between a pathological grief reaction and a depressive reaction that is normal in the context of loss. Further complicating the diagnosis is the prominent belief that any way grief unfolds is normal.


Bereavement is very prevalent in the elderly population: As people get older, more of their close friends and family members die. Widowhood is particularly common in the elderly, especially in women: ~41% of women >65 years of age are widowed (Slide 1).1





Common Misconceptions About Grief


There are many common misconceptions about grief which have been dispelled by empirical evidence. (A) Effective grief is a process of letting go of the person who died in order to move on. Empirical findings show that effective grief requires accepting the loss; (B) Grief work (experiencing emotional anguish) is necessary in order to move on. It turns out that grief is a natural process that works if it is not impeded; (C) The more intense a person’s pain is, the more effectively they are grieving. Data show that the less intense the initial pain is, the more favorable the outcome is; (D) People who do not grieve early will pay later. In fact, longitudinal studies have shown that delayed grief is very rare and only occurs in 4% to 5% of people who do not grieve early on; (E) Once a person has grieved effectively, they never have to grieve again. Empirical findings indicate that grief is a permanent state that can be reactivated indefinitely; (F) There is some timeframe within which grief should be completed. In actuality, grief is never completed; and (G) Problems with grief are seen primarily in people who have an ambivalent relationship to the person who died. In actuality, complicated grief is seen in people who have a very positive and close relationship with the person who died.


Defining Grief



A study by Boerner and colleagues2 identified four trajectories of grief and depression from pre-loss to 48 months post-loss. The most common group of mourners (40%) were actually “resilient” and did not experience much depression or grief as demonstrated by scores on the Center for Epidemiologic Studies Depression scale. People with “common grief” were those who had increased depression until 6 months after the loss, at which point their depression began to improve until they became resilient at ~18 months. “Chronic depression” occurred in a subset of individuals as did “chronic grief,” which contains the syndrome of complicated grief.


Grief is a complex emotional state best defined as the overall psychological reaction to bereavement. It is an evolving mental state that changes as people cope with the different feelings and the new way that they need to live after someone that they love has died. In the model we use for treatment at the University of Pittsburgh, primary grief transitions to integrated grief. Dysphoric emotions of grief include anxiety (eg, about how the surviving person will manage on their own), guilt (eg, about surviving or not having done enough for the person while they were alive), anger (eg, about others not doing or caring enough), and shame (eg, about sense of vulnerability and uncontrollable emotionality). However, there are pleasurable emotions associated with grief as well, including enjoyment in the recall of happy times, amusing anecdotes, pride in honoring the deceased, warmth in recollecting closeness, relief from burden, and pleasure and joy in being alive. Sadness, which is the predominant emotion associated with grief, is the bittersweet feeling of loss of something valuable.


Primary Grief



Primary grief is the form that grief takes immediately following the death of a loved one and is the dominant mental state of the person. It is characterized by a sense of disbelief or difficulty accepting the death; relative disinterest in the rest of the world; a mix of emotions where painful emotions are usually dominant; and preoccupying thoughts and memories of the deceased. These features can last for days or months and may recur transiently for many months or even years.


The dual process model of coping with grief focuses on both loss and on restoration of life. The dual processes proceed in tandem with natural oscillation, alternating between attention to loss and attention to restoration. By coping effectively, in an oscillating manner with primary grief and its associated problems, the person moves into a state of integrated grief, in which the death is accepted.


Integrated Grief


A major characteristic feature of integrated grief is acceptance of the death; there is a mix of emotions, but they transition to a state where more positive emotions are more dominant.2 While the memories of the person who died are accessible, they are not preoccupying and the mourner begins to experience a renewed interest in engagement in life. This state is usually achieved by about 6 months after the death and is permanent.


The state of integrated grief has been depicted in several well-written works, notably a short autobiography by Frederick Buechner3—a Presbyterian pastor who’s father committed suicided when he was 10 years old—and a collection of poetry written by Donald Hall4 after his wife’s unexpected illness and death.


After the Grieving Process



When a person has gone through the normal grieving process, there is effective coping and a transition to integrated grief. This includes coping with loss-focused issues such as gaining a satisfying sense of relationship to the deceased; accessible memories; and subsiding of guilt, remorse, and anger. It also includes coping with restoration-focused problems, such as achieving role transition and becoming engaged in satisfying daily activities and relationships. When grief does not work, there can be an onset of major depressive disorder (MDD), and/or complicated grief. A person suffering from complicated grief may have loss-related problems such as difficulty accepting the death, memories which are excessively painful or hard to access, or intrusive images. The mourner may also have restoration-related problems, such as not achieving role transition, finding little pleasure and satisfaction in daily activities, and feeling a sense of estrangement from others.

Major Depression in Bereaved Spouses



Bereavement-related depression is not a normal reaction to loss. In several studies led by Zisook,5-7 many bereaved spouses met criteria for MDD in the very early stage of the loss. However,  only 24% to 30% of mourners met criteria for MDD 2–6 months after the loss, and only 16% still met criteria for MDD at 1 year. Persistent depression was associated with past history of MDD (24% versus 8%) and family history of MDD (37% versus 24%). Bereaved individuals who are depressed at 2 months have rates of MDD similar to non-bereaved individuals 1 (30%) and 2 (20%) years later. They also have similar duration of time spent in a full-blown episode (38%), time spent with residual symptoms (48%), and depression-free time (24%).

Treatment of Bereavement-Related Depression

Studies suggest that antidepressant medication is efficacious for the treatment of bereavement-related depression. There are open studies in bupropion, escitalopram, and nortriptyline. In the only randomized controlled treatment study of bereavement-related depression, Reynolds and colleagues8 found nortriptyline to be efficacious in the study population of elderly adults (Slide 2). Surprisingly, interpersonal psychotherapy was not as effective as expected.




In a small study by Pasternak and colleagues,9 13 elderly widowed patients treated with nortriptyline showed significant improvement in depression symptoms but only slight improvement in grief symptoms as demonstrated by scores on the Inventory of Complicated Grief. This study was replicated by Zisook and colleagues10 using bupropion (N=22).


Complicated Grief Versus Major Depression



It is important to know the difference between complicated grief and MDD as treating depression does not necessarily improve the symptoms of complicated grief, as demonstrated by the abovementioned studies.6,7 MDD is characterized by pervasive sad mood, guilt related to “I am worthless, a bad person,” pervasive loss of interest or pleasure, and intrusive images which are not prominent. Complicated grief is characterized by painful emotions that occur in pangs triggered by reminders of loss, guilt specific to bereavement and related to having let their loved one down, strong interest in things related to the loved one, prominent intrusive images of the deceased, a yearning for contact with the deceased that persists, and frequently entering a dissociative state where they imagine the deceased is with them.


A study by Boerner and colleagues11 showed that 15 weeks after the death of Alzheimer’s care recipients, their caregivers often developed grief, depression, or both. The more positive the relationship with the care recipient was, the more likely the caregiver was to develop complicated grief.


Natural Grief



In a model of natural grief developed at the University of Pittsburgh, bereavement triggers a state of primary grief which is characterized by symptoms of traumatic distress (disbelief; recurrent, almost intrusive images and memories of the person), separation distress (longing and yearning for the person who died), guilt, and social withdrawal. This is a transient dominant state that is painful and preoccupying, but transitions into acceptance, positive emotions, forgiveness, and compassion. After the transition period of ~6 months, the person reaches a state of integrated grief, which is a permanent background state where bittersweet memories are still present, accessible, and changing (Slide 3).





Complicated Grief



In a model of complicated grief developed at the University of Pittsburgh, bereavement triggers primary grief (traumatic distress, separation distress, guilt, and social withdrawal), but instead of being transient it becomes a persistent dominant state that can last for years. This occurs when bereavement triggers secondary emotions and reactions that block the pathway to integrated grief. These secondary emotions include fear of painful emotions, loss of control, losing or betraying the deceased, and loss of sense of self; excessive guilt or anger; moral indignation; and rumination and/or excessive avoidance (Slide 4).



Core symptoms of complicated grief include experiencing the following >6 months after the death: traumatic distress (recurrent intrusive images of the death, bitter or angry, avoidance of situations, activities, or people); separation distress (intense yearning, longing; urges to reminisce, reveries, seeking proximity to items belonging to the deceased, feeling that life has no meaning without the deceased); guilt (prominent self-blaming thoughts of not helping the person or not preventing the death); and failure to adapt (emotion overwhelming, sense of alienation, feeling that having less grief is a betrayal).


A Proposed Treatment for Complicated Grief



Antidepressant medication has shown no effect and IPT has shown surprisingly little effect, on complicated grief symptoms. In treating patients with complicated grief, posttraumatic stress disorder (PTSD)-like symptoms of distress were the ones that seemed to interfere IPT. Therefore, researchers at the University of Pittsburgh developed a new psychotherapy for complicated grief based on an IPT framework and augmented by a treatment for PTSD. The model of natural grief was used, in which coping occurs in the loss-oriented (imaginal revisiting of the experience of the death, structured behavioral change, structured memories work, imaginal conversation with the deceased) and restoration-oriented (personal goals, meeting with significant other, structured behavioral change) ways.


This new complicated grief treatment showed greater response rates (51% compared to 28%) and faster time to response compared to IPT in a recent randomized controlled trial.12 The study included 95 men and women 18–85 years of age who met criteria for complicated grief. Both treatments were administered in 16 sessions during an average interval of 19 weeks per participant. Treatment response was defined as Clinical Global Improvement score of 1 or 2, or as time to a 20-point or better improvement in the self-reported Inventory of Complicated Grief.





Bereavement is a major life stressor. While most people cope with loss and do not develop bereavement-related depression, there is a significant minority that does. MDD and complicated grief are the two most common problematic clinical sequelae. Bereavement-related depression shows similar response to medication treatment as MDD in other contexts. Complicated grief, however, differs from MDD and requires a targeted treatment. Complicated grief has shown small statistically significant response to selective serotonin reuptake inhibitors and very efficacious response to targeted psychotherapy. Combination treatment may be the best option for patients with complicated grief.




1. US Census Bureau Web site. Available at: Accessed July 2, 2005.

2. Stroebe M, Schut H. The dual process model of coping with bereavement: rationale and description. Death Stud. 1999;23(3):197-224.


3. Buechner F. The Sacred Journey. San Francisco, CA: Harper; 1991.


4. Hall D. Without. New York, NY: Houghton Mifflin; 1998.


5. Zisook S. Shuchter SR. Depression through the first year after the death of a spouse. Am J Psychiatry. 1991;148:1346-1352.


6. Zisook S, Devaul RA. Grief, unresolved grief, and depression. Psychosomatics. 1983;24:247-256.


7. Zisoook S, Shuchter SR. Major depression associated with widowhood. Am J Geriatr Psychiatry. 1993;1:316-326.


8. Reynolds CF 3rd, Miller MD, Pasternak RE, et al. Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry. 1999;156(2):202-208.


9. Pasternak RE, Reynolds CF 3rd, Schlernitzauer M, et al. Acute open-trial nortriptyline therapy of bereavement-related depression in late life. J Clin Psychiatry. 1991;52(7):307-310.


10. Zisook S, Shuchter SR, Pedrelli P, Sable J, Deaciuc SC. Bupropion sustained release for bereavement: results of an open trial. J Clin Psychiatry. 2001;62(4):227-230.


11. Boerner K, Schulz R, Horowitz A. Positive aspects of caregiving and adaptation to bereavement. Psychol Aging. 2004;19(4):668-675.


12. Shear K, Frank E, Houck PR, Reynolds CF 3rd. Treatment of complicated grief: a randomized controlled trial. JAMA. 2005;293(21):2601-2608.




Steven P. Roose, MD

Vascular Depression: A Subtype Specific to Late-Life?


Depression Subtypes


There is evidence to suggest that vascular depression should be considered a unique subtype of depressive disorder that has particular relevance to late life. Within the unipolar versus bipolar subtype, there are three phenomenologically defined subtypes which are recognized in the DSM-IV. Atypical depression is characterized by oversleeping, overeating, leaden paralysis, and rejection sensitivity. Delusional depression (ie, psychotic depression), is characterized by delusions sometimes accompanied by auditory hallucinations. Melancholic depression is the classic depressive illness first described over 5,000 years ago. Patients within one subtype often have different family histories, psychobiology, and differential treatment response and course of the illness, compared to those within another subtype. Therefore, the establishment of a subtype has both heuristic and clinical importance.


The Vascular Depression Subtype


In 1991, Figiel and colleagues1 reported that patients with late-onset depression (>60 years of age) had a significantly higher rate of white matter and basal ganglia hyperintensities compared to those with early-onset depression (Slide 5). Bots and colleagues3 demonstrated that severity of the deep white-matter lesions is correlated with the wall thickness of the carotid artery and with prevalence of myocardial infarction (MI).



The hypothesis that there may exist a vascular depression subtype that is unique to late life was stated by Hickie in 1995,2 which stated that “cerebral vascular insufficiency in elderly people leads to major changes in their subcortical and basal ganglia structure. The resultant late-onset depressive disorders are characterized by deficits in functions that are dependent on intact cortical striatal connections (eg, psychomotor speed and interactiveness), as well as subcortical hyperintense lesions and reduced basal ganglia volumes.” The three criteria associated with vascular depression are late onset; vascular disease and hyperintensities as demonstrated by magnetic resonance imaging (MRI); and interference with cognitive capacities, such as sequencing, planning, organizing, and abstract thinking.


The evidence for vascular depression is consistent with the well-established phenomenon of post-stroke depression. Intermittent and progressive ischemia leads to structural damage, which leads to depression (and associated executive dysfunction). Risks for ischemic disease include smoking, hypertension, and a family history. In turn, depression is a risk factor for the development of cardiovascular disease and stroke, and confers a worse mortality rate in patients with ischemic disease and those with congestive heart failure.4


The Vascular Depression Model


The strong evidence that vascular disease relates to the hyperintensities prominent in late-onset depression contributes to a compelling model of vascular depression. In this model, cardiovascular risk factors lead to cerebral ischemia which leads to frontal and basal ganglia lesions. Depression early in life is a risk factor for the development of both ischemic heart disease and stroke. This risk may be mediated by increased cortisol, insulin resistance, and platelet reactivity, all of which can contribute to vascular damage and ischemia. Vascular damage creates a vulnerability to depression that can be expressed depending on other variables such as psychological factors (eg, low social support), negative life events (eg, death in the family), genetic factors, and social factors (Slide 6).



Criteria for Vascular Depression


Criteria for vascular depression include vascular disease, cognitive impairment, late age of onset, and depression. Definitions of these criteria have vary among studies. For example, some studies of vascular depression include patients with cardiovascular risk factors, while others require MRI lesions. Some studies have assessed impairment of activities of daily living,5 while others have defined executive dysfunction by neuropsychological testing.6 The age defining late onset differs from one study to the next (eg, 40, 50, or  60 years of age). Finally, most studies only include patients who meet criteria for major depressive disorder (MDD); however, many patients with vascular disease have dysthymia or subsyndromal symptoms. According to the post-MI literature, ~20% of patients develop MDD post-MI, and another 20% to 25% develop significant depressive symptomatology.7 The same is true in the post-stroke literature.


Treatment Resistance


One component of vascular depression is the executive dysfunction syndrome of late-life, and it is hypothesized that depression, executive dysfunction, and treatment resistance are all related to frontostriatal dysfunction. Furthermore, it is believed that dysfunction of the basal ganglia and their frontal connections contributes to poor and unstable treatment response in geriatric depression.


Many neuropsychological tests have been used as markers of executive dysfunction, conceptualized as the skills that lead to sequencing, planning, organization, and abstraction. An association has been observed between poor executive functioning and poor response to antidepressants. Kalayam and Alexopoulos8 showed that scores of initiation perseveration on the Dementia Rating Scale are lowest in patients who did not respond to antidepressants. In a study using the Color Word Score, patients who had intact executive dysfunction (high color word score), showed a better antidepressant response rate compared to patients with executive dysfunction.9 Data on relapse in depressed elderly patients receiving nortriptyline showed that those with impaired executive function had a much higher rate of relapse on continuation treatment (Slide 7).10



Once of the challenges clinicians face is that many depressed patients also present with mild cognitive impairment (MCI). In a study by Pelton and colleagues, 39 patients with depression and amnestic MCI were treated with sertraline up to 200 mg/day for 12 weeks (unpublished data, 2005). Twenty-two were followed for 1 year and showed good response to the antidepressant but very little improvement in cognitive function. At the end of 1 year, 54% had converted to dementia. The expected 1-year conversion rate of a group of nondepressed patients with MCI is about 15%.


Thus, patients with depresssion and executive dysfunction have poor treatment response and progressive cognitive decline. Depressed patients who have vascular lesions, regardless of whether or not they have executive dysfunction, seem to be particularly refractory to monotherapy, have a longer time to recovery (measured in months, not weeks), show cognitive decline, and are at risk for stroke.


Future Directions for Establishing the Subtype


A subtype has external validity and is clinically meaningful if it informs the clinician about treatment response and course of illness. The association of late onset, progressive vascular disease, executive dysfunction, and poor treatment response to antidepressant monotherapy adds compelling support to the notion of a vascular depression subtype. However, vascular depression still requires a definition of the core features of the illness, be it age of onset, executive dysfunction, or vascular lesions, and their relationship to one another. The final determination of criteria (eg, vascular lesion, executive dysfunction, age of onset) and operational criteria (eg, size and location of lesions, what age is considered late onset?) still need to be established.


In addition, although there is compelling evidence for vascular depression, important new data has been inconsistent with previous findings. For example, a study from the Duke group shows no significant difference in deep white matter lesion between patients with early-onset depression and those with late-onset depression. However, it does show a significant difference in executive function between early- and late-onset depression on the Trails B. Data from a study of depression in patients >75 years of age showed that late-onset and early-onset patients responded equally well to citalopram treatment. Regarding MRI hyperintensities, the old-old study is consistent with the Duke study, in that the load of hyperintensities was the same in both the late-onset and early-onset patients. Contrary to what the expectation would be, the antidepressant responders in the Duke study had the same degree of MRI hyperintensities as nonresponders.


Implications for the Clinician


Although more research is needed, there are some useful clinical implications that can be derived from existing data when it comes to evaluating depressed patients >60 years of age. First, it is important to try to establish the age of onset for first episode of MDD, although it is often difficult to have confidence in the reliability of the result. Second, one should assess cardiovascular risk factors, such as smoking, high blood pressure, family history, lipid profiles, and lack of exercise. Third, the clinician must assess cognition and routinely evaluate for cognitive decline; one of the best assessments is the 3/3 object recall at 5 minutes from the Mini Mental Status Exam. Fourth, the clinician must know the patient’s current medication regimen and evaluate anticholinergic load. Most people >65 years of age are on at least five prescription agents in addition to their over-the-counter medication. The psychiatrist and primary care physician must form a relationship so that both are familiar with the patient’s full medical profile and ongoing care. Finally, the clinician must determine whether an MRI is needed. This might be warranted in a depressed patient who has several cardiovascular risk factors and cognitive impairment.



1. Figiel GS, Krishnan KR, Doraiswamy PM, Rao VP, Nemeroff CB, Boyko OB. Subcortical hyperintensities on brain magnetic resonance imaging: a comparison between late age onset and early onset elderly depressed subjects. Neurobiol Aging. 1991;12(3):245-247.


2. Hickie I, Scott E, Mitchell P, Wilhelm K, Austin MP, Bennett B. Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic significance in patients with severe depression. Biol Psychiatry. 1995;37(3):151-160.


3. Bots ML, van Swieten JC, Breteler MM, et al. Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet. 1993;341(8855):1232-1237.


4. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. Vascular depression’ hypothesis. Arch Gen Psychiatry. 1997;54(10):915-922.


5. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Silbersweig D, Charlson M. Clinically defined vascular depression. Am J Psychiatry. 1997;154(4):562-565.


6. Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997;154(4):497-501.


7. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med. 1989;149:1785-1789.


8. Kalayam B, Alexopoulos GS. Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry. 1999;56(8):713-718.


9. Baldwin I, Jeffries S, Jackson A, et al. Treatment response in late-onset depression: relationship to neuropsychological, neuroradiological, and vascular risk factors. Pyschol Med. 2004;34:125-136.


10. Alexopoulos GS, Meyers BS, Young RC, et al. Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry. 2000;57(3):285-290.





Eric J. Lenze, MD

Recognizing Late-Life Depression Comorbid With Medical Illness


The Scope of the Problem


Practically every medical illness or acute medical event is followed by an increased risk of depression in both young adults and elderly people. Ischemic heart disease, stroke, cancer, endocrine diseases, chronic lung disease, kidney disease, arthritis, hip fracture, and neurodegenerative disease have all been shown to increase ones risk for depression. In a meta-analysis across specialty medical settings, Dew1 observed an increased prevalence of major depressive disorder (MDD) in practically every illness compared to the community rate in the Epidemiologic Catchment Area study. Conversely, elderly people with MDD have a high rate of comorbid medical illness. Descriptive data from a sample of 449 elderly patients at the Western Psychiatric Institute and Clinic in Pittsburgh, showed that most elderly people with depression had 2–4 comorbid medical conditions; >50% had hypertension, and almost 50% had osteoarthritis (R Mantella, PhD, unpublished data, 2005; Slide 8). Hyperlipidemia, diabetes, and hypothyroidism were present in 20% to 35% of patients. These medical conditions are  common in the elderly population in general, but are much more prevalent in the depressed elderly.



Why is Late-Life Depression Common in Medical Illness?


According to standard epidemiology, when two things are associated either A causes B, B causes A, or C causes both A and B. It is thought that all three are the case when it comes to the association between depression and medical illness. Medical conditions increase the risk for depression through several routes. First, neurodegenerative diseases (eg, stroke, Parkinson’s, Alzheimer’s) can cause direct disruption of neurotransmitters or neural circuits involved in mood regulation. Second, cardiac surgery, serious cardiopulmonary event, or hip fracture, can cause severe physiologic stress, which can lead to depression. Finally, the functional disability that occurs with these medical illnesses is a major risk factor for late-life depression. Conversely, depression can increases the risk of several medical conditions in elderly people. Depression can increase the risk for cardiovascular disease, falls and fractures, and possibly cancer. Finally, some theories suggest that there is some shared, perhaps genetic, vulnerability to both depression and medical conditions.2


Many studies have shown that the onset of disability in elderly people is a major risk factor for late-life depression.  In the short-term, someone who becomes disabled acutely has to deal with immobility, pain, an extensive hospitalization and rehabilitation period, and anxiety about their situation and their future. Long-term consequences include loss of perceived control, poor self-esteem, demoralization, hopelessness, social or interpersonal activity restriction, and a strain or reduction in one’s interpersonal relationships. Thus, many of the things that keep people resilient to depression are taken away when a person suffers a disabling medical event.3


In a study of 115 hip fracture patients, 19% developed MDD over a 6-month period (EJ Lenze, MD, unpublished data, 2005). The greatest period of onset occurred 1–2  weeks after the hip fracture (Slide 9). In contrast, the peak period of risk for depression after a stroke appears to be 3 months. Time to depression may be unique to the type of disabling medical condition.


Sequelae of Late-Life Depression


In medically ill elderly patients, depression amplifies disability, medical mortality, and healthcare utilization.



The very features of depression, such as apathy, psychomotor retardation, and hopelessness, are disabling. In addition, late-life depression is associated with executive dysfunction, which is the most disabling cognitive deficit. Depression in elderly people also leads to increased medical events, such as heart disease and hip fracture. And finally, depression leads to an impaired ability to recover from disabling medical events; these patients are less likely to participate in medical rehabilitation or adhere to medical recommendations. Despite the fact that studies have shown that depression improves with rehabilitation, disabled depressed elderly are often considered less appropriate candidates for rehabilitation because they are more likely to be amotivated and cognitively impaired. Therefore, it is often the psychiatrist who must advocate for these patients.


In a sample of hip fracture patients, both depressed and nondepressed patients who went to a rehabilitation hospital had much better improvement of disability over 2 weeks than those who went to a nursing home, as demonstrated by FIM score—a measure of functional ability commonly used in rehabilitation settings (EJ Lenze, MD, unpublished data). This suggests that depression does not adversely affect these patients’ ability to benefit from rehabilitation.


Medical Mortality



In a study of >2,000 elderly patients with cardiac disease, Penninx and colleagues4 found that those with MDD had a greatly increased risk of cardiac mortality. Frasure-Smith’s5 landmark study of depression and cardiac mortality demonstrated that heart attack patients with elevated depressive symptoms had a greatly increased risk of mortality over 6 months (Slide 10). MDD was actually a greater risk for mortality than other well-known risk factors, such as history of previous heart attack or worsening ventricular function. Depression worsens cardiac outcome because these patients are more likely to have increased sympathetic and decreased vagal or parasympathetic tone, hypothalamic pituitary axis hyperactivity, systemic inflammation, platelet/endothelial activation, poor health behaviors (smoking, physical inactivity), and poor adherence to medical recommendations.6 There is no evidence that treatment of depression actually reduces cardiac mortality; however, the SADHART study found an improved quality of life attributable to depression treatment.


Healthcare Utilization



Some of the signals of depression in both outpatients and inpatients is persistent help-seeking somatic complaints, such as pain, headache, fatigue, insomnia, gastrointestinal symptoms, arthritis, multiple diffuse symptoms, and weight loss. Katon and colleagues7 looked at 6-month healthcare costs in elderly people with MDD or dysthymic disorder compared to controls. Visits to the primary care physician, diagnostic tests, specialty visits, emergency room visits, prescription medications, and inpatient costs were all increased in MDD/dysthymia patients compared to controls.


Barriers to Diagnosis


All patients with medical disability (eg, cardiac disease, hip fracture) should be assessed for depression. One problem is that medical settings are not optimal for diagnosing MDD in elderly people. Although the onset of depression is very common after disability, MDD is much less common. In addition, symptoms may remit spontaneously and the patient may be in another setting or already suffering the consequences of depression by the time it is recognized. To add to those substantial barriers, other medical conditions can confuse the diagnosis of depression: Many of the symptoms of depression, such as fatigue, insomnia, and loss of appetite, are common in other medical problems as well. In addition, older people are less likely to use the word “depressed,” but will report anhedonia if asked. Many elderly people in medical settings are cognitively impaired which makes them less insightful about their symptoms. They are also commonly delirious, which can be confused with depression.


One clue that a medically ill person with depressive symptoms is suffering from an episode of MDD is refusal of treatment. It is not uncommon for patients to be unmotivated for medical rehabilitation for the first couple of days; however, those who persistently refuse rehabilitation and seem depressed require treatment. Finally, prolonged hospitalization is a sign that the patient may have MDD.


Barriers to Adequate Treatment


Many antidepressants required initiation at a subtherapeutic dose. This becomes a problem in depressed elderly who may be transferred to a different setting before the effective dosage is achieved. Rapid switches between settings makes medication treatment/titration and certainly psychotherapy very difficult. Some data suggest that medication for depression is not as efficacious in medically ill patients. However, many studies do not support this finding. Another barrier to treatment is patient or family refusal for various reasons. Confronting their concerns through psychoeducation can reduce refusal of treatment and help to reduce early discontinuation of treatment. Common reasons for discontinuation include side effects (62%), lack of perceived need (57%), claims that the patient is feeling better (50%), or claims that the medication does not work (32%).8




Depression is extremely common after a disabling medical event, and many patients require rehabilitation for disability. MDD can interfere with rehabilitation; however, depressed elderly people seem to do well with high-quality rehabilitation, and therefore, treating physicians should not allow providers or practice settings to deny their patients these services. MDD in the context of cardiac disease increases mortality, which reinforces the need to provide treatment in this context. Finally, substantial barriers to diagnosis and treatment can be overcome with good prospective psychoeducation and long-term follow-up. However, given these barriers, new approaches to managing medically ill depressed patients, such as preventive or early intervention approaches, need to be developed.



1. Dew MA. Psychiatric disorder in the context of physical illness. In: Dohrenwend BP, ed. Adversity, Stress, and Psychopathology. London: Oxford University; 1998:177-218.


2. Whyte EM, Mulsant BH. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol Psychiatry. 2002;52(3):253-264.


3. Lenze EJ, Rogers JC, Martire LM, et al. The association of late-life depression and anxiety with physical disability: a review of the literature and prospectus for future research. Am J Geriatr Psychiatry. 2001;9(2):113-135.


4. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58(3):221-227.


5. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. JAMA. 1993;270(15):1819-1825.


6. Zellweger MJ, Osterwalder RH, Langewitz W, Pfisterer ME. Coronary artery disease and depression. Eur Heart J. 2004;25(1):3-9.


7. Katon WJ, Lin E, Russo J, Unutzer J. Increased medical costs of a population-based sample of depressed elderly patients. Arch Gen Psychiatry. 2003;60(9):897-903.


8. Lin EH, Von Korff M, Katon W, Bush T, Simon GE, Walker E, Robinson P.  The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33(1):67-74.




George S. Alexopoulos, MD

Treatment of Late-Life Depression


Pathway to Late-Life Depression


Imaging studies have shown that aging and disease-related changes in the brain (eg, vascular, inflammatory, endocrine and immune responses) may either directly initiate mechanisms leading to depression (neocortical hypometabolism and limbic hypermetabolism), or create a state of vulnerability to depression (impairment in the function of the frontostriatal, amygdala, and hippocampal abnormalities). Psychosocial adversity acts at all three levels, meaning it can increase aging-induced brain changes; it can directly cause vulnerability to depression; or it can directly initiate mechanisms mediating depression. Many depressed elderly experience disability, which further compromises their ability to cope with the environment. Therefore, in addition to medication, it is important to consider therapies that address the psychosocial adversity these patients experience.


Treatment of Late-Life Depression


While both mild and severe geriatric depression respond equally well to antidepressants, severe depression is less likely to respond to nonspecific treatments. In studies that include elderly patients with mild depressions, active treatments often do not show separation from placebo because the placebo response rate is very high.1,2 This rather lower remission rate raises the concern that the available drugs are not effective enough.Interestingly, studies that have compared active drugs in geriatric major depressive disorder,3,4 seem to show a higher remission rate than studies comparing drug to placebo.


There is good evidence that combining drug therapy with psychotherapy is a more effective way of treating geriatric depression. Almost every psychotherapy treatment that has been tried in the elderly appears to be effective, and seems to have an additive effect to medication therapy. Thompson and colleagues5 demonstrated that cognitive-behavioral therapy (CBT) alone was more effective than desipramine alone. Reynolds and colleagues6 showed that interpersonal therapy (IPT) plus nortriptyline was more effective than IPT plus placebo or nortriptyline plus placebo. Finally, Arean and Cook7 demonstrated that the benefits of psychotherapies are sustained over time.


Treatment Recommendations


Residual Anxiety



Remission rates with antidepressants are not very impressive; patients are often left with residual anxiety. When this occurs, the dosage of antidepressant should be increased or alternative pharmacologic methods considered. Benzodiazepines should be avoided or used only short term. Concerns are memory impairment, gait disturbance/falls, disinhibition/agitation, potential habituation, and refusal to stop the medication.


When an Antidepressant Fails


Clinical data are limited; however, treatment guidelines have been created on the basis of expert opinion. A 2002 guideline developed from a statistical analysis of the opinions of 50 experts in late-life depression, recommended that a patient who fails a trial of a selective serotonin reuptake inhibitor should be switched to venlafaxine or bupropion (Slide 11). If there is no response to velafaxine, the patient should be switched to an SSRI, followed by trials of nortriptyline, bupropion, or mirtazapine. If the patient fails to respond to bupropion, the patient should be switched to an SSRI, followed by trials of venlafaxine, nortriptyline, or mirtazapine. If the patient fails a tricyclic antidepressant, he or she should be switched to venlafaxine. The experts did not strongly endorse augmentation in geriatric patients who have a partial response to an initial antidepressant trial (Slide 12).




Maintenance Treatment


The dosages required for continuation/maintenance treatment of late-life depression are the same as those effective in acute treatment. Combination treatment is more likely to prevent relapse than either drug or psychotherapy alone.6 In a multi-centered study by Sackeim and colleagues,8 ECT-treated patients, because of drug resistance, had a lower relapse rate when treated with an antidepressant plus a mood stabilizer than an antidepressant alone.


Medical Illness in Late-Life Depression


Many medical disorders are associated with a high rate of depression, including autoimmune disorders (cytokine hypothesis), metabolic disorders (hypercorticolemia hypothesis, impaired neurogenesis), vascular disorders (vascular depression hypothesis), neoplasms (leukemia, lymphoma, pancreatic carcinoma), and viral infections (hepatitis, human immunodeficiency virus). In such cases, both the medical and depressive disorders need to be treated simultaneously. For example, if a depressed patient has a high thyroid stimulating hormone (TSH), suppressing the TSH with thyroxin may bring the patient into partial remission. However, if only the depression is treated (eg, with an SSRI), the patient will at best achieve partial remission.


In a recent study by Alexopoulos and colleagues,9 vascular risk factors were associated with poor remission rate in elderly patients who were treated with the antidepressant citalopram at 40 mg/day. The value of the vascular depression hypothesis (See pg. 6) is that, if vascular disease contributes to the development of depression, then providing prevention for vascular disease, such as antihypertensive treatment, statins, aspirin, and antioxidants, may protect patients from depression. In addition, if in fact there is such a syndrome as vascular depression, that might influence the choice of antidepressants used. For example, drugs that enhance neurotransmission of norepinephrine (desipramine), dopamine (bromocriptine), or both (amphetamine), may promote behavioral recovery after an ischemic lesion. Other drugs like a-antagonists (trazodone, amitriptyline), benzodiazepines, and dopamine antagonists, inhibit behavioral recovery from ischemic lesions.


Several studies have shown that depression is a risk factor for stroke.10 It has also been demonstrated that depression interferes with functional recovery from stroke.11 Finally, studies have shown that antidepressants reduce the incidence of post-stroke depression12 and post-stroke mortality.13


Cognitive Impairment in Late-Life Depression


Data suggest that cognitive impairment, particularly executive dysfunction, may influence the course of depression. Abnormal initiation perseveration (executive dysfunction), is associated with a high incidence of dementia during long-term follow-up. Another predictor of development of dementia is late age of depression onset. However, it is often difficult to determine the onset of depression. Moreover, early-onset depression predisposes to late-onset depression syndromes because it interferes with the brain’s neuroanatomy and increases vulnerability to late-life syndromes of a different depressive etiology. Nonetheless, late onset of depression has been shown to be a robust predictor of later development of dementia.


Alexopoulos and colleagues14 treated 112 depressed elderly patients with citalopram 40 mg/day. Patients who had executive functioning impairment were less likely to achieve remission over a period of 8 weeks (Slide 13). Similarly, the patients who had abnormal response inhibition (inability to select a correct response and suppress a spontaneous response), did not respond well to citalopram. However, depressed patients responded well to problem-solving therapy (PST), which is a simplified form of comorbid behavioral therapy. Disability was also reduced in those who received PST compared to those who received supportive therapy. PST did not improve executive functions, however.





Antidepressants alone may not always be a sufficient treatment for depressed elderly people, and psychotherapies should be considered. Medical comorbidity contributes to depression significantly and it is important to treat both depression and medical diseases contributing to depression simultaneously whenever possible. Cognitive impairment, particularly executive impairment, may require greater clinical vigilance because executive dysfunction may predispose patients to poor response to antidepressants and require additional interventions. Disability is not fully explained by the clinical pathology of the patient and, therefore, requires an individual rehabilitation plan for reestablishing behavioral competence.



1. Schatzberg AF. New indications for antidepressants. J Clin Psychiatry. 2000;61(Suppl 11):9-17.


2. Roose SP, Sackeim HA, Krishnan KR, et al; Old-Old Depression Study Group. Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. Am J Psychiatry. 2004;161(11):2050-2059.


3. Bondareff W, Alpert M, Friedhoff AJ, et al. Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry. 2000;157(5):729-736.


4. Newhouse PA, Krishnan KR, Doraiswamy PM, et al. A double-blind comparison of sertraline and fluoxetine in depressed elderly outpatients. J Clin Psychiatry. 2000;61(8):559-568.


5. Thompson LW, Coon DW, Gallagher-Thompson D, Sommer BR, Koin D. Comparison of desipramine and cognitive/behavioral therapy in the treatment of elderly outpatients with mild-to-moderate depression. Am J Geriatr Psychiatry. 2001;9(3):225-240.


6. Reynolds CF 3rd, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA. 1999;281(1):39-45.


7. Arean PA, Cook BL. Psychotherapy and combined psychotherapy/pharmacotherapy for late life depression. Biol Psychiatry. 2002;52(3):293-303.


8. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285(10):1299-1307.


9. Alexopoulos GS, Kiosses DN, Murphy C, Heo M. Executive dysfunction, heart disease burden, and remission of geriatric depression. Neuropsychopharmacology. 2004;29(12):2278-2284.


10. Larson SL, Owens PL, Ford D, Eaton W. Depressive disorder, dysthymia, and risk of stroke: thirteen-year follow-up from the Baltimore epidemiologic catchment area study. Stroke. 2001;32(9):1979-1983.


11. Gainotti G, Antonucci G, Marra C, Paolucci S. Relation between depression after stroke, antidepressant therapy, and functional recovery. J Neurol Neurosurg Psychiatry. 2001;71(2):258-261.


12. Rasmussen A, Lunde M, Poulsen DL, Sorensen K, Qvitzau S, Bech P. A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics. 2003;44(3):216-221.


13. Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1839.


14. Alexopoulos GS, Raue P, Arean P. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry. 2003;11(1):46-52.



Question-and-Answer Forum


Q: What is the relationship between depression and Alzheimer’s dementia?



Dr. Roose: Studies have shown that people who have depressive symptomatology at baseline have a much higher rate of developing dementia 4–5 years later. At this point, we know that there is a strong association between depression and developing dementia. We do not know whether depression is a risk factor for developing dementia, or whether depression is a prodromal symptom of dementia.


Q: Could the relationship between vascular illness and depression be attributed to reactive depression?



Dr. Roose: When we were first recognizing post-myocardial infarction (MI) depression, the concept  was that people get depressed after a heart attack. However, when you look at the data, it does not work out that way. In fact, depression precedes the heart attack in 50% of cases. Some data have shown that there is a high rate of intense depressive states 2 hours before the MI, which do not exist in the preceding 24 hours or 6 months prior. Therefore, the concept of reactive depression may apply in some cases, but we should not overlook the fact that the depression may be the precipitating trigger for the ischemic event.


Q: Is it possible that vulnerability to depression in later life is related to a decrease in resilience factors?



Dr. Lenze: To some extent, depression is the absence of resilience or resilience is the absence of depression. Resilience is a concept in psychiatry that comes mostly from studies of children who flourish and do not develop depression even after having been in terrible social, economic, and adverse settings. In elderly people, there is a similar concept. One of the factors that lead to resilience in elderly people is good social support. There is also a basic personality composed of optimism and mastery of one’s life that prevents depression. The onset of a severe disability can cause patients to challenge their optimistic way of thinking and reduce the quality of their social relationships. Although there has not been a lot of research on it, it is certainly a pathway.


Q: Is it possible that the reason medical illness is common in late-life depression is because it is common in elderly people rather than due to a strong relationship between depression and medical illness?



Dr. Lenze: There is a fairly strong association between depression and medical illness. It seems that medical conditions are more common in the depressed population of elderly than they are in the general elderly population. In both elderly and young populations, increased medical illness is associated with increased incidence of depression.


Q: Would you wait before starting antidepressants in a bereaved person?



Dr. Shear: If a  patients meets criteria for major depression 2 weeks after the death of a loved one, it makes sense to treat that person because the higher the distress early on after bereavement, the worse the outcome. Therefore, it is a good idea to mitigate some of that distress if possible.  There is no evidence that selective serotonin reuptake inhibitors blunt the normal emotional reaction. In fact, it is probably the case that very intense emotions interferes more so than the antidepressant medication would.


Q: Are there any data relating to reactions to the death of a spouse in an unhappy relationship or after a long illness where death is partly a relief?



Dr. Shear: The small amount of data we have is quite consistent with the idea that the grief problems do not come from bad or ambivalent relationships. The Longitudinal Follow-up Study of Caregivers of Alzheimer’s Patients study found that caregivers who become depressed have a lessening of depression after the death. We can infer from this, grief proceeds normally with that the death of someone who has been suffering or with whom the caregiver has been suffering. This occurs so long as long as the caregiver is not guilt ridden, and allows themselves to feel  the natural relief that comes from the resolution of a difficult situation.


Q: When you referred to depression as a risk factor for stroke or MI, does the prediction pertain to untreated depression, treated depression, or both?



Dr. Alexopoulos: The studies were done in untreated depression and showed that increased depression increased the likelihood of stroke. I am unaware whether treatment of depression was studied as a predictor of stroke, but clearly proactive treatment of depression, reduces the incidence of stroke and improves mortality after stroke.


Q: When we consider the level of evidence in antidepressant therapy in the elderly, why is nortriptyline not rated higher than the other antidepressants?



Dr. Alexopoulos: My assumption is that nortriptyline is a more difficult drug to use. It requires longer training and has some contraindications. Nortriptyline has side effects such as loss of memory, dry mouth, constipation, tachycardia, and other anticholinergic symptoms that may compromise the patient’s quality of life. These are reasons to worry about nortriptyline. Nonetheless, nortriptyline is highly efficacious.


Dr. Roose: I think clinicians are enamored with the therapeutic plasma level of nortriptyline as a treatment for late-life depression. It does not mean that we have the double-blind placebo-controlled trials to support that.  Most of the trials of nortriptyline have been psychotherapy controlled, not necessarily placebo-controlled. And while nortriptyline has shown vast evidence of efficacy, there are safety concerns in terms of cardiovascular risk and other side effects. But certainly the same thing should be said about stimulants, which has become a standard of care in the absence of strong evidence-based medicine.


Q: Stimulants are used regularly and extremely effectively in the elderly. What are the effects of these drugs on executive dysfunction?



Dr. Alexopoulos: Stimulants are becoming the standard of care in rehabilitation after stroke. Patients who have suffered a stroke often have executive dysfunction. Perhaps by enhancing dopamine and norepinephrine neurotransmission, stimulants may improve behavioral recovery after ischemic lesions. Whether stimulants work as antidepressants per se, has not been established. There is not a single well-designed study of stimulants in geriatric depression. At this point, it is unclear whether psychostimulants work as single antidepressants in geriatric major depression, although they may serve as augmentation to antidepressants in patients with depression, executive dysfunction, or vascular depression.


Dr. Roose: There is a significant concern about the use of stimulants, particularly in older people, on the basis of its ability to increase QT variability and a vulnerability to arrhythmia and sudden-death.  The oldest story about that is the interaction between digitalis and quinidine. We used to give digitalis and quinidine to the patients with the worst cardiac conditions. They would die, which is what was expected, and we did not realize that there was a drug-drug interaction that was promoting the death. Therefore, before we ever enthrone something as a standard of care, we have to look at the evidence and the relevant safety data.


Q: What do you recommend for insomnia in depressed elderly patients?



Dr. Alexopoulos: The expert consensus guideline recommends sleep hygiene first, followed by trazodone. They did not recommend benzodiazepines or hypnotic medications. We sometimes use small doses (5 mg) of zolpidem in those who do not respond to trazodone.


Q: What is your first choice for agitated depressed elderly patients? Are small doses of antipsychotics acceptable?



Dr. Alexopoulos: Our practice at Cornell is not to use antipsychotic medicines in nonpsychotic depression unless it is absolutely necessary. However, there is emerging evidence that there may be a role for antipsychotic medications in geriatric depression. A study was recently conducted in patients who had failed to respond to at least two antidepressants as well as a citalopram trial. These patients achieved good response with risperidone 0.5–1.5 mg/day.


Q: It has been demonstrated that medical rehabilitation helps depressed as well as nondepressed hip fracture patients. Does this generalize to other illnesses?



Dr. Lenze: The study I conducted was in hip fracture patients, but I don’t see any reason why it would not generalize to other disabling medical events. If the disability from the medical illness calls for medical rehabilitation, the treating physician should advocate for their depressed and cognitively impaired patient. Several studies have shown that when someone goes to rehabilitation and recovers function, their depression gets better. This is not at all surprising considering that disability is one of the major risk factors for depression in the elderly.


Q: Is there a role for cholinesterase inhibitors in the treatment of late-life depression given the high rate of conversion to Alzheimer’s or cognitive deterioration?



Dr. Alexopoulos: The theory has been that Alzheimer’s disease begins many years before it becomes clinically evident. Depression is a prodrome of dementia. Therefore, it makes eminent sense to use whatever we have to prevent the development of dementia in high-risk patients such as the depressed patients. I do not believe that there is sufficient evidence to tell us whether we should use cholinesterase inhibitors or not, but in a patient with cognitive impairment, late-onset depression, executive dysfunction, and serious depression, I would be more inclined to consider a cognitive enhancer.


Dr. Lenze: There is a large-scale study being done in late-life depression, looking at whether donepezil added to antidepressant monotherapy in remitted depressed patients will delay or prevent cognitive decline. Those findings will be available in about 4 years.


Q: Are sympathetic stimulants, such as bupropion and venlafaxine, likely to cause similar side effects as anticholinergic medications?



Dr. Roose: With anticholinergic drugs, there is particular concern about cognitive side effects and the data has shown that increased anticholinergic load is associated with decreased performance on certain neuropsychological evaluation tests. In terms of the cardiovascular risk, anticholinergic load decreases the already reduced parasympathetic tone that occurs as a result of age or depressive illness. Reduction of parasympathetic tone increases vulnerability to arrhythmia. Sympathetic drugs such as the stimulants and other drugs that may stimulate noradrenergic activity, may increase sympathetic tone, increase QT variability, and increase arrhythmic potential.



Funding for this symposium monograph supplement has been provided through an unrestricted educational grant by Forest Pharmaceuticals, Inc. Sponsorship of this supplement does not imply the sponsor’s agreement with the views expressed herein. Although every effort has been made to ensure that the information is presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher, the sponsor, nor the participants can be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.


Copyright ©2005 MBL Communications, Inc. 333 Hudson Street, 7th floor, New York, NY 10013. Printed in the USA.

All rights reserved, including the right of reproduction, in whole or in part, in any form.