Constantine G. Lyketsos, MD

Alzheimer dementia (AD) represents a profound global health concern. By the year 2050, the prevalence of AD in the United States is expected to reach 15 million. At present, there are 4.5 million cases in the United States,

 which equals an estimated cost of $100 billion each year in medical and family expenses.

 Clinically, AD is characterized by the progressive deterioration of patients' cognitive and functional abilities over several years from the initial onset of symptoms.

Neuropsychiatric symptoms are highly prevalent in this patient population and often represent the greatest source of distress to both the patient and his or her caregivers. Depression is one of the most common of these symptoms and often presents differently from major depressive episodes in younger persons. Although the treatment of depression in AD remains challenging, both pharmacologic and nonpharmacologic approaches can offer relief to patients and caregivers. This article highlights the significance of depression of Alzheimer disease (dAD) as a diagnostic entity, elucidates the issues surrounding its recognition, and ultimately offers some practical treatment strategies to physicians dealing with these complex cases.


Neuropsychiatric symptoms in AD are a heterogeneous group, representing a spectrum of expressions including depression, agitation, hallucinations, delusions, insomnia, and others. Two recent population-based studies examined the epidemiology of these symptoms in AD. In the Cache County Study on Memory in Aging, 53% of AD patients exhibited at least one of the previously mentioned symptoms during the previous month, as defined by the Neuropsychiatric Inventory, with depression occurring in about 20%.

 Similar results were seen in the cardiovascular health study, with depression being the most prevalent symptom at 32.3%.

 Comparable studies in the United Kingdom reported similar findings.

Additional analyses of the Cache County data found that despite the broad spectrum of neuropsychiatric symptoms, participants could be classified into 3 groups of symptom constellations: those with a monosymptomatic disturbance (19%; mostly delusions), those with a primarily psychotic syndrome (13%), and those with a primarily affective syndrome (28%).

 Studies from clinical settings reported that an estimated 30% to 50% of AD patients had depression. Neuropsy chiatric symptoms are reported to affect as many as 90% of AD patients over the course of their illness, with depression being among the most prevalent. These data confirm the overarching need for improved interventions in this area.

Depression can often be the first symptom in AD. Some evidence indicates that it is most common in mild to moderate illness but has a symptom constellation differing from that of depression in younger patients. For this reason, the National Institute of Mental Health (NIMH) sponsored a workgroup in 2002 to develop a set of criteria that would crystallize the cur rent consensus in the field.

 These criteria were predicated on the understanding that al though dAD has some similarities to major depressive disorder (MDD), it represents a unique clinical entity. Because of this qualitative distinction, existing criteria for the assessment of MDD consistently tend to underestimate the prevalence of dAD. Key differences in these criteria include: (1) dAD requires only 3 symptoms versus the 5 for MDD; (2) dAD symptoms can fluctuate more than those of MDD; (3) dAD includes symptoms of irritability and social isolation/withdrawal; and (4) dAD places greater emphasis on anhedonia (a decrease in positive affect or pleasure in response to social contact and usual activities). Generally speaking, patients with dAD tend to be more anxious, agitated, delusional, or inattentive but have less guilt and self-deprecation and are rarely suicidal. The hope among investigators is that the diagnostic criteria developed by the NIMH can more accurately capture these phenomena.


A commonly encountered belief among caregivers of patients with dementia is that receiving the diagnosis of Alz heimer disease will inevitably result in depression. This is the reason that families frequently protect their loved ones from hearing the details of their condition. However, there does not appear to be a clear association between a patient's insight into the disease and the risk of a mood disorder. In fact, many patients in whom an affective syndrome ultimately develops have little or no insight into their cognitive condition. In addition, dAD can occur at any stage in the disease process, including in advanced illness, where insight is almost universally absent.

Research is beginning to shed light on some of the proposed biologic foundations of dAD. Several pathologic studies

 consistently showed a relationship between depression in dementia and a loss of noradrenergic neurons in the locus caeruleus. A fluorodeoxy glucose positron emission tomography (PET) study found hypometabolism in the right superior frontal gyrus in patients with dAD as opposed to those without.

 A previous PET study also demonstrated frontal lobe hypometabolism that was most prominent on the left side in depressed patients with dementia.

 In addition, a recent autopsy study dem onstrated the consistent finding of Lewy bodies in the amygdala of dAD patients.

 The further elucidation of these underlying mechanisms may help to guide future treatment efforts.


One major challenge for clinicians is the limited capacity of AD patients to accurately convey their mood state. Both impaired language and executive functioning may contribute to a patient's inability to fully integrate and convey the subjective experience of depression despite profound sadness. In that regard, much of the diagnosis relies on the caregivers' observations, since they have frequent contact with the patient.

Experience teaches that it is best to interview informants separately to allow for the greatest opportunity to be candid. A careful history must accurately assess the time course and pattern of any symptoms, and the use of rating scales can aid the clinician in assessing symptom severity. The Cornell Scale for Depression in Dementia (CSDD) is particularly useful because it integrates the patient and caregiver interviews to reach a composite rating.

Careful at tention in this often medically complex population to comorbid physical factors that may mimic or complicate the diagnosis of dAD is of equal importance (

). Delirium should be considered when the changes are acute. Issues such as medication toxicity (especially from anticholinergic agents), infections, metabolic abnormalities, pain, con stipation, and other primary medical problems are common.


Once an accurate diagnosis is made, treatment requires a pragmatic ap proach. In all cases, specific nonbiologic interventions should be made first. Nonpharmacologic treatment approaches offer an advantage over medication therapies because of their safety and are often a first-line treatment in more mildly depressed patients or in cases in which the caregiver is depressed.

 In more severe cases, or in situations in which patients fail to respond to these efforts, biologic treatments take precedence. Unfortunately, many good treatment plans fail or yield only partial benefit. These cases require a persistent effort that continually con siders alternative approaches.


Several fundamental principles guide effective caregiver interventions; these are briefly outlined in 

. An es sential first step in interventions is to focus on education about dementia and depression. In many circumstances, this includes helping caregivers make needed changes in the patient's environment (providing adequate structure, increasing physical comfort, and reducing overstimulation) or their own ap proach (having reasonable expectations, remaining calm and reassuring, not rushing the patient). The importance of developing a predictable daily rou tine that incorporates pleasur able activities for the patient should be paramount. In addition, caregivers vary in their aptitude to problem-solve when difficult situations arise. Working with them systematically as problems pre sent can help them cultivate this skill. It is essential to convey a sense of hope, allow an opportunity to "vent,&334; and praise their successes. It is also important to help caregivers recognize when the level of care a patient requires ex ceeds their abilities and may necessitate a change in living arrangements. Another key support is the clinician's 24-hour availability in case of crisis.

Additional resources, such as a local Alzheimer Association support group (go to 

 for listings) and reading material, including The 36-Hour Day


There are few studies of behavioral interventions in AD. One controlled study examined 2 interventions-one targeted to the patient, which focused on the provision of pleasant activities, and one that was caregiver-oriented and taught problem-solving skills.

 Both were more effective than usual care or a "wait list" control group in reducing depression in AD patients. In another controlled trial, an exercise training program combined with caregiver training also demonstrated an improvement in depression ratings.

 Often, interventions such as these are best implemented in the context of adult day treatment or in a senior citizens' center. Helping caregivers acquire information about local programs through a local chapter of the Alzheimer Association or the local department of aging can go a long way in establishing the most appropriate setting for clinical benefit.


When depression is severe or a CSDD score is above 12,19 when the patient is suicidal or violent, or when the patient is not eating or drinking, antidepressant therapy is likely required.

 Currently, there is no FDA-approved treatment for dAD; however, 

 summarizes the results of existing controlled trials of antidepressant medications in AD. It should be noted that most of these studies used DSM-IV diagnostic criteria, because the NIMH criteria for dAD were not in existence at the time.

As discussed, routine diagnostic criteria do not likely capture an accurate picture of the condition and could overlook aspects of treatment response. Other challenges in the interpretation of this literature are inconsistencies in efficacy findings, limited replication studies, and several negative studies that indicated no superiority of the drug over placebo. As a function of these limitations, these data cumulatively serve as a general guide to the treatment of dAD, but do not yet offer any definitive man agement recommendations.

At this point, the initial approach is to begin with an SSRI. The evidence seems to indicate a similar efficacy be tween tricyclic antidepressants (TCAs) and SSRIs, with the latter being better tolerated with fewer cognitive side ef fects. Common side effects of SSRIs are largely related to their serotonergic activity and include GI distress, tremor, headache, restlessness, and insomnia. No controlled studies exist that examine the effects of newer antidepressant categories (serotonin-norepinephrine reuptake inhibitors, bupropion, or mirtazapine) in dAD. The best safety and efficacy data exist for sertraline and citalopram (with the latter arguably extrapolated to escitalopram based on their pharmacologic similarity), which make them a reasonable starting point in treatment.

These clinical trials seem to indicate that antidepressant dosing in dementia should be similar to that in younger patients. This is a key distinction from the standard lower dosing of other neuroleptic agents in this population. Titration to the maximal target dose over 4 weeks is ideal; however, slower schedules are appropriate as clinically indicated. If no response is seen after that time, a change is likely warranted or consideration may be given to augmentation with an antipsychotic or anticonvulsant. If partial benefit is seen after 4 weeks, full benefit may require up to 12 weeks of treatment. Scales such as the CSDD can be useful in monitoring this response.

If there is still inadequate response at 12 weeks, consider a medication change following a 2-week taper. Reasonable second-line agents include nor adrenergic drugs such as venlafaxine, mirtazapine, secondary amine TCAs, or a monoamine oxidase inhibitor. This choice theoretically relates to the previously described finding of the loss of noradrenergic neurons in the locus cae ruleus. If mood is im proved but agitation remains, a subsequent step can include adding an anticonvulsant such as divalproex. In our experience, initial dosages of 250 mg bid or 500 mg qhs are often required, with a titration to a serum level of 50 to 100 µg/mL; how ever, clinical re sponse is often seen at lower levels. This initial dosing may be somewhat higher then standard geriatric dosing.

For treatment-refractory patients, consideration should be given to electroconvulsive therapy, especially when patient safety is at risk because of suicidality, violence, or poor self-care. The concern for increased postictal delirium can be minimized by careful patient selection and in many cases, treatment has also been demonstrated to result in improved cognitive functioning in dementia.


Depression is a very frequent neuropsychiatric symptom in AD and is responsible for significant morbidity and caregiver burden. The symptom constellation of dAD differs from that of major depressive episodes, frequently including irritability, agitation, delusions, anxiety, and anhedonia. This syndrome has only recently been identified and provisional diagnostic criteria for dAD should help in understanding causes and treatments. Successful management requires the thoughtful integration of pharmacologic and non pharmacologic treatment strategies. The desire to maximize the quality of life for those dealing with this devastating disease fuels this effort.

Dr Kozauer is a neuropsychiatry postdoctoral fellow in the division of geriatric and neuropsychiatry, Dr Rosenberg is assistant professor of psychiatry and behavioral sciences in the division of geriatric and neuropsychiatry, and Dr Lyketsos is professor and chair of the department of psychiatry at The Johns Hopkins Hospital in Baltimore, Md. Dr Kozauer and Dr Rosenberg report that they have no conflicts of interest concerning the subject matter of this article. Dr Lyketsos receives grant support from NIMH, NIA, Associated Jewish Federation of Baltimore, Forest Labora tor ies, GlaxoSmithKline, Eisai, Pfizer, Astra-Zeneca, Eli Lilly, Ortho-McNeil, Bristol-Myers Squibb, and Novartis. He is a consultant/advisor for Astra-Zeneca, GlaxoSmithKline, Eisai, Novartis, Forest Laboratories, and Supernus Pharmaceuticals. He has received speaking honoraria from Pfizer, Forest Laboratories, and GlaxoSmithKline.

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Articles

Alzheimer dementia (AD) represents a profound global health concern. By the year 2050, the prevalence of AD in the United States is expected to reach 15 million. At present, there are 4.5 million cases in the United States, which equals an estimated cost of $100 billion each year in medical and family expenses.

Depression in Patients With Alzheimer Dementia

The recent approval of psychosomatic medicine (PM) as the newest psychiatric subspecialty by the American Board of Medical Specialties

 was predicated, in significant part, on the public health significance of the field and on the existence of a well-developed body of knowledge to support its validity and activities. The continued growth of the evidence base is crucial to the future of the field and to improving the care of the patients who are its focus, thus leading to a reduction of the public health burden associated with their condition. In this article, we present a brief overview of the existing evidence base of PM in the context of its public health significance; we also provide some suggestions for its future development. 

Examples of the evidence Because the PM evidence base is rich and varied, it cannot be fully covered in an article of this length. Nevertheless, the following examples serve to illustrate the current status and depth of the research. Psychiatric comorbidity is very common in patients with medical conditions, with a prevalence ranging from 20% to 67%. Patients in the general hospital have a higher rate of psychiatric disorders than community samples or patients in ambulatory primary care. Compared with community samples, depressive disorders in hospitalized medical patients are more than twice as common, major depression 2 to 3 times as common, substance abuse 2 to 3 times as common, and somatization disorder more than 10 times as common. Delirium occurs in 18% of hospitalized patients, a rate much higher than one would expect in the community. Similarly increased rates are seen in primary care and long-term care.

Psychiatric comorbidity has serious effects on physically ill patients and is often a risk factor for their medical conditions. It is well established that depression is both a risk factor and a poor prognostic factor in coronary artery disease. Psychiatric illness worsens cardiac morbidity and mortality in patients with a history of myocardial infarction, diminishes glycemic control in patients with diabetes, and decreases return to functioning in patients who have had a stroke. Mood and anxiety disorders compound the disability associated with stroke. In the context of neurodegenerative disease (eg, Parkinson or Alzheimer disease), depression, psychosis, and behavioral disturbances are significant predictors of functional decline, institutionalization, and caregiver burden.

Hospitalized patients with delirium are significantly less likely to improve in function than patients without delirium. Delirium is associated with worse outcomes after surgery, even after controlling for severity of physical illness.

 Dialysis patients with psychiatric conditions experience more difficulties in adjusting to dialysis, such as placement of the shunt, dependence on a machine, multiple needle-sticks, and accepting the reality of blood circulating outside their bodies. Psychopathology adversely affects patients during the long wait for an organ transplant. After organ transplantation, relatively minor disruptions in compliance with immunosuppressant medication such as may be associated with depression, may result in graft rejection and death.

In addition, depression and other psychiatric disorders significantly impact quality of life and the ability of patients to adhere to treatment regiregimens. For example, psychiatric disorders are linked to nonadherence with antiretroviral therapy, adversely affecting the survival of patients with HIV infection. Psychiatric disorders worsen the prognosis and quality of life of patients with cancer. Psychiatric disorders are also linked to nonadherence to safe sex practices and to the use of sterile needles in HIV-infected injection drug users, leading to major public health implications.

With regard to clinical services, failure to identify, evaluate, diagnose, treat, or achieve symptom resolution of psychiatric morbidity in medical care settings results in significant adverse outcomes. Depression, dementia, and delirium,

 common psychiatric disorders found in hospitalized medical patients, are associated with higher medical care use, both in the hospital (more than 30% longer duration of hospitalization) and after discharge.

Although it is the treatment of choice, fewer than 1 in 5 patients with agitated delirium receive neuroleptic treatment in the hospital. When delirium is unrecognized and untreated in the hospital, patients are needlessly placed in nursing homes instead of being sent home.

Physically ill patients with depression whose condition is not diagnosed and who therefore do not start treatment while hospitalized have only an 11% chance of receiving treatment for depression in the next year. Untreated depression is associated with a higher need for medical services after hospital discharge and with higher morbidity and mortality in coronary disease, hypertension, diabetes, and stroke.

Based on existing research findings, the presence of co-occurring physical and psychiatric disorders can be explained by an adverse bidirectional interaction.

 This model proposes that the seemingly disparate medical and psychiatric disease states are, in fact, integrally related in their causation and pathophysiology and, ultimately, should be treated together. Underlying risk factors, including genetic vulnerability, childhood adversity, maladaptive attachment, and adverse life events are associated with depression and biobehavioral risk of chronic disease. A recent editorial summarizing findings of a conference on depression in medical illness called for more research "to understand this bidirectional relationship and identify possible common pathogenic, mechanistic pathways that link depression and serious medical illness."

Results of PM research in the context of cardiovascular disease (CVD) can be used as a model to illustrate developments in the broader PM research agenda as they relate to understanding mechanisms linking psychiatric morbidity to poorer medical outcomes, as well as the effect of treating psychiatric morbidity on medical outcomes. This model also provides an illustration of the challenges and the future directions in this line of investigation for PM research concerning other physical conditions.

A confluence of evidence suggests that major depression is a risk factor for CVD and poorer cardiac outcomes in patients with CVD. Even minimal elevation in depressive symptoms increases the risk of subsequent cardiac events and mortality. What are the mechanisms underlying this? There has been a great deal of research to find physiologic pathways that explain this link. One plausible mechanism points to dysregulation of the autonomic nervous system as playing a critical role. Decreased activity of the parasympathetic nervous system and increased activity of the sympathetic nervous system are associated with risk of myocardial ischemia, ventricular tachycardia, ventricular fibrillation, and sudden cardiac death in patients with CVD.

Patients with depression are more likely to exhibit autonomic dysfunction as evidenced by increased catecholamine levels, increased heart rate, decreased heart rate variability, baroreflex dysfunction, and higher variability in ventricular repolarization. Additional mechanisms to explain the relationship between depression and CVD include alterations in platelet function, immune system parameters, and behavioral risk factors. Although a number of physiologic parameters have been identified, a conclusive underlying mechanism remains elusive.

If depression adversely affects CVD outcomes, what is the benefit of treating depression to CVD outcomes? Some evidence suggests that treating depression in patients with CVD results in improved cardiac autonomic function. The use of selective serotonin reuptake inhibitors and psychological therapies has proved safe and effective in the treatment of depression in patients who have CVD.

The Sertraline Antidepressant Heart Attack Trial (SADHART)

 was a landmark trial because it combined psychiatric, cardiovascular, and physiologic data. Its findings demonstrated a trend for an association between treatment with sertraline and decreased incidence of severe cardiac events. It should be noted, however, that patients treated with sertraline demonstrated decreased platelet and endothelial activation markers. This suggests that the benefit of sertraline may be achieved through its antiplatelet effects rather than through its effects on depression. 

The Enhancing Recovery in Coronary Heart Disease (ENRICHD)

 trial, which used a tailored cognitive-behavioral intervention, did not show a relationship between psychotherapeutic treatment and recurrent cardiac events or all-cause mortality in the overall sample, although post hoc analyses demonstrated cardiac benefits among white males. However, a significant proportion of the participants across study arms were taking antidepressant medications, which may have significantly decreased the risk of nonfatal reinfarction or death. Further research is needed to identify the most effective treatments that improve both depression and cardiovascular outcomes by targeting their shared pathophysiology. Once identified, research examining the dissemination of these interventions will be warranted.

PM is now involved with a wide and ever-expanding spectrum of investigations looking at the relationship between physical and psychiatric illness. Important contributions have occurred in HIV/AIDS; cancer; transplantation; cardiac, neurologic, pulmonary, renal, and GI disease; and obstetrics-gynecology. In each of these areas, first-generation studies have identified the extent and nature of psychiatric morbidity associated with the most common diseases or hospitalization. More sophisticated second-generation cross-sectional, epidemiologic studies have established the prevalence rates of a broader range of psychiatric disorders in several medical conditions, as well as less common or newly proposed psychiatric syndromes, such as Alzheimer-associated affective disorder. 

In some cases, a new body of research has extended our knowledge about genetic, neurochemical, and behavioral factors contributing to the development of psychiatric disorders among complex medically ill populations. This work has shown that many different mechanisms are involved. Examples include the relationship between the location of brain lesion after stroke and poststroke major depression, or between childhood sexual abuse and the later development of chronic pain syndromes. This has led to more rational intervention studies focused on reducing the rate of occurrence of these disorders, including successful programs that reduce postcardiotomy delirium and other forms of ICU delirium.

The future research agenda for PM will continue to revolve around these themes. The 

 displays examples of the sorts of studies that are anticipated in the next few decades. They are grouped by type of study, with specific examples provided within each group. For brevity, the examples are focused on specific psychiatric or medical conditions, even though similar studies might be envisioned involving a range of psychiatric and medical conditions. As is evident, PM research will slowly move away from descriptive studies and focus increasingly on studies of mechanisms while continuing with key treatment studies, until mechanism studies lead to the development of "designer" therapies informed by better mechanistic understanding. There will, by necessity, beincreasing application of newer research methods from genetics, brain imaging, animal models, pharmacology, psychology, epidemiology, and clinical trials. 

The major challenge for the field will be the funding of its research. This is especially true given the funding limitations faced by the NIH in the next few years. Increasingly, the field will have to connect with a broader spectrum of research funding through closer relationships with the pharmaceutical industry and investor philanthropy. A critical component of the ability to grow and sustain funding will be the ability of PM to work closely with the NIH, especially within the context of the NIH Roadmap for Medical Research that calls for clinical and translation research in areas of high significance to public health and that crosses traditional basic and clinical disciplines. Already, the Academy of Psychosomatic Medicine, the American Psychosomatic Society, and the American Psychiatric Association are working closely to articulate a systematic work plan for PM research and research capacity in the next decade and are seeking NIH funding to support the development of this work. In all, the next decade promises to be highly exciting for the PM research field.

Dr Lyketsos is a professor in the department of neuropsychiatry and the Memory Group at the Johns Hopkins University School of Medicine in Baltimore. Dr Alter is associate professor and director of policy and community outreach in the department of psychiatry at the Georgetown University Medical Center in Washington, DC.

 The authors have indicated that they have no conflicts of interest.

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A discussion of the current evidence base of psychosomatic medicine in the context of its public health significance and suggestions for the future development of the field.

Author | Constantine G. Lyketsos, MD

Articles

Depression in Patients With Alzheimer Dementia

Research in Psychosomatic Medicine: Beginning to Set the Future Agenda