Treatment of Depressive Syndromes in Dementia

Lilian Thorpe and Bernard Groulx

Published in Treating Dementia – Cognition and Beyond. Edited by R.J. Ancill, S.G. Holliday, L. Thorpe and K. Rabheru. Canadian Academic Press, Vancouver, 2000.

Introduction

Depressive syndromes are common in dementia and their occurrences may, in fact, be an integral part of the development and course of various dementias. There appears to be a complex relationship between depression and dementia, it is not surprising to find that diagnostic issues continue to remain a central concern to researchers and caregivers alike. However, our understanding of depressive syndromes in dementia has advanced to the point that we can move past diagnosis as a single focus and consider the management of the various depressive syndromes that can be a major source of patient and family distress. In addition to major depressive disorders, patients with dementia often exhibit depressive symptoms, experience grieving, and present with apathy, mood-disregulation, and chronic dysthymia. These conditions are both common and are amenable to treatment. As we will argue, the imperative appropriate diagnosis of depression must not result in these conditions being ignored.

The most frequent focus of articles on depression in dementia has the diagnostic distinction between depression and dementia (see, for example, the relevant section in the 1989 Canadian Consensus Conference on the Assessment of Dementia (Clarfield, 1989)). But despite an increased awareness of the nature of later life depression, and the publication of numerous articles identifying core diagnostic issues, diagnostic errors including both the misdiagnosis of depressive symptoms as dementia (Small, 1991) and the over diagnosis of depression in dementia continue to occur. For example, Verley et al. (1996) found that specialist consultants diagnose disorders that are in their area of expertise more often than do comprehensive multidisciplinary teams. A certain degree of diagnostic variability is understandable and reflects (a) the considerable symptom overlap between depression and dementia, and (b) the frequent comorbidity of the two disorders (reference). This situation may reflect an intrinsic linkage between dementia and depression is seen in Emery and Oxman's (1993) data demonstrating that the patients whose depression initially presents with reversible cognitive impairment often have associated organic abnormalities and will eventually go on to develop more permanent cognitive impairment.

Considerable gains have been made in the ability to provide effective treatment to persons with depression and dementia, and treatment of depression with pharmacological interventions have been shown to result in both specific and general benefits. In addition to the relief of primary symptoms of depression, treatment of depression in dementia is associated with improvements both in quality of life, and in cognitive, affective and general functioning (Greenwald et al., 1989; Stoudemire et al., 1991). Treatment with antidepressants, however, is not without risk, and when not managed properly can lead to significant morbidity. This issue is particularly relevant with respect to the tricyclic antidepressants, where documented problems include anticholinergic effects such as delirium (Flacker et al., 1998), and falls leadind to hip fractures (Ray et al., 1991). This points to the need to be sensitive to both the tendency to over-diagnose depression in dementia and the need to maintain awareness that medications, when appropriately used, can have a detrimental effect on patient function.

Cause of depressive syndromes in dementia

There is active debate about the reasons for the high prevalence of depressive syndromes in dementia. One possibility is that earlier depressive syndromes predispose to the development of dementia (Kral, 1983; Agbayewa, 1986; Jorm et al., 1991; Clayton, 1991; Speck et al., 1995; Steffens, 1997; Reifler et al., 1986; Devanand et al., 1996; Jost and Grossberg, 1996), and once the dementia is established, the depressive disorder still continues to manifest itself. Conversely, the underlying cause of the dementing illness may also have direct effects on depressive syndromes. This is supported by literature suggesting that in some neuropsychiatric disorders increasing degree of cognitive loss may increase the likelihood of depressive syndromes (Robinson and Travella, 1996), and that there is a preferential association of certain types of dementia, such as vascular dementia with depression (Cooper and Mungas, 1993, for example). Likely of importance are biological factors, including the depletion of neurons in the locus ceruleus (Zubenko and Moosy, 1988; Zweig et al., 1988; Förstl et al., 1992), or in the central superior (raphe) nucleolus (Zweig et al., 1988), leading to decreased levels of both serotonin and norepinephrine (Zubenko et al., 1990), or even increased intracellular calcium (DeVry et al., 1997). Psychological factors are likely of most significance in the production of depressive symptoms (rather than depressive illness) in early dementia; see discussion in the next section.

DIFFERENTIAL DIAGNOSIS OF DEPRESSIVE SYNDROMES IN DEMENTIA

Depressive symptoms

Depressive symptoms are more common in dementia than are major depressive disorder. Burn et al., (1990) found that of 178 patients with Alzheimer disease 63% had at least one depressive symptom, 43% were considered depressed by their relatives, and 24% were rated as being depressed by trained researchers. In fact, such depressive symptoms as reduction of motivation and interest, occasional clear changes in mood, social withdrawal and suicidal ideation are present in the majority of patients a number of years before the clinical diagnosis of dementia is made (Jost et al., 1996).

The literature documenting depressive symptoms in dementia (Migliorelli, 1995; Fisher et al., 1990; Gottlieb et al., 1998; Moye et al., 1993 ; Cummings et al., 1995 ; Reisberg et al., 1989; Troisi et al., 1993), suggests that while that are variations, some trends exist. Of note is that the pattern of depressive symptoms within the course of the dementing process varies with the degree of insight, ability to verbalize feelings, and severity of the dementia. Somatic depressive symptoms such as weight loss and sleep change appear to increase as a function of the severity of dementia, in direct opposition to subjective complaints. Therefore scales like the Hamilton Depression Rating Scale, which has a high dependence on somatic symptoms, tend to be sensitive to the symptoms that occur in later dementia, whereas those that focus more on cognitive symptoms, such as Geriatric Depression Scale, are sensitive to symptoms that may occur in the course of the illness (Brodaty and Luscombe, 1996; Sultzer, 1992). Overall, depressive symptoms are an intrinsic and prominent part of the dementing process, and seem to be identified most frequently by family members (Burns et al., 1990; Logsdon and Teri, 1995).

A possible reason for the high rate of depressive symptoms in early dementia is the retention of insight into cognitive deterioration (Kral, 1983; Migliorelli, 1995), although not all studies replicate this (Feher et al., 1991; Sevush and Leve, 1993; Reed et al., 1993). Loss of control is also thought to be a significant factor for the development of depressive symptoms (Bungener et al., 1996). It would seem intuitive that an awareness of increasing cognitive deficits might interact with the gradual loss of autonomy and control cause demoralization. Neuropathological and neurotransmitter changes in dementia alluded to earlier might also be involved etiologically.

Treatment for depressive symptoms in the absence of depressive illness usually consists of support to the person and their family, including appropriate referral to community agencies with dementia specific resources such as day programs, educational programs and self-help groups. General programming that maintains intellectual activity, physical activity, and socialization, may not slow the course of the disease, but often improves mood and enhances quality of life. In the early stages of dementia, providing a patient with information about new treatments for dementia, including possible preventative, symptomatic or neuroprotective agents (see related chapter), might instil some hope, even if the data in this area shows modest rather than striking improvements. Nihilistic approaches, such as telling the families that "nothing works" are very dispiriting to patients and families, and are probably the reason for that families make large expenditures of money on the unproven herbal remedies that are dispensed from supportive and friendly health-food store proprietors. Specific recommendations should be made for regular daily exercise (in light of recent reports suggesting possible protective effects; Smith et al., 1998), and socialization in a suitable program, regardless of the concordant use of one of the new cognitive enhancing agents. Assurance that there is active, ongoing research into dementia and that the outcome may start to improve soon, is also often of help.

If there is a dementia research program nearby, referral might be a positive experience for the whole family, as they may receive individualized attention, information, hope for possible improvement, and the knowledge that they are contributing in a positive way to ongoing medical research. As the awareness of deficits and feelings of uselessness often occur in early dementia, this last factor may be very significant.

Most recently there have been reports suggesting that improvement in depressive symptoms related to dementia can occur during trials of medications initially designed as cognitive enhancers, or even anti-Parkinsonian agents (Tolbert and Fuller, 1996; Kaufer, 1998; Kaufer et al., 1996; Haase et al., 1996). Concordant with these published studies is our clinical experience with donepezil, indicates that some people seems to exhibit improved initiative, motivation and dysphoria, and these effects may be more pronounced than any effect on cognition.

Organic emotional lability and pathological laughing or crying constitute a recognizable sub-type of depressive symptomatology, which will be discussed separately here. Although it is most frequent in vascular dementia (Starkstein et al., 1996) and in other sub-cortical disorders, it is also found in 30% of patients with mild to severe Alzheimer's disease, and is often associated with such psychiatric symptoms as anxiety, depressed appearance, increased activity and aggression (Haupt, 1996). Women are most likely to present with this symptom complex (Ott et al., 1996). Hormonal factors (Adler et al., 1997), anatomical localization (Robinson and Travella, 1996; Morris et al., 1993), family history (Starkstein et al., 1988), cholinergic mechanisms (Fritze, 1995) and overall severity of cognitive impairment (Feinstein et al., 1997) may be significant in the production of lability.

Patients with either emotional lability or pathological laughing or crying may respond to antidepressants (Christe, 1961; Lawson & MacLeod, 1969; Panzer, 1992; Seliger et al., 1992; Sloan et al., 1992; Robinson et al., 1993; Iannaccone & Ferini-Strambi, 1996; Mukand, 1996), valproic acid (Himelhoch & Haller, 1996) or possibly even thyrotropin releasing hormone (Komurasaki, 1989). The mechanism of action of these interventions may be different than in depression, as the improvement has been noted to be independent of changes other than depressive symptoms (Robinson et al., 1993; Shiffer et al., 1985). Over time, the condition may gradually improve without medical intervention.

Practically speaking, emotional lability in the context of a dementing disorder is often not treated pharmacologically, as frail demented people are more sensitive to adverse medication effects, and the beneficial desired outcome is often equivocal. At times, treatment attempts are worthwhile and, in our experience, occasionally successful. Often the course of time, or a second larger stroke, may remove this symptom. The most important intervention is education of the family and caregivers, who often think that the patient must be upset by something specific, or have a treatable depressive illness.

In summary, although their cause is not fully understood, depressive symptoms are common in dementia, and vary with its course. Most interventions are not pharmacological, but rather supportive and educational. New agents with possible benefit in dementia, such as the cognitive enhancers, should be described to the family, and made available if there is interest. The therapeutic approach should always be a positive one, with the promotion of self-respect and hope.

Apathy

Personality or behavioural change consisting of apathy and passivity (sometimes referred to as "negative symptoms"), is a very frequent concern of families of cognitively impaired patients. This phenomenon is most pronounced in the later stages of dementia, but exists even in the very early stages, and is not necessarily related to depression (Galynker, 1995). Apathy (Marin, 1996). It can occur in a variety of disorders, including white matter disease, basal ganglia disorders, and schizophrenia, as well as in cortical dementia (Selzer & Sherwin et al., 1983; Rabin et al., 1987; Perry et al., 1988; Bozzola et al., 1992). Some SSRIs (Hoehn-Saric et al., 1990; Duffy and Marin, 1995; Oliveira-Souza & Figueiredo, 1996) or neuroleptics may themselves cause apathy. Apathy appears to be a more frequent symptom than emotional lability in demented men, whereas lability is more common in women (Ott et al., 1996).

It is important to inform families that symptoms such as apathy are an integral part of the dementing process, and may not resolve completely with pharmacological interventions. Supportive interventions such as structured activity programs may provide some benefit. Occasionally stimulants (Galynker et al., 1997; Kaplitz, 1996) or cognitive enhancers such as tacrine (Kaufer et al., 1996), donepezil or metrifonate (Kaufer, 1998) might be tried. The apathy related to basal ganglia disorders (Campbell and Duffy) and other bran injuries (Van Reekum et al., 1995; Marin et al., 1995; Muller & Von Cramon, 1994) might respond to increased anti-Parkinsonian medications. Risperidone (Raheja et al., 1995) in low doses sometimes also improves apathy in dementia, probably through its 5HT2 antagonism, as do some antidepressants such as bupropion (Marin et al., 1995).

The treatment decision depends on the overall assessment of likely positive and negatives outcomes for a particular patient on a given agent. Patients with significant overall cognitive impairment and associated mild to moderate apathy will likely not have much overall functional and affective benefit from a stimulant agent, but may benefit from a trial of one of the newer cognitive enhancers. However, a patient with apathy out of proportion to their cognitive losses might show some improvement on stimulants or anti-Parkinsonian agents, although other adverse effects may be limiting factors. In this situation a trial of low-dose risperidone might be worthwhile trying. Non-sedating antidepressants might also be tried, although even the newer agents are not free of side effects.

In our clinical experience, environmental and educational approaches are the major treatment interventions, but pharmacological therapy may be moderately effective.

Grieving

Grieving is common in old age not only because of the loss of spouses and close friends, but also to lose independence such as the ability to live in the family home. This loss can be more pronounced in the cognitively impaired senior, whose experiences may be repeatedly relived as a result of their inability to retain new memories. Family members are often very stressed by the appearance of grieving, as they themselves may not only be grieving deceased family member, but are also often still grieving the functional loss of the demented relative. The decision about how much information to share with the patient is often a difficult one, and must be approached with great sensitivity. Despite a widely held belief that honesty and full disclosure for patients is a good thing. Aggressive reality therapy i.e. repeatedly announcing that a spouse, for example, has died, may not be in the best interest of a distressed demented person who is unable to retain the information.

Dysthymia (or chronic sub-acute depression)

Classical dysthymia is observed less frequently in dementia than either depressive disorder or individual depressive symptoms. However, some clinical samples may have specifically high dysthymia rates. For example, Bungener et al., (1996) found a dysthymia rate of 8% in her neurology clinic sample of 188 patients with Alzheimer disease, and Migliorelli et al., (1995) cite a dysthymia rate of 28% in a sample of 103 patients. Migliorelli's group found that dysthymia was most pronounced early in the course of dementia, and was correlated with awareness of cognitive deficits. There is overlap between the dysthymia and the depressive symptom categories, as studies have used variable diagnostic systems. Etiological factors and suggested interventions are similar in the two categories.

Major Depressive Disorder

Major depressive disorder can occur at all stages of a dementing illness and, except in the latest stages of dementia, presents with similar signs and symptoms as depression without dementia (Greenwald et al., 1989). Its frequency of occurrence is likely stable throughout the course of dementia (Migliorelli, 1995), although some contradictory reports exist (Reifler et al., 1982; Rovner et al., 1989; Troisi et al., 1993). The cited prevalence varies from zero in a neurology clinic sample (Bungener et al., 1996) to 10-20% (Wragg and Jeste, 1989) in a wide survey of the published literature, which may reflect differences in the sample populations or in the diagnostic approaches (Klatka et al., 1996; Weiner et al., 1994; Brodaty and Luscombe, 1996). The most reliable working estimate is likely in the 10-20% range.

Possible risk factors for the development of depression in demented people include a past history of depression (Rovner et al., 1989; Weiner et al., 1994), a family history of depression (Pearlson et al., 1990; Strauss and Ogrocki, 1996), early onset of dementia, and female gender (Reifler et al., 1986; Lazarus et al., 1987; Rovner et al., 1989; Loreck and Folstein, 1993). However, many patients developing depression in dementia have none of these risk factors.

Bipolar Disorder, Depressed Phase

Bipolar disorder is not common in old age, but is occasionally encountered, even in the absence of a previous history. Late onset bipolar disorders are more likely to have organic pathology such as vascular lesions than the early-onset "functional" bipolar disorders. Early and late onset bipolar disorders can be associated with very severe depressive episodes, which are more likely than unipolar depressions to produce psychotic symptoms and to require ECT. In late dementia, mood swings and irritability have often been ascribed to the dementing process itself, so the diagnosis has often not been made. Unfortunately, treatment with antidepressants may precipitate a mania and cause rapid cycling, which, when superimposed on dementia, is often very difficult to manage.

DIFFICULTIES IN DIAGNOSING MAJOR DEPRESSION IN DEMENTIA

The diagnosis of depression in the elderly without dementia is already more complicated than in the young (NIH Consensus Development Panel, 1992). Reasons for this include, among others, ageist assumptions, comorbidity with other medical illnesses, and heterogeneous presentations. This difficulty is in reliably establishing a diagnosis even more pronounced in the demented elderly.

Overlapping Symptoms

The most challenging problem in the separation of mood from cognitive disorders is disentangling overlapping symptoms. Common symptoms include cognitive changes, weight loss, sleep changes, expressions of sadness or demoralization, irritability and loss of interest, or apathy. Each of those symptoms, although occurring in both illnesses, has a different characteristic clinical pattern in each case that can help to distinguish its etiology.

Depressive illness in older people is often accompanied by cognitive deficits, which are generally reversible with the resolution of the illness. The deficits are most frequently found on demanding tasks that deplete limited attentional capacities. On neuropsychological testing there are usually at least mild deficits in secondary memory, verbal fluency, visuospatial skill, novel problem solving, and sustained attention (Nussbaum, 1997). Clinically, although both demented people and depressed people often score poorly on cognitive and functional measures, demented patients often volunteer incorrect information and answers and appear undisturbed by this, whereas depressed patients are more concerned about their actual (and perceived) deficits than seems appropriate. The time course of the loss is also significant: Cognitive symptoms of depression appear subacutely, whereas those from dementia tend to have a chronic, unremitting course. Treatment of the depressive illness with anticholinergic antidepressants (even at low serum anticholinergic levels) can, unfortunately, further worsen cognition (Nebes et al., 1997).

Weight loss is a hallmark of depressive illness, but recently it has been shown that dementia is also accompanied by gradual loss of weight, sometimes beginning before the diagnosis of dementia is made (Barrett-Connor et al., 1996). The reasons for this are not completely clear, and may include both "forgetting to eat", and other, as yet undefined, factors. Weight loss in depression tends to be more "subacute" than in the case of dementia, i.e. occurring over the course of weeks, rather than months or years.

Sleep changes are typical of both depression and dementia, an can be the main caregiver concern. In depression the characteristic pattern again is a subacute change of sleep habits: either an increase or a decrease over the course of weeks. The most typical sleep changes are intermittent nighttime wakening and terminal insomnia. In dementia there is a gradual loss of the normal diurnal pattern of sleeping and waking, probably due to progressive destruction of brain tissue, but possibly partly due to the loss of normal outside light exposure of patients in nursing homes.

Irritability can also occur in both dementia and depression. The development of this is again gradual in dementia, except when acute medical conditions such as impaction are present. However, if a patient with dementia develops increased irritability subacutaly, accompanied by changes in sleep and appetite, the diagnosis of depression superimposed on dementia is likely.

Ill-defined feelings of sadness and lack of interest are not uncommon in the early stages of dementia, as discussed in the section above on specific depressive syndromes. If this becomes consistent and gradually more severe over the course of a few weeks, however, the possibility of a superimposed depression must also be considered.

Communication Difficulties

Most criteria for depression rely heavily on the patient's ability to communicate. Making a diagnosis of depression in a poorly communicating dementing person is very difficult and requires lengthier interviewing of caregivers as well as the careful observation of behaviors. Subspecialty consulting clinicians may not know the patient well enough to notice significant changes, and family physicians do not always have the necessary time to conduct necessary tests. Clinician bias either for or against depression can also adversely influence the accurate detection of clinical syndromes.

Assessment tools

Although standard depression tools have been used in the assessment of depression in dementia, difficulties in their application led to the development of specialized scales for use in dementia. The most widely used are the Cornell Scale for Depression in Dementia (Alexopoulos et al., 1988: appended) and the Dementia Mood Assessment Scale (Sunderland et al., 1988). Both these scales are easy to use and have focussed on signs that are easy to rate in cognitively impaired people, and that have a high correlation to the diagnosis of depressive disorder. Other scales such as the Depressive Signs Scale (Katona and Aldridge, 1985) and Greenwald and Kramer's Gestalt rating of depression in advanced dementia (1991) have also found useful by some. Very recently, Jacobs et al., (1998) described the successful application of the CERAD Behaviour Rating Scale (Tariot et al., 1995; Mack & Patterson, 1996; Patterson et al., 1997) to differentiate depressed from non-depressed demented people, although this scale requires more training and time than other scales. In general, the scales described are only screens and not a replacement for a full assessment by a clinician skilled in dealing with persons with dementia. They are, however, useful in screening for mood disorders and might help in identifying missed depressed people.

Neuroimaging and electroencephalographic data might eventually be helpful in differentiating between dementia and depression, but this work is in early stages (Morault, 1994; Curran et al., 1993; Starkstein et al., 1995; Pozzi et al., 1995; Pozzi et al., 1993; Azorin et al., 1990; Reynolds et al., 1988).

Currently there is no simple, quick way to differentiate dementia with associated changes from either depressive illness or the various depressive syndromes. The gold standard remains a careful assessment of past history, family history, symptom type (see earlier) and temporal course: (i.e. subacute progression versus slow chronic change), coupled with mental status examination. In many cases some doubt will remain as to the diagnosis, and careful trials of medications with longitudinal follow-up are needed.

NON-BIOLOGICAL TREATMENT OF DEPRESSIVE ILLNESS

Non-biological interventions are not only important adjuncts of medical management, but can also stand alone, especially in the less "biological" depressive syndromes such as reactive depressive symptoms in early dementia. Teri (1994) argued that adversive events and interactions can perpetuate depression in dementia, and described strategies to alter aversive events and to increase pleasant interactions. She notes that teaching caregiver's these strategies, together with other problem solving skills, is important in achieving behavioural change. Adjusting the caregiver's expectations to a more realistic level and thus decreasing both patient and caregiver frustration can be very helpful. The tendancy to personalize difficult behaviours and to attribute them to deliberate maliciousness can be reduced with education and support.

The support of caregivers is not only important to the reduction of patient symptoms, but also to the well being of the caregivers themselves. The rate of stress and psychiatric symptomatology in caregivers is considerable (Haley et al., 1987), leads to a greater use of psychotropic medications in these carers (Clipp & George, 1990) and is often a key issue in the decision to institutionalise. Family interventions may slightly delay institutionalization of the patient (Lawton et al., 1989; Mohide et al., 1990; Mitelman et al., 1996) as well as improve the caregiver's quality of life, although significant reductions in health care utilization for the caregiver are less robust (Weinberger et al., 1993).

Various therapies have been used in different stages of the dementing process. These include counselling, individual and group insight-oriented psychotherapy, life review and reminiscence therapy, cognitive therapy, problem solving therapy, behaviour therapy, relaxation techniques and family therapy (Baldwin, 1991; Morris and Morris, 1991; Teri and Gallagher-Thompson, 1991). Other approaches include music, art, and aromatherapy. Most of these approaches are difficult to evaluate objectively, but continue to play a role in the individualized management of the depressed demented person.

BIOLOGICAL TREATMENT

There are published clinical reports of the use of antidepressants to treat depressive syndromes in people with dementia, chart review type publications, a few open prospective trials, and a few double-blind, placebo-controlled (DBPC) studies. The studies are hard to compare as diagnostic categories vary from negative symptoms of dementia to classical depressive illness superimposed on dementia. Authors describing controlled studies have found a positive antidepressant response with a variety of agents including clomipramine (Petracca et al., 1996), maprotiline (Fuchs et al., 1993), fluoxetine or amitriptyline (Taragano et al., 1997), citalopram (Gottfries et al., 1992), moclobemide (Roth et al., 1996),selegiline (Tolbert and Fuller, 1996), metrifonate (Kaufer, 1998), tacrine (Kaufer et al., 1996) and Ginkgo biloba extract (Haase et al., 1996). Some authors report poor antidepressant outcome with tricyclics (Reifler, 1989), SSRIs (Olafsson et al., 1992), and other agents (Dehlin et al., 1985). Most open label studies describe a positive antidepressant response to a variety of agents including tricyclics, SSRIs, MAOIs, stimulants and ECT (Swartz et al., 1997; Lebert et al., 1994; Volicer et al., 1994; Nelson and Rosenberg, 1991; Ancill et al., 1991; Price & McAllister, 1989; Greenwald et al., 1989; Venna et al., 1988; Reynolds et al., 1987; Woods et al., 1986; Jenike, 1985; Reding et al., 1983). Two well-quoted retrospective chart reviews also show positive response: Reifler et al., (1986) and Burke et al., (1997).

In general, the literature suggests both that response to the treatment of depressive illness in dementia appears to be less robust: (Reynolds et al., 1997; Trappler and Cohen, 1996) than that seen in patients with uncomplicated depression, and more severe dementia is associated with poorer prognosis (Reynolds et al., 1986). Placebo response is thought to be particularly high in this group: Reiffler et al., (1989) found a 50% rate, which was comparable to the imipramine response. Most significantly, Trappler and Cohen (1998) in their prospective, open label study, compared antidepressant response in various diagnostic subgroups and found that the following percentage of people showed at least a 50% decrease in their Ham-D scores: 93% in major depression alone, 8% in major depression and Alzheimer's Disease, 6% in major depression and vascular dementia, and 83% in major depression and other CNS disorder. The reasons for this poorer response is not well understood, but it is likely relates to the neuropathological changes in dementia. Zubenko et al., (1990) and Zweig et al., (1988) show that patients with depressive illness and Alzheimer's Disease have greater cell loss in the raphe nuclei, locus ceruleus and the substantia nigra than those with just Alzheimer's Disease. Clinically, Alexopoulos (1996) found that response to tricyclics may be reduced in the face of enlargement of lateral brain ventricles.

Theoretically, the use of moclobemide makes sense as there is both an increase of monoamine oxidase with age, especially in dementia (Adolfsson et al., 1980), and the presence of norepinephrine lesions in the locus ceruleus in patients with dementia (Chan-Palay, 1992). Studies cited below in depression in dementia appear positive.

The clinical use of a particular antidepressant needs to be guided by current rational prescribing approaches in the non-demented elderly, as recently summarized by Flint (1997). Issues such as changes in pharmacodynamics and pharmacokinetics are similar in the demented elderly, as are many of the other side effects such as anticholinergic effects, postural hypertension, arrhythmias and drug-drug interactions. However, in-patients with dementia there is an exacerbation of some of these, especially anticholinergic effects (Reifler, 1989; Sunderland et al., 1987). There is also evidence that antidepressant treatment can cause mild cognitive impairment even in non-demented, elderly, depressed patients (Marcopulos and Graves, 1990). Tricyclics such as imipramine have also been shown to cause subtle cognitive decrements in depressed Alzheimer patients (Teri et al., 1991) even at as low as 25 mg per day. Most recently, Petracca et al., (1996) show a drop in the anticholinergic properties. This effect is clearly less likely with the SSRIs: in a recent randomised trial with either fluoxetine or amitriptyline in depressed patients, Richardson et al., (1994) showed significant increases in anticholinergic toxicity and decreases in verbal learning in the amitriptyline but not the fluoxetine group.

Some studies, however, suggest that clinical improvement of depression in a demented patient might outweigh the anticholinergic effect, and overall lead to improved memory functioning (Cole et al., 1983), and functional improvement (Fitz and Teri, 1994). The relative efficacy of antidepressants may be a key factor. Although in general geriatric patients meta-analysis has concluded that all the antidepressants are equally effective (Menting et al., 1996), in severe, melancholic depression, serotonin manipulation (Perry et al., 1996): i.e treatment with tricyclic antidepressants (ideally nortriptyline or desipramine), or perhaps, with the newer, less toxic serotonin-norepinephrine agent venlafaxine. Also, although the SSRIs have fewer serious adverse effects overall, there are other adverse effects including extrapyramidal symptoms (see recent review by Caley, 1997), headache, sleeplessness, agitation or gastrointestinal symptoms, and these effects may limit their use.

Hypotension due to tricyclic antidepressants (and trazodone) is also particularly worrisome, as the fall risk is already greater in patients with poor judgment, and sensory impairment.

Electroconvulsive therapy (ECT) is the most effective and quickest treatment for very severe depressions, but, although it generally does not cause permanent cognitive deficits, its propensity to cause increased confusion during the treatment course means that it is not used as a first line intervention for depressed patients with dementia. Ethical dilemmas also arise, as families of severely demented patients often specify that no extraordinary than antidepressants. There are also remaining negative emotional societal (and medical) responses to ECT, which may result in the refusal of this potentially life-saving treatment option.

Overall, prescribing for the cognitively impaired elderly must both embody the best of the current knowledge about geriatric prescribing but also allow for the increased vulnerability of this group.

SUMMARY

Depressive syndromes are common in dementia, and may be integral aspects of its natural development. The treatment of each syndrome varies, as does the successfulness of the intervention. The treatment of depressive illness in particular needs to adhere to the general guidelines for antidepressant management of the elderly person, to insure the prevention of further cognitive and other functional disability. The trend of the current literature is to support the efficacy, albeit slightly reduced, of the usual antidepressants that are clinically useful in the general geriatric population. First line agents likely should be the non-tricyclics due to their general lack of anticholinergic effects, although geriatric clinical experience still finds the tricyclics helpful at times. It is clear that the treatment of serious depressions in dementia will improve the functional status more overall, even with some anticholinergic effects, but treatment decisions will remain difficult in milder depressions where the risk-benefit ratio is less clear. Not to be forgotten in severe cases, is the use of ECT, although this is not the first line of therapy.

Of interest in the future, and in need of further study, is the possibility of the so-called cognitive enhancers improving the less classical depressive symptoms interwoven with dementia. Other interventions for mood symptoms not classical of major depressive illness such as mood stabilizers, stimulants, gingko biloba, and dopaminergic medications also need further study. Finally, it is crucial to remember that non-pharmacological interventions can improve the quality of life of demented patients, ameliorate the less classical depressive syndromes, and help families cope better with their stressful task.

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