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Behavioral and Psychological Symptoms of Dementia and Bipolar Spectrum Disorders: Review of the Evidence of a Relationship and Treatment Implications


Jean-Michel Dorey, MD, MS, Olivier Beauchet, MD, PhD, Catherine Thomas Anterion, MD, Isabelle Rouch, MD, Pierre Krolak-Salmon, MD, PhD, Jacques Gaucher, PhD, RĂ©gis Gonthier, MD, PhD, and Hagop S. Akiskal, MD


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CNS Spectr. 2008;13(9):796-803



Faculty Affiliations and Disclosures

Dr. Dorey is in the Department of Geriatrics at Saint-Etienne University Hospitals in France and is in the Santé Individu Société (SIS) Unit at LYON 2  Lumière University in France. Dr. Beauchet is in the Department of Internal Medicine and Geriatrics at Angers University hospital in France. Dr. Thomas-Anterion is in the Department of Neurology/Neuropsychology-CMRR Unit at Saint-Etienne University Hospitals. Dr. Rouch is in the Department of Neurology/Neuropsychology-CMRR Unit at Saint-Etienne University Hospitals. Dr. Krolak-Salmon is the Charpennes Geriatrics hospital at the Hospices civils de Lyon  and in the Dynamique cérébrale et cognition unit at Lyon1 Claude Bernard University at the Vinatier Hospital in France. Dr. Gaucher is in the SIS unit at LYON 2  Lumière University. Dr. Gonthier is in the Department of Geriatrics at the Saint-Etienne University Hospitals and is in the SIS unit at LYON 2  Lumière University. Dr. Akiskal is professor of psychiatry and director of International Mood Center at the University of California in San Diego in San Diego.

Faculty Disclosure: Drs. Dorey, Beauchet, Anterion, Rouch, Krolak-Salmon, Gaucher, and Gonthier do not have an affiliation with or financial interest in any oprganization that might pose a conflict of interest. Dr. Akiskal is a member of the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and GlaxoSmithKline.

Submitted for publication: June 10, 2008; Accepted for publication: August 21, 2008.

Please direct all correspondence to: Jean-Michel Dorey, MD, MS, Department of Geriatrics, Saint-Etienne University Hospitals, 42055 Saint-Etienne Cedex 2, France; Tel: 334-77-12-71-09; E-mail: j.michel.dorey@chu-st-etienne.fr.


Focus Points

• Treatment of behavioral and psychological symptoms of dementia (BPSD) is complex and often needs recourse to psychotropic drugs, although there is no consensus concerning their use.
• A better understanding of BPSD etiology could lead to better management strategies.
• After reviewing the concept of the bipolar spectrum disorder, some BPSD could be the common clinical expression of both dementia and an undiagnosed comorbid bipolar spectrum disorder.

 

Abstract

Dementia is a neuropsychiatric disorder characterized by cognitive impairment and behavioral disturbances. The behavioral and psychological symptoms of dementia (BPSD) are common, contributing to caregiver burden and premature institutionalization. Management of BPSD is complex and often needs recourse to psychotropic drugs. Though widely prescribed, there is a lack of consensus concerning their use, and serious side effects are frequent. This is particularly the case with antidepressant treatment based on the assumption that BPSD is depressive in nature. A better understanding of BPSD etiology could lead to better management strategies. We submit that some BPSD could be the consequence of both dementia and an undiagnosed comorbid bipolar spectrum disorder, or a pre-existing bipolar diathesis pathoplastically altering the clinical expression of dementia. The existence of such a relationship is based on clinical observation, as far as the high frequency of bipolar spectrum disorders in the general population, with a prevalence estimated to be between 5.4% and 8.3%, and the psychopathological similarities between BPSD and mood disorder episodes in bipolar illness. We will review the concept of the bipolar spectrum and explain BPSD before proposing clinical pointers of a possible bipolar spectrum contaminating the phenomenology of dementia, which could lead to the targeted prescription of mood-stabilizing agents in lieu of antidepressant monotherapy. These considerations are of heuristic interest in reconceptualizing the origin of the behavioral manifestations of dementia, with important implications for geriatric practice.

Introduction

Behavioral and emotional symptoms are prevalent in progressive dementia, whatever their etiology and the stage of dementia.1 Up to 90% of demented subjects experience these non-cognitive symptoms.2,3 Though disparate, they are grouped under the heading of behavioral and psychological symptoms of dementia (BPSD).4 Patient management and quality of life for their families are conditioned by their presence and intensity.5,6 Consequently, one of the management issues in treating dementia focuses on the often complex and difficult treatment of BPSD. This must, above all, be preventive and is based both on pharmacologic strategies, using specific anti-dementia agents and non-pharmacologic strategies through a psychosocial approach.7 Once these disturbances have set in, recourse to psychotropic medications is often inevitable. Though widely prescribed, there is nevertheless a lack of consensus concerning their use. Variable in effectiveness and widely disputed, they also expose patients to a significant risk of possible serious side effects.8

We need to improve our diagnostic and therapeutic practice by trying to define prescription criteria. The hypothesis that some BPSD could be the common clinical expression of both cognitive deterioration and unrecognized comorbidity with a bipolar spectrum disorder may be advanced. According to this hypothesis, the targeted use of mood stabilizers in dementia patients with a comorbid bipolar spectrum disorder could have a beneficial effect on BPSD. We will review the concept of bipolar spectrum and explain BPSD before proposing some clinical pointers of a possible bipolar spectrum disorder in dementia, which could lead to the targeted prescription of mood stabilizers. Although “personality change” is more characteristic in Pick’s disease (Presenile dementia), our clinical experience suggests that the interaction of premorbid bipolartemparament with Alzheimer’s disease too can lead to sexual disinhibition and related disinhibited behaviors.


Bipolar Disorder, Bipolar Spectrum, and Affective Temperaments

Bipolar illness is a mood disorder characterized by the succession of depressive episodes and excited periods of more or less regular intervals. Its description depends on the rapidity of cycling, whether there is a mixed affective state or not, and the severity of the episodes. The etiopathogenesis of bipolar disorders is based both on inherited vulnerability and epigenetic factors. The search for a family history is an important part of the diagnostic process.
Already hinted at by Kraepelin, the concept of a “milder” form of bipolar disorder was raised again by Dunner and colleagues,9 who first identified bipolar I and bipolar II disorders. Both forms are defined by the presence of at least one depressive episode, but can be distinguished by the intensity of excited periods: in  bipolar I disorder there is severe mania sometimes accompanied by psychotic symptoms, while in bipolar II disorder excitement is less severe, just below the threshold of mania (hypomania), with less interpersonal disturbance. Since then, the bipolar spectrum has gradually been expanded to include subsyndromal and atypical forms of hypomania. The definition of bipolar spectrum continues to develop with variations depending on the authors.10-13 Table 1 lists the various possible clinical presentations of the bipolar spectrum according to a consensus review performed by Akiskal and colleagues with European and United States collaboration.14 These authors consider the minimum 4-day cutoff criteria for hypomania required in the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition to be too long; they propose a duration of 2 days, and even as short as 1 day, for the brief recurrent hypomania subtype. Unlike the DSM-IV, these authors consider hypomania occasioned by antidepressant treatment to belong to the bipolar spectrum. Subsequent research has supported this contention.15



Prevalence of bipolar I and bipolar II disorders in the general population is estimated as being between 1% and 1.6%.16-17 Studies by Angst18 and Judd and Akiskal19 have redefined the epidemiologic boundaries of bipolar spectrum disorders. In addition to manic and hypomanic episodes, they include brief hypomanic episodes (whether recurrent or not) for Angst,18 and subsyndromal episodes for Judd and Akiskal19 (ie, fulfilling only two DSM-IV criteria for manic or hypomanic episodes). Prevalences rates found were 8.3% and 6.4%, respectively, suggesting the considerable underestimation of bipolar disorders in the general population. In subjects presenting brief hypomania, the presence of a family history of depression or mania, personal history of depression, substance abuse (smoking, alcohol, cannabis), and anxiety disorders was significantly higher than in the control subjects.18 In both Angst’s brief hypomania group18 and Judd and Akiskal’s subsyndromal hypomania group,19 the prevalence of suicide attempts was high, reaching a relative risk of 4 compared with the controls. The psychosocial impact of the subsyndromal forms of hypomania showed increased use of welfare services, hospitalizations, rates of celibacy and divorce. Using a more conservative threshold for bipolar I and bipolar II disorders, the latest figure on the US population for bipolar spectrum is 5.4%.20 These three studies18-20 support and validate the clinical relevance of the concepts of bipolar spectrum and soft bipolarity as originally proposed by the senior author.10,12

While the diagnosis of bipolar disorder can be obvious in its most typical forms, it is far more problematic when the clinical presentation departs from bipolar I disorder and the manic symptoms are not clear cut.21 Often episodes of mild hypomania and cyclothymic oscillations are not found in the case history, as the patient either forgets them or does not consider them to be an illness.22 Furthermore, often narcissistic personality is invoked in lieu of an energetic-confident, lifelong hyperthymic temperament.23

Bipolar depression could be regularly mistaken for unipolar depression. The French EDIDEP study24,25 showed that diagnosis of bipolar disorder rose from 21% to ~40% in patients presenting with depressive syndrome after a systematic search for a history of hypomania according to DSM-IV criteria. The final reports from the national EPIDEP project, which considered all possible clinical refinements in the bipolar spectrum diagnostic process, places the rate of bipolar spectrum in patients presenting to psychiatrists, both outpatient and inpatient, with major depression at 65%.26

The bipolar nature of depression must also be considered based on specific psychopathological features. Borderline personality patients present a frequent source of error as their clinical presentation is often close to that of the bipolar spectrum.27 According to Akiskal and colleagues,28 25% of the consultations in psychiatry for a diagnosis of borderline personality show criteria for bipolar II disorder or cyclothymia after a few months of follow-up. Substance abuse, anxiety disorder, and obsessive-compulsive disorder comorbidity are common in bipolar disorders and can mask the diagnosis.21,29 Overall, bipolar disorder, though widespread, is vastly underdiagnosed and undertreated.

In close connection with bipolar spectrum disorders, and as already hinted (Table 1), certain temperaments could represent a phenotypic form of pre-bipolar state. Cyclothymia involves alternating periods of hypomania and subclinical depression, without ever meeting the diagnostic thresholds for the full disease. Moreover, in the ICD-1030 and DSM-IV,31 cyclothymic disorder is classified under the bipolar disorder. According to the predominant affective tendencies in cyclothymic patients, Akiskal and colleagues32 identify hyperthymic, irritable, depressive temperaments, and purely cyclothymic. The connection between these subaffective temperaments and bipolarity is now established.33 Although progression to a bipolar disorder is not always observed, subaffective temperaments are considered either as a risk factor or as a softer form of bipolar disorder, most often bipolar II disorder,14 with the diagnosis only being made largely after the onset of a typical depressive episode. The expression of bipolar disorder in subjects presenting such temperamental vulnerabilities could be environmentally context-dependent, acting either as a protective factor or as a precipitating factor.


Behavioral and Psychological Symptoms of Dementia

Dementia, with Alzheimer’s disease at the top of the list, is a frequent disorder in subjects >65 years of age and prevalence increases with age.34 More than the cognitive deterioration and loss of autonomy, difficulties in managing these patients are mainly due to the presence of BPSD. They are present in 50% to 90% of cases1 and become more pronounced as cognitive decline progresses. It has been shown that the inter-individual variability may be considerable. Some patients develop severe disorders from the early stage of Alzheimer’s disease, while the clinical presentation in others is less striking, despite severe deterioration.35

The impact of BPSD on patients’ families varies depending on the type of disorder presented: apathy, depression and anxiety are better tolerated than wandering, psychotic symptoms and aggressiveness.36 Several studies have demonstrated the negative effects of behavior disorders on the patients and their home and/or institutional environment. Thus, early onset, frequency, and intensity of BPSD are associated with the worsening of difficulties with activities of daily living,1 more rapid cognitive deterioration,37 increased risk of hospitalization and premature institutionalization.5 BPSD relates to caregiver burden, depression, and diminished quality of life.6,38 The prevalence of BPSD in institutions is high, first because of more marked cognitive deterioration and secondly because placement is motivated or generally accelerated by BPSD. Patients with BPSD create difficulties for caregivers and hamper coexistence with the other patients with a risk of destabilizing the latter.
   
After excluding complex partial seizures, cerebrovascular lesions, systemic disease, and iatrogenic causes have been ruled out, the management of behavioral symptoms uses two main therapeutic approaches.36  The first, a non-pharmacologic approach, is focused on prevention, information, support, and psychosocial management of patients and their families.7,39 A pharmacologic approach, which may be categorized into two possible options. On the one hand, specific non-curative treatments for dementia that supposedly slow the rate of cognitive decline and consequently delay the appearance of behavioral disorders. These treatments are represented by acetylcholinesterase inhibitors40 and in the last few years by memantine.41 On the other hand, once the disorders have set in, the use of non-specific psychotropics to treat symptoms is frequent. However, in dementia there is no consensus on prescription criteria, and their use exposes patients to a significant risk of untoward effects,8 of which the most grave is increased cardiovascular death from the use of antipsycjotics (inclusive of atypicals).

Schneider and colleagues,42 in a study of the effectiveness of antipsychotics in dementia, advised that prescriptions be continued only in responsive patients after an assessment of risks and benefits. Would it be possible to optimize pharmacologic treatment not only according to the symptoms observed, expected benefits and side effects, but also taking into account the underlying psychopathological diathesis? We should not lose sight of the fact that psychotropic drugs are, above, all indicated in psychiatry.

Bipolar Disorder and BPSD

BPSD belong by definition to the domain of dementia. However, the symptoms that constitute BPSD, whether affective, psychotic, or behavioral, belong to the domain of psychiatric disease. The psychiatric component of BPSD is far too often overlooked in favor of the cognitive one. One of the reasons undoubtedly lies in the DSM-IV hierarchical diagnostic criteria43 that rule out a psychiatric cause if an organic cause better explains the signs observed. A related explanation could be that the condition is considered from a purely neurological standpoint or rather completely ignores psychiatric components. However, the possibility of neurological and psychiatric comorbidity should always be considered.

The hypothesis of a bipolar disorder/dementia interrelationship seems to be a promising line of thought toward the better understanding and management of some BPSD. Akiskal and colleagues44 suggested that a particular form of bipolar disorder accompanied by cognitive symptoms exists in elderly subjects. This clinical presentation associates mood instability, irritability, and memory disorders, and occurs in a temperament described as “energetic” with a tendency to overactivity. Antidepressants seem to worsen the disorders. Tentatively considered a bipolar VI disorder, this condition is in the clinical interface of bipolarity and dementia, typically in the early course of dementia. With the progression of cognitive decline, depression and other affective symptoms recede.

Rather than distinguish a new subtype of bipolar disorder, in this collaboration with our French geriatric group, in this article the foregoing interface is being hypothesized to represent cognitive dysfunction destabilizing or even unmasking a preexisting and undiagnosed mood vulnerability. Some BPSD could thus be the combined symptomatic expression of dementia and an associated mood disorder. Affective episodes, mixed or hypo-manic, may have occurred in the past, but what we are considering here as more typical are subthreshold and more subtle manifestations of pre-existing bipolarity. This hypothesis is based on the frequency of bipolar spectrum disorders in the general population (prevalence between 6.4% and 8.3%), the large number of undiagnosed patients and the clinical similarities between BPSD and the mood disorder episodes in bipolar illness.

The behavioral disorders observed in Alzheimer’s disease are multidimensional. Subsumed under the generic term of BPSD, a wide range of disorders and symptoms exists which can be classified in four dimensions: affective disorders, psychotic disorders or distortions of reality, behavioral disorders in the strict sense, and modifications in instinctive actions. The NeuroPsychiatric Inventory (NPI) scale45 distinguishes 12 behavioral dimensions, which are listed and classified in Table 2.



The affective disorders of BPSD are nonspecific and may be a component of a mood, manic, or depressive episode in a bipolar illness. Inappropriate motor behavior could be a form of disorganized hyperactivity. Delusional ideas are present in both disorders with themes that are often similar; the denial and anosognosia of dementia can be confused with the omnipotence of mania. Prodigality and excessive spending are typical of mania, but can also be a reflection of disturbed discernment in dementia. Familiarity, joviality and the loss of social etiquette could well be a component of frontal region symptoms and also be secondary to an overexcited mood. Sleep disturbance is a fundamental finding in the diagnosis of mood disorders and occurs commonly during the progression of dementia. According to Akiskal and colleagues,44 even though some authors consider BPSD to be the direct outcome of a neurodegenerative process, they could also just as well be the reflection of previous temperament exacerbation.

Once dementia has set in, the search for bipolar spectrum comorbidity becomes complex as the affective symptoms are masked and transformed by the prism of mental deterioration. Moreover, regardless of the cognitive disorder, the additional effect of age can also modify the clinical presentation of bipolar disorders with a greater frequency of mixed episodes and rapid cycling according to some authors.46

Parallel to clinical observation, exhaustive exploration of the patient’s past history is thus necessary in search of signs indicating an unrecognized bipolar disorder. Interviewing family members enables cross-checking of information, limits memory bias due to cognitive decline, and provides a more objective evaluation of the patient’s previous personality. This approach, following the standard psychiatric interview model, consists of nvestigating and taking specific note of psychiatric history: depression, suicide attempts, treatments with psychotropic drugs, hospitalizations, anxiety disorders, alcoholism and substance abuse. Describing the premorbid personality in search of cyclothymic disorder or affective temperament at risk for bipolarity (Akiskal and Mallya’s12 descriptions of the cyclothymic and hyperthymic temperaments the most often associated with bipolarity are listed in Tables 3 and 4). Retracing their life history in search of life events that could have been the consequences of inappropriate behavior or disturbance of interpersonal relations: celibacy, repeated separations, divorce, frequent conflicts, multiple house moves, unemployment, criminal acts and so on. Drawing the family tree in search of a family history of depression, bipolar disorders, suicide attempts and suicides, anxiety disorders, hospitalizations, treatments with psychotropic drugs, and alcoholism and other substance abuse. As the patients are generally advanced in age, a wealth of information can be obtained from several generations of both ascendants and descendants.





In clinical practice, it could be considered that the presence of BPSD with affective features, the existence of a premorbid personality at risk of bipolarity, knowledge of behavior with negative psychosocial or handicapping consequences, and existence of a family history are arguments indicating the diagnosis of a possible bipolar spectrum disorder concomitant with dementia. This retrospective diagnosis of bipolar spectrum mood disorder may seem to be rash. However, considering the not infrequent dramatic consequences of BPSD and the absence of specific treatments, recognizing such a disorder provides a chance for the patient and family, whereby etiology-based therapy can then be envisaged.

Medical Treatment Implications

Documentation on the use of mood stabilizers in older adults with bipolar disorder is scarce.47 In standard practice, titration is slower and the maximum dose is lower. Three types of drugs are available: lithium salts, anticonvulsants, and antipsychotics. Lithium is rarely prescribed because its use after 70 years of age is complicated by frequent side effects and a risk of neurotoxicity. The main anticonvulsants used are carbamazepine and valproate. Valproate is usually well tolerated. The most frequently reported side effects are sedation, tremor, weight gain, and drug interactions. Therefore, it could be the reference treatment for bipolar disorders in elderly subjects, as it is better tolerated than carbamazepine.48 Antipsychotics are indicated in the presence of psychotic symptoms associated with mania or depression or, in the case of agitation, in addition to another mood stabilizer.49

Some studies deal with the effectiveness of valproate in the treatment of BPSD. Meinhold and colleagues50 showed a dose-dependent beneficial effect of valproate on behavioral disorders, delirium, and sleep disturbance. Tariot and colleagues51 found a significant diminution in agitation in dementia patients with symptoms of mania; however, the study did not run to its full length because of somnolent-type of side effects. Porsteinsson and colleagues52 concluded that valproate conferred a moderate diminution in agitation. However, studies by Sival and colleagues53 and Tariot and colleagues54 did not show superiority of valproate over placebo.

To date, publications concerning the relevance of valproate in BPSD are not conclusive.55 They show contradictory results yet, except for the study by Tariot and colleagues,51 which included dementia patients with symptoms of mania, the indication for mood stabilizers is based only on the presence of BPSD regardless of the underlying psychiatric diathesis. For this reason, in the specific context of BPSD with possible comorbid underlying bipolar disorder, we propose that valproate could prove to be more effective. An obstacle to its prescription could be the onset of side effects and in particular drowsiness. The gradual uptitration by 125–250 mg/day to a maximum dose of between 500 mg and 1,000 mg/day improve tolerability.47

If considering the possibility of dementia/bipolar disorder comorbidity results in the targeted prescription of a mood stabilizer, then the role of antidepressants must also be reconsidered. The latter are frequently administered during disease progression. In bipolar patients their administration involves the risk of conversion to mania which, in the context of dementia, would be expressed by a worsening of BPSD. Inversely, the onset of agitation under antidepressant treatment in a patient with dementia should prompt the search for an underlying bipolar spectrum disorder.

Conclusion

The present overview emerged independently from the French team, based on their clinical observations in geriatric practice, while acknowledging the previous work of Akiskal with Brazilian collaboration.44 In this review we have suggested that behavioral and affective dysregulation in early dementia patients should be conceptualized to include the likelihood of comorbid or pre-existing  bipolar dysregulation to its origin. Some BPSD could be the consequence of both dementia and an undiagnosed comorbid or pre-morbid bipolar spectrum diathesis.

The existence of such a relationship is based on clinical observation,  as far the high frequency of bipolar spectrum disorders in the general population (prevalence between 5.4% and 8.3%), and the psychopathological similarities between BPSD and mood disorder episodes in bipolar illness. History taking must be extremely thorough to unearth elements indicating bipolarity in the psychiatric history, description of the premorbid personality or temperament, life history or a family history of mood disorders, and more specifically that of familial bipolarity. Depending on the data obtained, the retrospective diagnosis of possible comorbid or premorbid bipolar disorder can be made that could be postulated to be contributory to the affective dysregulation in the dementia patient.

The significance of this approach is twofold: introducing a more specific psychotropic treatment that could be effective in the particular context of BPSD comorbidity with bipolar disorder; and avoiding the prescription of a potentially iatrogenic antidepressant with the risk of conversion to excitability, hypomania or mania.

This hypothesis of a relationship between BPSD and comorbid bipolar spectrum disorders raises questions: Is the risk of BPSD higher in bipolar spectrum disorders? Do they have an effect on the early onset of BPSD? Are there specific signs of BPSD associated with bipolar spectrum disorders? While the indication for mood stabilizers seems logical and clinically intuitive in these patients, it must be validated by future clinical, familial-genetic and psychopharmacologic investigation.

Addendum

After this paper was submitted to CNS Spectrums, a case series illustrating the bipolar spectrum dementia interface appeared in the literature.56

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