Classification of Neuropsychiatric Symptoms Requiring Antipsychotic Treatment in Patients with Alzheimer’s Disease: Analysis of the CATIE-AD Study

Abstract

Background:

The Neuropsychiatric Inventory (NPI) comprises 12 items, which were conventionally determined by psychopathological symptoms of patients with dementia. The clinical rating scales with structured questionnaires have been useful to evaluate neuropsychiatric symptoms (NPSs) of patients with dementia over the past twenty year.

Objective:

The aim of this study was to classify the conventional NPSs in patients with Alzheimer’s disease (AD) requiring antipsychotic treatment for their NPSs into distinct clusters to simplify assessment of these numerous symptoms.

Methods:

Twelve items scores (product of severity and frequency of each symptom) in the NPI taken from the baseline visit were classified into subgroups by principle component analysis using data from 421 outpatients with AD enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) Phase 1. Chi square tests were conducted to examine the co-occurrence of the subgroups.

Results:

We found four distinct clusters: aggressiveness (agitation and irritabilities), apathy and eating problems (apathy and appetite/eating disturbance), psychosis (delusions and hallucinations), and emotion and disinhibition (depression, euphoria, and disinhibition). Anxiety, aberrant motor behavior, and sleep disturbance were not included by these clusters. Apathy and eating problems, and emotion and disinhibition co-occurred (p = 0.002), whereas aggressiveness and psychosis occurred independent of the other clusters.

Conclusions:

Four distinct category clusters were identified from NPSs in patients with AD requiring antipsychotic treatment. Future studies should investigate psychosocial backgrounds or risk factors of each distinct cluster, in addition to their longitudinal course over treatment intervention.

Keywords

Alzheimer’s disease delusions neuropsychiatric symptoms principal component analysis

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by episodic memory disorder, visuospatial impairment, attentional impairment, and executive dysfunction [1, 2]. During the course of this disease, various neuropsychiatric symptoms (NPSs) of dementia emerge, including delusions, depression, behavioral disturbances, agitation, sleep disturbances, and eating problems, which in turn increase burden of stress and direct costs of care among caregivers [3 –6]. Thus, clinical rating scales with structured questionnaires are necessitated to evaluate NPSs accurately, which are also important in making an appropriate care plan and predicting the illness development course. One of the rating scales currently used to examine NPSs is the Neuropsychiatric Inventory (NPI) [3]. The NPI comprises 12 items, which were conventionally determined by psychopathological symptoms [7]. Each NPI subscale score (score range: From 0 to 12 points) is described by a product of its disease severity score (score range: From 0 to 3 points) and frequency score (score range: From 0 to 4 points) [3, 7]. The subscale scores have been recommended to evaluate NPSs over the past twenty years [3 , 7–10]. There are several other rating scales that examine NPSs. For example, the Behave-AD was designed to specially reflect and measure characteristic behavioral symptoms in AD in 1987, according to the following seven psychopathological categories: paranoid and delusional ideas, hallucinations, activity disturbances, aggressiveness, diurnal rhythm disturbances, affective disturbances, and anxiety and phobias [11]. Subsequently, ‘apathy’ and ‘disinhibition’ categories were added as Behave-AD subscale items, which led to the completion of NPI concepts.

Previous studies have emphasized the symptomatic variety and heterogeneity of NPSs in AD during the course of disease progression [4, 12]. Thus, the classification of individual NPSs into subgroups is necessitated to allow for clinicians to target distinct psychopathological clusters in their planning of treatments; doing so may lead to the reduction of caregivers’ burden [13 –15]. It is also crucial to elucidate the neurobiological mechanisms underlying heterogeneous NPSs by specifically examining targeted clusters.

Canevelli et al. conducted a systematic review in which previous studies classifying the NPI subscale items of patients with dementia using factor analysis were included [9]. They noted that each of the seven studies included in the review employedprincipal components analysis (PCA) to statistically classify NPSs using NPI items [9 , 13–19]. These studies also showed that 12 subscores were consistently classified into four clusters: psychosis, aggressiveness, affective syndrome, and apathy and eating/appetite problems [9 , 13–19]. However, the characteristics of subjects with AD in previous studies have been heterogeneous in terms of inclusion of both community- or clinical-based subjects, necessity of medication treatment for NPSs, and presence of NPSs [13–17 , 21]. Furthermore, the sample sizes of some studies were comparatively small [14 , 20]. Thus, these limitations warrant further research to classify NPSs into distinct clusters using a large-scale homogenous sample. On the other hand, to the best of our knowledge, no study has investigated independency or co-occurrence of these clusters. Thus, additional studies are necessitated to explore the overlap between each cluster in order to further examine any potential shared etiology between the clusters.

The Clinical Antipsychotic Trials of Intervention Effectiveness - Alzheimer Disease (CATIE-AD) multicenter study was performed in a series of National Institute of Mental Health (NIMH) CATIE trials, which were composed of samples with specific clinical characteristics and ultimately, a comparatively large sample size (n = 421) [22, 23]. The trial protocol was made to examine the effectiveness of atypical antipsychotics for NPSs in patients with AD longitudinally. The dataset of the initial phase provided information regarding background characteristics and NPI scores for each enrolled subject [22, 23]. Thus, the CATIE-AD data is ideal to explore distinct clusters of NPI 12 item scores in this clinically homogenous AD population.

The aim of the present analysis was to classify NPSs into distinct clusters by adapting PCA to NPI 12 item scores in patients with AD who needed antipsychotic treatment for their NPSs using CATIE-AD Phase 1 data (the initial stage). Subsequently, co-occurrence or independency of each cluster or subgroup was also explored.

METHODS

Participants

Four hundred and twenty-one consecutive AD ambulatory outpatients were enrolled in this study. The CATIE-AD trial was conducted between April 2001 and November 2004 at 45 sites. We used the only baseline data of CATIE-AD trial Phase 1, which occurred after the screening eligible subjects. All patients were diagnosed as having dementia of the Alzheimer’s type according to Diagnostic and Statistical Manual of Mental Disorders (DSM-4) or probable AD on the basis of the history, physical examination, and results of structural brain imaging [8, 9]. Regarding psychiatric disorders, patients with drug abuse, delirium, endogenic psychiatric disorders (e.g., schizophrenia or mood disorder), and other dementias (e.g., dementia with Lewy body and vascular dementia) were excluded [22, 23]. Patients were also excluded if they were receiving and benefiting from psychotropic medication treatments. All subjects had attended clinics or hospitals from their living home or were in assisted living homes during the trial term [22, 23]. Severity of psychotic symptoms or aggressive/agitation behaviors in eligible patients with AD was so serious as to cause a trouble in everyday life, and patients needed antipsychotic treatment. Enrolled subjects’ global cognitive state was evaluated by The Mini-Mental State Examination (MMSE: Total score range from 0 to 30) and activity daily living (ADL) was assessed by the Alzheimer’s Disease Cooperative Study (ADCS: total score range from 0 to 78) [22 –24].

Statistical analysis

Each NPI subscore (score range: from 0 to 12 points) was described by the product of its severity and frequency. We used PCA with promax rotation to classify clusters based on 12 NPI item subscores (the range from 0 to 12). If the eigenvalue of one factor was >1, and the absolute value of the factor loadings (FL) was >0.5, we selected the factor as a constituent of a corresponding cluster [25]. The previous seven studies employed a FL threshold of 0.4 or 0.45 [13 –19]; however, in the present study, we selected a higher threshold of 0.5 in order to avoid group classification due to a nonspecific symptom. Subsequently, χ² tests were used to assess the co-occurrence of each cluster. We defined ‘presence’ of each cluster as a score of 1 or higher for the corresponding component factors. In contrast, we defined ‘absence’ as a score of 0 for both corresponding component factors in acluster.

A p value <0.05/6 = 0.008 was considered statistically significant according to Bonferroni correction. Continuous variables were described as mean ± standard deviation. IBM SPSS Statistics for Windows, Version 22.0 (Armonk, NY: IBM Corp.) was used for all the statistical analyses.

RESULT

Patient characteristics

Four hundred and twenty-one patients with AD (235 females; age 77.9 ± 7.5 years) were included in this analysis. Baseline clinical and demographic characteristics are summarized in the Table 1.

PCA for NPI 12-items at baseline (Table 2)

Four optimal clusters were selected using the eigenvalue criteria. These clusters accounted for 54.7% of the variance in NPSs. Kaiser-Meyer-Olkin measure adequacy was 0.72, which indicated the appropriateness of the analysis. The first cluster identified aggressiveness syndrome, composed of agitation/aggression and irritability. The second cluster was apathy and eating problem syndrome, which was made up of apathy and appetite/eating disorders. The third cluster was psychosis syndrome, which was composed of delusions and hallucinations. Finally, the fourth cluster was emotion and disinhibition syndrome, which was made up of depression, euphoria, and disinhibition; the directions of the FL between euphoria (FL = 0.66) or disinhibition (FL = 0.51) and depression (FL = –0.56). The other three NPI items (anxiety, aberrant motor behavior, and sleep disturbance) were not classified into any clusters due to their lower absolute FL values.

Co-occurrence or independency between each cluster

Co-occurrences or independencies of the four clusters were explored. A significant co-occurrence between apathy and eating problem syndrome and emotion and disinhibition syndrome was found (χ² = 9.92; df = 1.00; p = 0.002) (Table 3). No other associations were found between co-occurrence of the clusters (Table 3).

DISCUSSION

The present study classified 12 NPI subscores in patients with AD requiring antipsychotic treatment for their NPSs by applying PCA to a huge dataset of the CATIE-AD trial. We found four distinct clusters: aggressiveness, apathy and eating problems, psychosis, and emotion and disinhibition syndrome. Symptomatic variety and heterogeneity of NPSs have been shown in patients with AD, dependent on the disease progression or the condition of participants in the present investigation [4, 16]. However, classifying 12 NPI subscores into four clusters, which comprise at least two NPI subscore symptoms, is consistent with previous studies, which include a severely demented group (MMSE score less than 10 point) [15], clinic outpatients [13 , 19], or community dwelling volunteers [17]. Our analysis included patients with AD who showed treatment-requiring NPSs and thus further expanded previous findings from differing AD populations in terms of heterogeneous background and severity of dementia which report that 12 NPI items can be classified into four syndromic clusters with PCA [13 –19]. Previous studies have consistently included psychosis, aggressiveness syndrome, and apathy and eating/appetite problems in the four clusters. However, some studies have also noted euphoria-disinhibition syndrome, and other affective syndromes (depression, anxiety) [13 –19].

In line with previous studies, we found that the four clusters included the psychosis cluster and aggressiveness syndrome cluster [13 –19]. It has consistently been noted that the psychosis cluster comprises delusions and hallucinations symptoms, while the aggressiveness syndrome cluster is composed of irritability and agitation subscores, which is compatible with our finding [13–17 , 19]. With regards to apathy and eating problems cluster, while apathy and eating problems have also been classified into separated subgroups in three previous studies [14 , 18], those symptoms constituted one unified subgroup in four other previous studies [13 , 19]. Apathy might be included in affective associate cluster (composed of depression and anxiety) [14, 17], however, whether apathy symptoms are associated with affective-related or behavioral-related problems is presently unclear [13 , 19]. Appetite/eating problem questions for the informant in the NPI consist of three aspects: reduction of appetite, increase of appetite, or eating behavior or food kinds change. In this study, the prevalence of appetite reduction (61%) was higher than that of increased appetite (18.8%) or other appetite/eating problems (from 18 to 46%) (data not shown), which indicates that eating problems may be attributable to the apathy state in the participants within the CATIE AD trial. Thus, these findings support our results that the apathy and eating problems cluster was extracted from the NPI [13 , 19]. On the other hand, the emotion and disinhibition syndromic cluster consisted of euphoria-disinhibition paired-subgroup and depression in the present study, which is not consistent with several previous studies classifying the two symptoms with opposite directions on the same factor axis (euphoria and depression) into separate subgroups [9 , 13–19]. The emotion and disinhibition cluster also did not include anxiety symptoms, even though depression and anxiety have often been classified into the affective or emotional associated cluster in previous studies [9 , 13–19]. Furthermore, three items (anxiety, aberrant motor behavior, and sleep disturbance) among the 12 NPI subscore items were not classified into any clusters, which was comparable to the findings from two previous studies [15, 20]. There are several potential reasons for this difference. Firstly, to avoid the group formation due to a nonspecific symptom, we defined greater than 0.5 as an absolute value of the FL score [25], which is comparatively higher than previous studies [9 , 13–19]. Secondly, the sample within the CATIE AD trial mainly consisted of patients with treatment-requiring psychotic and agitated symptoms. Thus, our cluster classification may have excluded some nonspecific symptoms such as anxiety and sleep disturbance in the NPI.

Among the four clusters, we found a co-occurrence or co-manifestation between the apathy and eating problems and emotion and disinhibition clusters. As neuroanatomical mechanisms of NPSs, the frontal-subcortical circuit damage has been studied in neurodegenerative disorders, including AD, Huntington’s disease, Parkinson’s disease, frontotemporal dementia, and progressive supranuclear palsy [26 –32]. It has been reported that apathy is linked with the anterior cingulate circuit, mood disorder (depression and manic symptoms) with the prefrontal cortex (dorsolateral and orbitofrontal) and caudate nucleus, and disinhibition with the orbitofrontal cortex [26 –31]. Thus, the co-occurrence of the apathy and eating problems syndrome and the emotion and disinhibition syndrome may reflect symptoms originating from the prefrontal cortex dysfunction. In support, depression, but not euphoria, in the NPI subscores was correlated with appetite/eating disorders score (Pearson correlation coefficient: r = 0.21, p < 0.001; not shown data) and apathy score (Pearson correlation coefficient: r = 0.25, p < 0.001; not shown data), which appeared to cause the co-occurrence of the apathy and eating problems and emotion and disinhibition clusters in the present study.

The aggressiveness and psychosis syndrome clusters existed independently among the four clusters, which indicated that these two clusters may be caused due to distinct neuroanatomical pathogenesis. Aggressiveness syndrome in patients with AD has been reported to be associated with medial temporal hypoperfusion [33]. While the mechanisms of psychosis have been discussed in several studies [31], a recent neuroimaging study by the Alzheimer’s Disease Neuroimaging Initiative concluded the frontal metabolic impairment and reduction in working memory as psychosis manifestation pathogenesis in AD [34]. Given that the other two clusters may be related to the frontal dysfunction as described before, it may be difficult to explain the independency between psychosis and the other clusters only with brain anatomical viewpoints. Taking neurotransmitters into account, it has been reported that psychosis in AD is associated with the relative preservation of norepinephrine in the substantia nigra, while aggressive behavior negatively correlated with a ratio of choline acetyltransferase per dopamine activity in the temporal cortex of AD postmortem brains [35, 36]. It has been noted that depression is associated with abnormalities in the serotonergic system, including decreased cortical serotonin reuptake sites, receptors, and locus coeruleus cells within postmortem AD brains [31]. Moreover, apathy was previously reported to be associated with dopaminergic neuron hypofunction in the mesolimbic reward system [37]. Thus, both psychosis and aggressiveness syndrome clusters may be associated with distinct mechanisms in terms of neurotransmitters and brain circuits in patients with AD. Taking this account, based on their distinct pathophysiologies, clinicians should consider developing treatmentinterventions.

The present study has some limitations. Firstly, the CATIE-AD trial enrolled subjects both with moderate cognitive impairment (mean MMSE score = about 15 points) and with psychosis or aggressiveness symptoms that needed medical treatment [26]. Importantly, patients were also capable of visiting a hospital to receive treatment. Thus, the results of the present study may not be generalizable to community-based subjects with mild NPS [17, 21]. Secondly, we did not focus on the psychosocial factors in the present study. For example, as psychosocial mechanism, the presence of companion including caregiver or environmental factors may influence the NPSs occurrence. In the present study, the association between psychosocial factors and NPSs has not been investigated, which should be studied in the future study[38, 39].

In conclusion, this analysis found that 12 conventional NPI subscores can be classified into four distinct clusters— aggressiveness, apathy and eating problems, psychosis, and emotion and disinhibition— in patients with AD requiring antipsychotic treatment for their NPSs using PCA on a huge dataset of the CATIE-AD trial. Given that each NPS cluster may be linked with distinct neurobiological or psychosocial pathogenesis, it may be useful for clinicians to decide pharmacological interventions or long-term care plans for each syndrome cluster. Furthermore, these clusters may serve as simple treatment outcomes for clinicians to quickly assess longitudinal effects of antipsychotic treatments. Future research is warranted to longitudinally investigate clinical trajectories, treatment responses, and biological characteristics specific to these NPS clusters in patients with AD who present with NPSs that require antipsychotictreatment.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://www.j-alz.com/manuscript-disclosures/15-0869r1).

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