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Keywords:

  • atypical antipsychotics;
  • CATIE-AD;
  • cognition;
  • dementia with Lewy bodies;
  • neurodegenerative disorders;
  • quetiapine

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

A recent large-scale randomized controlled clinical trial, the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study, found a significant worsening of cognitive functioning in a sample of patients with Alzheimer's disease. To date there have been no equally powered studies examining the cognitive effects of atypical antipsychotics in patients with dementia with Lewy bodies, the second most prevalent neurodegenerative disorder. This case report describes a significant cognitive improvement observed through the use of an atypical antipsychotic in a patient with dementia with Lewy bodies. The observed divergence in cognitive responsiveness is discussed mechanistically on both the clinical and neuromolecular level. Limitations to this case study design are presented and discussed. The prudence of caution in importing the results of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study to the dementia with Lewy bodies population is summarized and presented for psychiatrists, neurologists and primary care providers, with an intent to stimulate discussion and further research.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

The discouraging results of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study (CATIE-AD) have sombre clinical implications for psychiatrists, neurologists and family care providers. This randomized controlled trial of 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behaviour found that the use of atypical antipsychotics for management over 36 weeks was associated with worsening cognitive function at a magnitude consistent with 1 year's deterioration as compared to placebo.1 The observed 2.4 point average decline in the Mini-Mental State Examination (MMSE) score consolidates the similar outcome of two less-powered studies of cognitive response to atypical antipsychotics within the Alzheimer's disease population.2–4 Though this finding will inform the evidence-based management of Alzheimer's disease, clinicians should proceed cautiously in generalizing the CATIE-AD results to the general geriatric populations with neurodegenerative dementia.

Dementia with Lewy bodies (DLB), the second most prevalent neurodegenerative disease,5,6 is defined by a degenerative pathology in which there is sufficient reason to believe an alternate cognitive responsiveness to atypical antipsychotics may be observed. Empirical data within the DLB population are limited. The current model of atypical antipsychotics' cognitive effects in DLB primarily derives from studies of patients with schizophrenia and, now, the CATIE-AD.7–10 Given this dearth of empirical evidence, it is anticipated some clinicians may apply these findings in the treatment of the DLB geropsychiatric population and moderate the use of antipsychotics so as not to further worsen progressive cognitive decline.

This case presentation of significant observed cognitive improvement in a patient with DLB treated with atypical antipsychotics for psychosis, agitated, aggressive behaviour, and, initially, delirium intends to caution against this clinical response prior to the study and publication of stronger evidence within the DLB population. This case study intends to stimulate discussion and to encourage clinicians and researches to consider the magnitude of need for observational and/or randomized controlled trials examining the cognitive effect of atypical antipsychotics within the sizable DLB population. The neurochemistry that underlines the core features of DLB, which includes irregular diurnal cognitive fluctuations, rapid eye movement behaviour disorder and prominent, complex visual hallucinations,11,12 is susceptible to antipsychotics. This specific symptom susceptibility may account for a significant response difference compared to that observed in patients with Alzheimer's dementia. Indeed, the two trials, which incidentally report the MMSE score response to antipsychotics as compared to placebo in DLB, both found no significant decline in score.13,14 One of the studies found a mean 2.4 improvement in MMSE over placebo in the lowest-dose treatment arm with 5-mg olanzapine.14 The significant MMSE response in our presentation, 18 points over 3 weeks, suggests that the antipsychotic cognitive impact in DLB may in fact be of even greater magnitude in select patients.

CASE REPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

In 2011, a 60-year-old, right-handed retired manual labourer with 1 year of secondary education who had been diagnosed with dementia with Lewy body (DLB) presented to a New York City hospital with visual hallucinations. History confirmed by the patient's family revealed that his first symptoms of cognitive decline had occurred in 1997. Initial symptoms included misplacement of objects such as keys, frequent subjective uncertainty whether appliances were left on or doors were properly locked, and other complaints consistent with mild cognitive impairment.

The first symptom to initiate clinical attention was the development of violent parasomnias in 2004. A sleep study at that time revealed random eye movement dissociation as well as random eye movement-predominant obstructive sleep apnoea. The patient attended four outpatient psychiatric appointments where he was preliminarily diagnosed with major depressive disorder and psychosis not otherwise specified. The patient had a poor response to a selective serotonin reuptake inhibitor trial and was lost at follow-up.

In 2007, the patient lost the ability to manage his finances. He became increasingly paranoid, irritable and enveloped within jealous delusions. The patient experienced hallucinations of perceived lascivious male intruders carousing in the house. In one episode the patient drew a kitchen knife and attacked a bed pillow while narrowly missing his wife. The patient subsequently presented to a neurologist where an unremarkable computed tomography scan of the head and serum markers including vitamin B12, vitamin B1, thyroid function, rapid plasma reagent, complete blood count, and a comprehensive metabolic panel were found without abnormalities and ruled out reversible causes of dementia. Low-dose trials of various psychotropic classes failed to produce improvement, and the diagnosis of DLB was made based on consensus criteria for the clinical diagnosis of DLB as outlined by McKeith et al.15 Since 1997, the patient manifested progressive, fluctuating cognitive decline as described above, which has interfered with his social functioning as evidenced by severe short- and long-term memory loss as well as by visuospatial and executive deficits as exemplified by his inability to button his shirt or put on a tie. The patient also intermittently struggled with motor symptoms and signs of Parkinson's disease such as rigidity, shuffling gait, difficulty initiating movement, and a resting tremor that at times would together lead to imbalance and subsequent falls. The patient had no known history of central nervous system damage, such as stroke, trauma or mass effect, or medical or psychiatric history. The patient has no known family history of psychiatry disorders.

In 2011, the patient was hospitalized for increased agitation in the context of the above symptoms. He was discharged after a short stay and was given an oral medication regimen of twice daily dosing of carbidopa/levodopa 25/100 mg, gabapentin 200 mg, and quetiapine 50 mg, a morning dosing of diphenhydramine 25mg, and a bedtime dosing of clonazepam 0.5 mg. Within 1 week, the patient presented to our services after tearing gas pipes from the walls of his home. The patient provided the explanatory chief complaint of, ‘I wanted to let the worms out of there’.

On admission, the patient was found to have moderate parkinsonian symptoms including cogwheel rigidity and bradykinesia, frontal lobe release signs including positive palmomental reflex and snout reflex, and symptoms consistent with delirium. The patient was oriented to person only, had grossly dysarthric and disorganized speech, and was too inattentive to produce a valid MMSE score. Additionally, the patient's psychiatric symptoms corresponded to approximate Neuropsychiatric Index scores of 23 in severity and 38 in distress, with predominant contribution perceptual disturbances, disinhibited affect and behaviour, and psychomotor agitation. The patient's medication regimen was changed to quetiapine 100 mg in the morning and 200 mg at bedtime, as well as 100 mg every 4 h as needed for psychotic agitation with good resolution of parkinsonian kinsonian symptoms. He received daily serial MMSE testing administered consistently between 0800 and 1000 hours to monitor for diurnal cognitive fluctuations. Results are graphically represented in Figure 1. The first valid MMSE was produced on hospital day 5.

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Figure 1. Mini-Mental State Examination subsection scores by hospitalization day.

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Subsequent titration to 200-mg quetiapine in the morning and 300 mg at bedtime, initiated on hospital day 7, reproduced parkinsonism and cognitive impairment, and the patient's regimen was reverted on hospital day 9. The patient's cognition rapidly improved on this regiment, as evidenced by increasing MMSE scores in the domains of orientation to place, year, month, date, day, registration and recall, attention, calculation, and language with concurrent improvement of behavioural control and organization of behaviour and thought process. By hospital day 9 the patient's agitated episodes were reduced to no more than one episode a day, usually between the 1300 and 1600 hours. An increase in the patient's quetiapine regimen to 100 mg in the morning and 300 mg at bedtime on hospital day 10 was employed to target afternoon symptom exacerbations. This remained the patient's final atypical antipsychotic regimen. On hospital day 10, citalopram, donepezil and memantadine were introduced and slowly titrated.

The patient was discharged following the final recorded MMSE score of 24 with a full sustained remission of all symptoms of disorientation and agitation, complex visual hallucinations, and dependence on others in basic activities of daily living. Neurological exam on discharge did not show any motor sign changes. The patient was cooperative, well-related, fluent, goal directed, and with excellent insight into his prior hallucinations. His Neuropsychiatric Index score improved to a severity level of 2 and distress level of 4, with negligible anxiety and rare night-time disturbances, with complete resolution of all neuropsychiatric symptoms present on admission. Whereas long-term skilled nursing facility placement had been the presumed dispositional plan, the patient's clinical improvement allowed discharge home, with enrolment in an adult day program (Table 1).

Table 1. Schedule of quietiapine titration and Neuropsychiatric Index (NPI) severity and distress levels
 Day 1Day 5Day 7Day 8Day 11Day 12Day 14Day 15Day 18Day 19Day 20Day 41
Quietiapine titration, morning/evening (mg)100/200100/200200/300200/300100/200100/200100/200100/200100/200100/200100/200100/200
NPI severity level232314633322222
NPI distress level383010855555554

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES

This case report suggests an alternant cognitive responsiveness to atypical antipsychotics than that observed in Alzheimer's dementia patients in the CATE-AD. This study reinforces the need for observational studies and clinical trials that directly investigate the cognitive effects of atypical antipsychotics in patients with DLB.

Antipsychotic management of DLB is challenging given this population's propensity to develop unfavourable motor side effects and its greater risk of antipsychotic hypersensitivity relative to the other neurodegenerative populations.16 Our report demonstrates both the feasibility and rationale of overcoming this perceived clinical barrier: significant cognitive benefit may result from treatment with atypical antipsychotics in DLB in addition to these medication class' well-known efficacy behavioural disorganization, perceptual disturbance, and agitation. Whereas several trials have suggested a positive cognitive impact of antidepressants, acetylcholine esterase inhibitors, and memantadine,17–19 few studies have reported the suggested cognitive benefit of antipsychotics, and those that do rarely have emphasized this important finding. For example, a prior case report in Psychogeriatrics, in which an antipsychotic-predominant medication regimen in a patient with DLB was correlated with a rise in MMSE from 24/30 to 30/30, only briefly mentioned this important finding.20

Many clinicians, including Baskys, recommend limiting management to certain antipsychotics.21 The earlier and more extensive degeneration of dopaminergic and cholinergic pathways, as opposed to other neurotransmitter systems, restricts the use of high-potency antipsychotics such as haloperidol because of the greater incidence of extrapyramidal symptoms and neuroleptic malignant syndrome within their use. Even atypical antipsychotics such as olanzapine appear to be poorly tolerated in DLB patients. Quetiapine is the only antipsychotic found to relieve visual hallucinations without a significant increase in extrapyramidal symptoms.21,22 Quetiapine's sedative effects may be used to assist with sleep-cycle stabilization when administered in evening dosing regimens.23 A randomized, double-blind, placebo-controlled study by Kurlan et al. showed that quetiapine is well-tolerated in DLB patients: there was no significant increase in adverse effects in this study's quetiapine-treated group compared to its control group.24

Mechanistic correlations extrapolated from our study may be of interest to the biomedical research community. Several recent translational studies employing functional neuroimaging have suggested that occipital lobe hypoperfusion may be a unique feature in DLB,25 and this finding may be related to the pathophysiology of complex visual-perceptual disturbances and cognitive impairment observed in DLB. Ligand-binding imaging studies implicate serotonin 2A receptor system hyperactivity in DLB patients, especially the subgroup of patients with prominent, complex hallucinations.26–28 It is plausible that the use of quetiapine, a well-studied serotonin 2A receptor antagonist, may normalize serotonin 2A dysfunction and therein produce cognitive restoration. An alternate mechanism may derive from a reduction in hallucinatory distractibility or from circadian rhythm stabilization, and not via direct effect of antipsychotics on the DLB disease process.29 It is likely that cognitive benefits derive from contributions from both mechanisms, as well as from other yet-discovered effects upon neurotransmitter networks.

There are several limitations to this case report. The causality of our patient's cognitive improvement was confounded by several variables that were clinically necessary in the course of his hospitalization. It is plausible that the discontinuation of the patient's prior medication regimen, especially the carbidopa/levodopa component, contributed to the observed cognitive improvement. However, any discontinuation effect would have been observed prior to the first documented MMSE score on hospital day 7. Additionally, the 1-month administration period prior to hospitalization was too short to alter neurochemistry sufficiently to produce complex visual hallucinations and an altered mental state.28 Moreover, the content and quality of visual hallucinations experienced with levodopa use differ significantly from those experienced by this patient.28

Another artefact may arise from the initiation of citalopram, donepezil and memantine, all of which have been shown to have a positive cognitive impact,13–15 on hospital day 10. However, it is unlikely that these medications exerted such a significant positive cognitive effect during the course of this study given their well-defined latency of onset. Finally, it is important to consider the potential confounding effect of pre-hospitalization diphenhydramine administration on our patient's disturbed level of consciousness. Although this medication is known to cause delirium, especially in the geriatric patient population,30 several studies suggest that the anticholinergic effect does not play a significant role in acute mental status change.31,32 Additionally, the low dosage administered to this patient prior to hospitalization (25 mg by mouth daily) is very unlikely to have caused such profound neuropsychiatric abnormalities. The half-life of diphenhydramine, even in older patients, is 9–13 h and, as a result, this medication should have been metabolized to negligible levels approximately 2 days after its cessation in our patient.30,33,34 That our patient's symptoms persisted for up to 9 days suggests against a significant contribution of diphenhydramine discontinuation in the patient's recovery.

Final limitations for consideration include that the frequent indication for as-needed quetiapine early in the hospital course was irregular and distorts the correlation between standing quetiapine regimen dose and cognitive impact. The structuring effects of individual, group, milieu, and family therapy undertaken during this admission may also have affected the patient's clinical and cognitive improvement. However, these are unlikely to have had such rapid positive effect on cognition. There may have been a learner effect inherent in the sequential administration of the MMSE, although the MMSE administration was consciously standardized by training the person administering the MMSE to achieve optimal validity. Finally, the discrepancy in treatment setting between the CATIE-AD (outpatient) and this case report (acute to subacute inpatient) complicates comparison. These limitations portray the need for designed observational and clinical trials of atypical antipsychotic's cognitive effects in DLB.

The findings presented in this case report serve to assist psychiatrists, neurologists and primary care providers in the provision of evidence-based care for patient with DLB with debilitating neuropsychiatric symptoms. Patients with DLB, representing 15–25% of the dementia population,15 will benefit from future research generated by this increase in interest. In this vein, our case presentation presents an early caution against unconsidered application of the CATIE-AD findings to the clinically and mechanistically distinct DLB population.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CASE REPORT
  5. DISCUSSION
  6. REFERENCES