Annotated Abstracts of Journal Articles
2015, 4th Quarter
Annotations by Nicholas Kontos, MD
ANNOTATION (Nicholas Kontos)
The Finding: Cerebral small vessel disease affects a number of white matter tracts that connect the frontal lobes with subcortical regions and with the temporal lobes. These lesions may be specific to apathy as opposed to so-called “vascular depression,” and may operate by interrupting networks that integrate reward/salience, memory/associations, and behavioural initiation. Apathy and depressive disorder were also found to be dissociable in terms of quality of life impairment.
Strengths and Weaknesses: A relatively large sample size was used for this ambitious study incorporating neuropsychologist assessments, advanced imaging techniques, and quality of life measurements. It does launch into new-ish territory by taking apathy beyond its usual associations with prefrontal cortical-striatal-thalamo-cortical circuitry. The use of an apathy scale derived/extracted from the Geriatric Depression Scale seems to do little justice to the neuropsychiatric-phenomenological heritiage of apathy/abulia. On the one hand, this choice might have lessened the depression-apathy distinction in the study and, thus, the magnitude of the differences found. On the other hand, it leaves some ambiguity about what was actually studied—symptoms or a syndrome.
Relevance: Apathy/abulia is a critical neuropsychiatric syndrome to recognize, and a major item on the psychosomatic medicine specialist’s differential diagnostic list for “rule out depression” consults. This study provides some anatomic backing to go with one’s phenomenological diagnostic approach.
Small vessel disease is a stroke subtype characterized by pathology of the small perforating arteries, which supply the sub-cortical structures of the brain. Small vessel disease is associated with high rates of apathy and depression, thought to be caused by a disruption of white matter cortical-subcortical pathways important for emotion regulation. It provides an important biological model to investigate mechanisms underlying these key neuropsychiatric disorders. This study investigated whether apathy and depression can be distinguished in small vessel disease both in terms of their relative relationship with white matter microstructure, and secondly whether they can independently predict functional outcomes. Participants with small vessel disease (n = 118; mean age = 68.9 years; 65% male) defined as a clinical and magnetic resonance imaging confirmed lacunar stroke with radiological leukoaraiosis were recruited and completed cognitive testing, measures of apathy, depression, quality of life and diffusion tensor imaging. Healthy controls (n = 398; mean age = 64.3 years; 52% male) were also studied in order to interpret the degree of apathy and depression found within the small vessel disease group. Firstly, a multilevel structural equation modelling approach was used to identify: (i) the relationships between median fractional anisotropy and apathy, depression and cognitive impairment; and (ii) if apathy and depressionmake independent contributions to quality of life in patients with small vessel disease. Secondly, we applied a whole-brain voxel-based analysis to investigate which regions of white matter were associated with apathy and depression, controlling for age, gender and cognitive functioning. Structural equation modelling results indicated both apathy (r = -0.23, P ≤ 0.001) and depression (r = -0.41, P ≤ 0.001) were independent predictors of quality of life. A reduced median fractional anisotropy was significantly associated with apathy (r = -0.38, P ≤ 0.001), but not depression (r = -0.16, P = 0.09). On voxel-based analysis, apathy was associated with widespread reduction in white matter integrity, with the strongest effects in limbic association tracts such as the anterior cingulum, fornix and uncinate fasciculus. In contrast, when controlling for apathy, we found no significant relationship between our white matter parameters and symptoms of depression. In conclusion, white matter microstructural changes in small vessel disease are associated with apathy but not directly with depressive symptoms. These results suggest that apathy, but not depression, in small vessel disease is related to damage to cortical-subcortical networks associated with emotion regulation, reward and goal-directed behaviour
ANNOTATION (Nicholas Kontos)
The Finding: In patients with moderate to severe Alzheimer’s disease, discontinuation of donepezil was associated with a significantly increased risk of nursing home placement over the subsequent year. Presence or absence of memantine, alone or in combination with donepezil, made no difference.
Strengths and Weaknesses: Increased time to nursing home placement has long been a draw to cholinesterase inhibitor use. Decreased utility late in Alzheimer’s disease has long been a limiting factor in their use. This paper’s succinct review and description of the existing literature shows both of these ideas to be more received wisdom/observation than rigorously demonstrated facts. In fact, this study is a secondary analysis of a study showing cognitive and functional benefit of donepezil in moderate to late Alzheimer’s disease. As a secondary analysis, this study does not do what the original study was intended to, and the authors are appropriately conservative in discussing their results (despite industry sponsorship of the study; though there is a nice, explicit description of how/why industry influence was at least not an overt confound here). No difference between the various study groups was found after the one year mark, but the study design changes so much at that point that this seems unworthy of much discussion (even if it might make some sense).
Relevance: This study provides somewhat contrary evidence to the only prior trial looking at the effect of donepezil use on nursing home placement in patients with moderate to late Alzheimer’s disease. That trial (AD2000) still holds up as indicating that initiating donepezil does not delay placement for these patients (though other work suggests that it might not be absolutely without utility in other domains). This trial nonetheless holds up as suggesting that donepezil should not be discontinued in late stage (in fact, later stage than the AD2000) patients. The received wisdom about cholinesterase inhibitor use in moderate to late stage Alzheimers disease should be viewed with greater scepticism and nuance.
Background: Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer’s disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer’s disease.
Methods: In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer’s disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035.
Results: During a median follow-up period of 6.8 (range, 0-26.0) years, 3,260 individuals in the cohort were diagnosed with PD. The multivariable adjusted odds ratio (OR) for PD was 3.2 (95% confidence interval [CI], 2.5-4.1) within the first year of depression, decreasing to 1.5 (95% CI, 1.1-2.0) after 15 to 25 years. Among participants with depression, recurrent hospitalization was an independent risk factor for PD (OR, 1.4; 95% CI, 1.1-1.9 for ≥5 vs 1 hospitalization). In family analyses, siblings’ depression was not significantly associated with PD risk in index persons (OR, 1.1; 95% CI, 0.9-1.4).
Findings: Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]).
Interpretation: Withdrawal of donepezil in patients with moderate-to-severe Alzheimer’s disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear.
ANNOTATION (Nicholas Kontos)
Electroconvulsive therapy (ECT) can be safely administered to patients with a number of neurological comorbidities. The observational study component of the paper directly supports this statement to varying degrees based on number of patients evaluated and treated with each condition. The review component of the paper covers conditions not seen (or seen in insufficient numbers) by the authors. As per usual, no neurologic condition is considered an absolute contraindication to ECT, but the following are described as requiring a very strong indication for treatment or important modifications (usually by the anesthesiologist) of routine care: recent stroke or subdural hematoma, unstable intracerebral aneurysm, masses associated with increased intracranial pressure or edema, acutely exacerbated multiple sclerosis, neuromuscular diseases associated with muscle atrophy or paralysis (e..g., Guillain-Barre syndrome, stroke, “prolonged” catatonia, chronic inflammatory demyelinating polyneuropathy, reversible cerebral vasoconstriction syndrome. Metallic intracranial devices (including deep brain stimulators) constitute a significant, but seemingly purely theoretical, risk.
Strengths and Weaknesses: The combination of systematically organized experience and literature review makes up for experience-based limitations in the former (working in a large, purely psychiatric hospital, the authors only had only 68 cases to report on over a 2.5 year period, all with neurologic acuity sufficient to require general hospital admission for that indication alone), and limitations in the latter based on reporting bias. Still, the authors’ experience is somewhat limited by the setting in which they work (referral bias), and this limits the advice they can give to consultation psychiatrists. The advice they do give, however, is sound and well-balanced in terms of respecting neurologic and psychiatric risks equally.
Relevance: This report is an excellent summary statement on an issue of great concern to consultation psychiatrists, especially those working in centers that provide ECT but lack sub-sub-specialists (e.g., high-risk ECT providers, psychiatrically attuned neurologists) to rely on. Specific advice is given on modifying ECT for patients with several moderate-risk neurological conditions.
Pre-ECT neurology consultations are often requested to determine the relative risk of the procedure in patients with neurological comorbidities, but there is limited data to guide clinicians. The authors performed a retrospective chart review of all consecutive inpatients at McLean Hospital who underwent a pre-ECT neurological evaluation between January 2012 and June 2014 (N=68). ECT was safe and effective in patients with a wide variety of neurological diseases. Only one minor event was related to a neurological comorbidity, and there were no serious neurological complications. Based on the latest evidence, the authors provide guidance on the pre-ECT evaluation with respect to neurologic status.