ATYPICAL ANTIPSYCHOTIC DRUGS MAY NOT HELP ALZHEIMER'S PATIENTS

Adverse effects offset the advantages in the efficacy of using atypical antipsychotic drugs to treat patients with Alzheimer’s disease, according to a study published in the October 12 New England Journal of Medicine. Lon Schneider, MD, and colleagues treated 421 patients with Alzheimer’s disease who had delusions, hallucinations, aggression, or agitation. The patients were randomly assigned to receive olanzapine, quetiapine, risperidone, or placebo. The primary outcome measure was time until discontinuation of treatment, and the secondary outcome measure was whether patients displayed at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at week 12.

During a 36-week follow-up period, 82% of patients discontinued treatment for various reasons, ranging from lack of efficacy to intolerability to death. Median time to discontinuation was 8.1 weeks for patients taking olanzapine, 5.3 weeks for those receiving quetiapine, and 7.4 weeks for patients taking risperidone; there was no significant difference from the median eight weeks to discontinuation of placebo.

The authors reported that 24% of olanzapine patients, 16% of quetiapine patients, and 18% of risperidone patients discontinued treatment due to intolerance, adverse effects, or death; 5% of patients who received placebo discontinued for the same reasons. Twelve percent of those who received olanzapine or risperidone exhibited parkinsonism or extrapyramidal signs, compared with 2% of those who received quetiapine and 1% of those who took a placebo. Sedation occurred more commonly with the three drugs, as did confusion and changes in mental status with olanzapine and risperidone; cognitive disturbances and psychotic episodes were more frequent among patients taking olanzapine.

On average, patients discontinued use of placebo due to inefficacy after nine weeks, compared with 22.1 weeks for olanzapine and 26.7 weeks for risperidone. Median time to discontinuation for quetiapine was 9.1 weeks, not significantly different than that for placebo. Moreover, 63% of all patients had discontinued treatment by 12 weeks, and there was no significant difference among groups in minimal improvement on the CGIC scale.

The authors advised that the use of these drugs in patients with Alzheimer’s disease could be limited to "patients who have few or no side effects and for whom benefits can be discerned."

Suggested Reading
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;335:1525-1538.

EARLIER REVASCULARIZATION MAY REDUCE STROKE RISK IN PATIENTS WITH MYOCARDIAL INFARCTION

The risk of in-hospital ischemic stroke after acute myocardial infarction may be independently correlated with timing to revascularization, reported Eric van de Graaff, MD, and colleagues. Their findings were published in the October Stroke.

The researchers identified 45,997 patients who received thrombolytic therapy and 47,876 patients treated with primary percutaneous transluminal coronary angioplasty for myocardial infarction. Occurrence of in-hospital ischemic stroke was observed in 248 (0.54%) of the thrombolytic therapy patients and in 150 (0.31%) of patients who received angioplasty. The time to revascularization therapy and risk of in-hospital ischemic stroke had a statistically significant linear relationship. Researchers observed an association between thrombolytic therapy delivered 15 minutes into hospitalization and a lower stroke risk, compared with stroke risk in patients receiving therapy after 45 minutes. There was also a correlation between angioplasty delivered within 90 minutes of hospitalization and a nonsignificant trend toward lower risk of ischemic stroke.

"Our data suggest that the risk of thromboembolic stroke increases linearly with prolonged myocardial ischemia and that this risk seems to persist regardless of the extent of myocardial damage," stated Dr. van de Graaff and colleagues. "The relationship between delay in revascularization and ischemic stroke appears to be independent of size of infarction, the presence or absence of shock or congestive heart failure, and ejection fraction seen at time of discharge and therefore invokes the possibility of a mechanism for stroke risk that does not depend on ventricular structure."

The finding that the earliest therapy with a thrombolytic agent corresponded to increased stroke prevention "is likely the result of the very rapid reperfusion attendant with aggressive thrombolytic therapy and is not related to any direct effect of the drug on inhibition of cerebral thromboembolism," the researchers pointed out.

In an accompanying editorial, Jose I. Suarez, MD, pointed out that the study’s significance is threefold. "First, it underscores the importance of early revascularization for patients presenting with acute myocardial infarction, not only to improve cardiac outcome but also to reduce neurological complications," he stated. "Second, similar to what has been reported for acute ischemic stroke, earlier treatment for acute myocardial infarction improves outcome. Third, cardiac dysfunction may not be as important a factor as previously reported in the short-term risk of ischemic stroke in patients with acute myocardial infarction."

Dr. Suarez also recommended that future studies investigate whether patients who received earlier treatment may have benefited from ß-blocking drugs, along with reduced sympathetic activity.

Suggested Reading
Van de Graaff E, Dutta M, Das P, et al. Early coronary revascularization diminishes the risk of ischemic stroke with acute myocardial infarction. Stroke. 2006;37:2546-2551.
Suarez JI. Acute myocardial infarction, ischemic stroke, sympathetic stress, and inflammation: birds of a feather. Stroke. 2006;37:2449-2450.

MILD ANEMIA LINKED WITH IMPAIRED EXECUTIVE FUNCTIONING IN OLDER WOMEN

Among community-dwelling older women without dementia or advanced physical disability, there may be a strong and independent association between mild anemia and a greater risk of executive function impairment, as reported in the September Journal of the American Geriatrics Society.

Paulo Chaves, MD, PhD, and colleagues assessed 364 participants from the Women’s Health and Aging Study II who had a hemoglobin concentration 10 g/dL or greater and known status of executive function. Best, worst, and intermediate performance was measured using tertiles of time to complete the Trail Making Test (TMT) Parts B and A, as well as tertiles of the difference of TMT-B minus TMT-A. The highest percentage of participants in the worst performance tertiles for TMT-B, TMT-A, and TMT-B minus TMT-A were patients with anemia. The risk of worst performance on all three of the test measures was substantially increased by the presence of prevalent anemia.

"Whether the relationship between mild anemia and executive function impairment in community-dwelling older adults reported here is causal or noncausal remains to be determined," stated Dr. Chaves’ research team. Potential causal pathways could involve "chronic reduction of cerebral oxygenation secondary to decreased oxygen-carrying capacity of the blood linked to anemia," as well as anemia’s negative effect on physical function and conditioning, they noted. Noncausal possibilities include anemia’s status as a "marker of diseases and processes associated with chronic cerebral hypoperfusion in the prefrontal cortex," as well as a marker for inflammation or other neurodegenerative processes. "Anemia could also indirectly reflect the adverse effect of low testosterone levels on cognition, although the latter association remains controversial," the investigators stated.

Dr. Chaves and colleagues noted several limitations to their study. Due to the study’s cross-sectional nature, no assessment of the risk of incident executive function impairment as a function of baseline anemia or change in hemoglobin over time was performed. Furthermore, executive function impairment was based on a few measures of executive abilities, and "there is currently no well-established clinical criterion to define executive function impairment in older adults," they reported.

If the relationship between mild anemia and impaired executive function "is causal, this could offer an opportunity for preventing executively mediated functional decline through correction of reversible anemia," Dr. Chaves and colleagues concluded. "If it is noncausal, information on this association could still be potentially useful for screening vis-à-vis the identification of those at risk for functional decline."

Suggested Reading
Chaves P, Carlson MC, Ferrucci L, et al. Association between mild anemia and executive function impairment in community-dwelling older women: the Women’s Health and Aging Study II. J Am Geriatr Soc. 2006;54:1429-1435.

A NEW DIRECTION FOR INTRACEREBRAL HEMORRHAGE THERAPY?

Preliminary findings have revealed a new investigative avenue in the development of therapeutic interventions for patients with intracerebral hemorrhage, according to a study in the October Stroke.

Jeong Sook Kim-Han, PhD, and colleagues analyzed brain tissue samples from six patients with acute spontaneous intracerebral hemorrhage and six control patients undergoing brain resection for seizure management. In the former group, hemorrhages were found in the temporal lobe in three patients, in the cerebellum in two patients, and in the parietal lobe in one patient. Compared with control patients, those with intracerebral hemorrhage had an approximately 40% reduction in the average state 3 oxygen consumption for mitochondria. There was also a progressive decline in state 3 respiration from hemorrhage to testing; at six hours, reduced state 3 respiration decreased further to virtually no oxygen consumption at 72 hours.

In addition, among cerebrocortical intracerebral hemorrhage patients, state 4 respiration was three times greater than for control patients, which reflects inefficient production of mitochondrial energy. There was also a lower respiratory control ratio in mitochondria isolated from intracerebral hemorrhage patients.

"These preliminary findings have important potential implications," stated Dr. Kim-Han and colleagues. "They add to the growing body of literature indicating that cerebral ischemia is a contributor to secondary injury in intracerebral hemorrhage patients. This, along with the observation that cerebral autoregulation is intact globally and in the perihematomal region, alleviates one of the important concerns about treating hypertension in intracerebral hemorrhage patients. In addition, they suggest that neuroprotective strategies focusing on cerebral ischemia are unlikely to be effective in intracerebral hemorrhage patients."

In an accompanying editorial, Raymond A. Swanson, MD, noted, "The findings of Kim-Han et al set the stage for future work in which interventions that target mitochondrial damage can be assessed to more clearly delineate the cause-effect relationships suggested by this work." However, Dr. Swanson pointed out that "the use of tissue from human surgical resections unavoidably introduces variability into the study." He explained that the patients varied in age and had different underlying diseases; mitochondria were derived from multiple brain regions; and small changes in sturdier glial cells may have hidden larger changes in neuronal mitochondria.

"All of these factors tend to introduce ‘noise’ into the results," asserted Dr. Swanson, "but the key question, not definitely addressed by these studies, is whether the observed mitochondrial dysfunction is attributable primarily to local trauma and mass effect, or is in fact attributable to diffusible factors from the hematoma."

Suggested Reading
Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke. 2006;37:2457-2462.
Swanson RA. Intracerebral hematoma: beyond the mass lesion. Stroke. 2006;37:2445.

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