Strokes and Other Side-Effects of Atypical Anti-Psychotics on the Elderly

The FDA finally made it public in April, 2005, that elderly demented patients treated with atypical anti-psychotics in 17 controlled studies were 65% more likely to die from heart failure, sudden death or infections than those given placebo.  Much of this information has not been contained in published studies and has only been known to the Bush FDA and regulatory agencies in other countries.  Canada and Europe required some warning last year, but the FDA has been slower to react.  It is likely that the same is true for older anti-psychotics, but the data is only now being seriously studied!

Several recent published studies have conflicting finding about whether atypical anti-psychotics cause an increased risk of stroke when used in the elderly.  The largest study, a retrospective study, finds no increased risk.  However, two randomized trials, which are more scientifically accurate, suggest that there might be an increased risk.  For the simple practicing psychiatrist without access to hidden studies and hidden data, the correct answer is is very difficult to determine.

FDA Warns on Atypicals for Dementia: The FDA has finally issued a warning of fatal adverse events in elderly demented patients treated with atypical antipsychotic drugs: 17 controlled studies of elderly demented patients have shown that patients treated with the drugs were 1.6 to 1.7 times more likely to die than patients given placebo. The causes of death included congestive heart failure, sudden death, and infections, such as pneumonia. A "black box" warning will appear on drug labels—indicating an adverse reaction that may result in death or serious injury—noting the increased death rates and that "these drugs are not approved for the treatment of behavioural symptoms in elderly patients with dementia." The drugs affected include aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), clozapine (Clozaril), and ziprasidone (Geodon). A drug used for depression associated with bipolar disorder, olanzapine (Symbyax), was included in the advisory warning.  Zyprexa and Risperdal are the two top sellers. Whether Geodon and Abilify cause as severe a problem is not mentioned.  Although the FDA required diabetes risk labeling of these along with the older atypicals, research has been quite consistant in finding no increase diabetes risk with the later two. Benzodiazepines may increase the risk. Zyprexa was the world's fourth best selling drug in 2003.

Haldol and Benzodiazepines Associated with More Strokes in Elderly Than Atypical Anti-Psychotics: Using Medicaid data from 8 million enrollees  for the incidence of a stroke within 3 months of starting an atypical antipsychotic, haloperidol or a benzodiazepine, risperidone (OR=1.00 by definition) was no different from olanzapine (OR=1.05). Quetiapine (OR=0.66) did better, but the difference was not significant. Haloperidol was significantly worse (OR=1.91) as were benzodiazepines (OR=1.97. Risperidone treatment in elderly patients with dementia: relative risk of cerebrovascular events versus other antipsychotics. Finkel S, et al. University of Chicago. Int Psychogeriatr. 2005 Oct 5;:1-13

First Generation Anti-Psychotics Slightly Safer Than Second for Stroke, Especially Safer than Risperdal: Using the regional database of prescriptions reimbursed by the National Health Service of all patients aged 65 or older who received antipsychotic prescriptions during 2001, strokes occurred in 3.31% of elderly exclusively exposed to SGAs and 2.37% exposed to first-generation antipsychotics. Only risperidone showed a significant risk of 43% (OR = 1.43). Second-Generation Antipsychotics and Risk of Cerebrovascular Accidents in the Elderly. Percudani M, et al. University of Verona, Italy. J Clin Psychopharmacol. 2005 Oct;25(5):468-470.

Mortality Increased with Olanzapine (Zyprexa): In a review of 11 DB PC studies of patients with dementia, all-cause mortality was not increased with risperidone, but was with olanzapine (3.5% vs. 1.5% for placebo). N Herromann et al. Do atypical antipsychotics cause stroke? CNS Drugs 2005;19:91.

Quetiapine (Seroquel) Increased Dementia Impairment; Neither It Not Rivastigmine Helped Agitation: In a 26-week DB PC study of 93 agitated Alzheimer's patients comparing the atypical antipsychotic (quetiapine), cholinesterase inhibitor (rivastigmine) and placebo, neither medication group showed significant improvement on agitation either at six weeks or 26 weeks. For quetiapine, the worsening in severe impairment battery score from baseline was 14.6 points worse than in the placebo group at six weeks (P=0.009) and 15.4 points (-27.0 to -3.8) worse at 26 weeks (P=0.01). Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. Ballard C, Margallo-Lana M, et al. King's College, London SE5 8AF. Ed: Since haloperidol increases hyperphosphorylation of tau protein, a critical deterioration in Alzheimer's, perhaps some or all atypical anti-psychotics do as well. 

No Increased Risk of Stroke With Atypical Antipsychotics Found: In a population-based retrospective study of 32,710 older adults (< or = 65 years) with dementia (17,845 given an atypical antipsychotic, 14,865 a traditional antipsychotic), there was no significant increase in risk of ischemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01); this included risperidone, olanzapine, and quetiapine. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. Gill SS, Rochon PA, et al. Toronto, ON, Canada. BMJ. 2005 Feb 26;330(7489):445. 

Stroke Risk High with Olanzapine, too: Post-hoc analysis by the Eli Lilly drug company of 5 randomized clinical trials using olanzapine in patients with dementia, has shown that patients taking olanzapine have a risk of experiencing a stroke which is 3 times higher than patients taking placebo. van Marum RJ, Jansen PA. Universitair Medisch Centrum Utrecht, Netherlands. Ned Tijdschr Geneeskd. 2005 Jan 22;149(4):165-7. Ed: Strokes in the elderly are doubled by risperidone compared to placebo, but increased only 10% compared to traditional anti-psychotics.

Stroke and Death: Small Study Raises Concern About Risperidone in the Elderly: In 4 placebo-controlled trials lasting 1–3 months and involving more than 1200 patients with Alzheimer's disease or vascular dementia, strokes were twice as common in the risperidone-treated group (4%) as in the placebo group ( 2%). A further search of international databases of postmarketing adverse events revealed 37 cases (1 in Canada) of such events in elderly dementia patients taking risperidone, of which 16 (43%) were fatal. Risperdal (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials [Dear Healthcare Professional Letter]. Toronto: Janssen–Ortho Inc.; 2002 Oct 11. Available: www .hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english /advisory /industry/risperdal1_e.pdf (accessed 2002 Oct 25).

Stroke Only Mildly Increased with Risperidone Compared to Traditional Antipsychotics: In a retrospective population-based cohort study of patients over the age of 66, patients treated with typical antipsychotics (N=1,015) were compared with those given risperidone (N=6,964) and olanzapine (N=3,421). Model-based estimates adjusted for covariates hypothesized to be associated with stroke risk revealed relative risk estimates of 1.1 for olanzapine and 1.4 for risperidone. Atypical antipsychotics and risk of cerebrovascular accidents. Herrmann N, Mamdani M, Lanctot KL. Am J Psychiatry. 2004 Jun;161(6):1113-5. Am J Psychiatry. 2004 Jun;161(6):1113-5. Ed: Since traditional antipsychotics have all but disappeared from clinical practice, I don't think that they are a fair comparison group.  The newer anti-psychotics, such as ziprasidone, would be much better.  Still, the increase with risperidone (40%) found was not huge.

Thomas E. Radecki, M.D., J.D.

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