Drugs, Death, and Disconcerting Dilemmas: Page 3 of 3

Drugs, Death, and Disconcerting Dilemmas: Page 3 of 3

The antipsychotic-associated risk of stroke and death in dementia raises the obvious question of whether this is truly diagnosis-specific or more a phenomenon of risk inherent to age. This remains an unanswered question, and FDA warnings are thus far specific to dementia. Some retrospective data indicate an increased risk of stroke in older users of antipsychotics—even in those without dementia; however, the relative risk was higher in patients with dementia than in those with other symptoms (3.50 vs 1.41).12

A large study reported that persons aged 30 to 74 years with varied diagnoses taking antipsychotics had a doubled incidence rate (absolute rates) of sudden cardiac death compared with antipsychotic-naive persons. However, this remained a rare event (nonusers, 0.143%; typical antipsychotic users, 0.294%; atypical antipsychotic users, 0.28%).13 The risk appeared dose-related, and while rates of sudden death increased with age, this was not a medication-age interaction but rather a reflection of baseline higher rates of sudden cardiac death with increasing age. A postulated mechanism is antipsychotic interference with cardiac potassium channels that predisposes to prolonged QT intervals, which, in turn, increases the risk of arrhythmia.

A safe practice might include pretreatment and posttreatment ECGs with attention to corrected QT (QTc) intervals when prescribing antipsychotics for older adults, especially those with cardiac disease. While precise guidelines do not exist, a baseline QTc interval greater than 450 milliseconds would warrant cause for reconsidering antipsychotic treatment or at least close follow-up ECGs and coordinated care with a cardiologist. A QTc greater than 500 milliseconds or an increase of more than 50 milliseconds after starting an antipsychotic would probably prohibit further treatment with that agent. It may be fruitful to look for reversible causes that could be contributing to a prolonged QTc interval, such as untreated cardiac illness; electrolyte disturbances (especially hypokale-mia or hypomagnesemia); or other medications, such as tricyclic antidepressants, macrolide antibiotics, or methadone.14

Mood disorders

Research on antipsychotics for mood disorders among older adults is quite sparse. Various atypical antipsychotics are FDA-approved for a spectrum of indications in bipolar disorder (eg, acute manic or mixed episodes, bipolar depression, and/or maintenance mood stabilizer therapy). The same issues exist with studies submitted for FDA approval as with those previously described in reference to schizophrenia (ie, exclusion of older adults or including a small, nonrepresentative subsample). A post hoc analysis that examined the older adult subsample in a trial of quetiapine for bipolar mania reported similar positive efficacy among older adults compared with younger adults.15 No RCTs specifically designed for older adults with bipolar disorder were found.

In the absence of data, antipsychotics remain a reasonable choice for treating various phases of bipolar disorder in older adults—especially psychotic mania or depression. The same safety precautions, dosing suggestions, and monitoring protocols discussed in reference to schizophrenia apply in mood disorders.

Antipsychotics in combination with antidepressants are the mainstay of treatment of patients who have major depression with psychotic features, despite scant empirical studies. Older adults with psychotic depression respond well to electroconvulsive therapy, but many barriers may impede its implementation.

A recent RCT examined the efficacy of olanzapine (15 to 20 mg/d) with placebo or with sertraline (150 to 200 mg/d) for psychotic unipolar depression.16 This study included many older adults and compared response by age—older adults responded as well as younger adults, and combination treatment was found to be superior to monotherapy. Dyslipidemia was an adverse effect in older adults, but significant hyperglycemia occurred in the younger sample only, and weight gain was more prominent in the younger adults; this finding is consistent with accumulating evidence that atypi-cal antipsychotic-related metabolic changes are more prominent in younger adults.

Aripiprazole and quetiapine recently received FDA approval for augmentation in treatment-resistant major depression. Again, little is known about how to extrapolate these findings to older adults. The only relevant data were reported from an open-label trial of aripiprazole augmentation (mean dose, 9 mg/d) for adults 65 years or older with major depression without remission despite adequate trials of escitalopram followed by a trial of either duloxetine or venlafaxine.17 Aripiprazole augmentation yielded a remission rate of 50% after 12 weeks, although interpretation is clearly limited by the open-label trial design. However, a multisite clinical trial funded by the NIMH is currently under way to test the benefits—and risks—of aripiprazole augmentation in treatment-resistant late-life major depression.


Prescribing antipsychotics for older adults has never been under more scrutiny than now. Due diligence to considering and discussing the risks and benefits of antipsychotic treatment with older patients and/or their caregivers is critical. There is no perfectly safe or completely effective treatment for the symptoms of older adults that prompt consideration of antipsychotic therapy. Nevertheless, these agents remain reasonable treatment choices for patients with schizophrenia and bipolar disorder. Their use for dementia is more precarious, but on occasion, their use is within reasonable clinical practice, especially given the dearth of alternatives. The use of antipsychotics in patients with unipolar major depression or anxiety disorders requires further study before reasonable recommendations can be made. Antipsychotics can improve symptoms and quality of life for select older adults, but older adults’ sensitivity to the adverse effects of these medications warrants considerable vigilance.




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