Switching Antipsychotics Reduces Cardiovascular Risk Factors
If patients are stable on olanzapine (Zyprexa), quetiapine (Seroquel), or risperidone (Risperdal) but are experiencing adverse metabolic effects, it might make sense to switch to a medication that has a lower risk of causing such effects. But would such a switch reduce obesity and cholesterol at the risk of a relapse? A recent study examined this question, randomly assigning 213 patients with schizophrenia or schizoaffective disorder who were clinically stable on one of the aforementioned antipsychotics to either stay on their original medication (stayers) or switch to aripiprazole (Abilify) (switchers). (The study was supported by a grant from the Foundation for NIH (FNIH) and by a contract from NIMH. Bristol-Myers Squibb provided aripiprazole and funds to FNIH in support of the study.) Patients had a BMI of > 27 and a non-HDL cholesterol of > 130 mg/dl. Switchers were cross-titrated to an Abilify dose of 5 mg to 30 mg over a four-week period.
All patients received a behavioral intervention aimed at increasing exercise and improving diet during the trial. Although the study was not double-blinded, the clinical raters were blinded to treatment assignment. At the end of the 24-week study, patients who switched to Abilify showed clear metabolic improvements: a decrease of 20.2 mg/dl in non-HDL cholesterol (vs. –10.8 mg/dl for the stayers), a triglyceride decrease of 25.7 mg/dl (vs an increase of 7.0 mg/dl in stayers); and a weight loss of 3.6 kg (7.9 pounds) vs a loss of 0.7 kg (1.5 pounds) in the stayers. The improvements in non-HDL cholesterol and triglycerides were nearly fully realized by a month, while the changes in weight occurred more gradually.
Now how about relapse rates? The investigators defined “efficacy failure” as being need for hospitalization, substantial worsening of symptoms, or worsening global clinical status. There was no significant difference between stayers and switchers on this measure. However, patients who switched to Abilify were more likely to drop out of the study due to inefficacy (16.8% vs. 2.8%) (Stroup TS et al, Am J Psychiatry 2011;168:947–956).
TCPR’s Take:: For most patients, switching under close clinical monitoring and gradual cross-titration successfully reduced several cardiovascular risk factors, while generally maintaining clinical efficacy. The risk of drop out was higher with switchers, so bear that in mind as you try to get your patients off of the high weight-gaining antipsychotics. Only Abilify was tested, though we’d expect similar results from other antipsychotics with low metabolic liability such as Geodon or perphenazine (Trilafon).
FDA Warning: High Doses of Citalpram May Be Dangerous for the Heart
The editors at TCPR, as well as many of you, received a notice issued by the FDA on August 24, 2011 warning us that citalopram (Celexa) at doses higher than 40 mg may cause dangerous prolongation of the QT interval, which can increase the risk of cardiac arrhythmias (including the potentially fatal torsade de pointes). These data led to the FDA to lower the recommended maximum daily dose of citalopram from 60 mg to 40 mg.
This warning and change in product labeling has left many of us with more questions than answers. Why citalopram and not the other SSRIs? Why now, considering the Celexa brand of citalopram was approved by the FDA back in 1998. What’s the real clinical risk and what do I need to consider now when using citalopram and other SSRIs?
According to an FDA official we emailed, the agency singled out citalopram because it received sporadic post-marketing reports of QT interval prolongation. It asked Forest to study the effect systematically, resulting in a randomized placebo-controlled study of 119 healthy adults which found mean QT interval prolongations of 8.5 milliseconds (ms) for the 20 mg dose and 18.5 ms for the 60 mg dose (Celexa [package insert]. St. Louis, MO:Forest Pharmaceuticals;2010).
Unfortunately, the 40 mg dose was not tested, but the data were extrapolated to suggest a mean QT prolongation of 12.6 ms for this dose. The data were also interpreted as suggesting a dose-side effect relationship, although in our opinion a study with only two data points such as this cannot reliably determine that a dose relationship truly exists. As a point of comparison, ziprasidone (Geodon), well known for this side effect, causes a mean QT prolongation of 20.6 ms and thioridazine (Mellaril) causes a mean 35.8 ms prolongation (Huffman JC, Prim Care Companion J Clin Psychiatry 2003;5(6):278–281).
Have any comparable studies of QT interval been done with other newer antidepressants? Only a few. Forest conducted a similar study of escitalopram (Lexapro), reporting in its package insert that in 113 healthy adults, escitalopram showed mean QT prolongation of 4.5 ms with 10 mg per day and 10.7 ms with 30 mg per day. The data were extrapolated to suggest a mean prolongation of QT of 6.6 ms with 20 mg per day (Lexapro [package insert]. St. Louis, MO. Forest Pharmaceuticals;2011).
Since 2005, the FDA has required detailed QT data for any newly approved antidepressants, so this data appears in the package inserts of both Viibryd (vilazodone), and Pristiq (desvenlafaxine). Viibryd was tested in 157 subjects at four doses (20 mg, 40 mg, 60 mg, and 80 mg/day) and the QT interval stayed below 10 ms in all cases (Viibryd [package insert]. St. Louis, MO:Forest Pharmaceuticals;2011).
In Pristiq’s package insert, few details are provided, but the following reassuring statement is printed: “In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation” (Pristiq [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2011).
Other than Celexa, Lexapro, Viibryd, and Pristiq, the only other SSRI with similar cardiac safety data is fluoxetine (Prozac), which, as the first SSRI to be marketed, was tested to show cardiac safety compared to the standard antidepressants available at that time (tricyclic antidepressants). One study of fluoxetine, up to 60 mg per day for seven weeks in 27 depressed patients with cardiac disease (average age was 73 years) showed no effects on cardiac conduction (Roose SP et al, Am J Psychiatry 1998;155(5):660–665). Another study, comparing fluoxetine (mean dose of 37 mg per day) to doxepin (Silenor), (mean dose of 169 mg per day) in 40 patients with major depression, also showed no effect with fluoxetine on QT intervals (vs 22 ms increase with doxepin) (Baker B et al, J Clin Psychopharmacol 1997;17(1):15–21).
In addition to limiting the maximum daily dose to 40 mg, the FDA warning lists the usual cautionary measures accompanying medication that can prolong QT intervals, such as lowering the dose in patients with cardiac disease, and not combining it with other medications that affect cardiac conduction—you can read the full warning at http://1.usa.gov/roSXS4.
How should this affect our use of citalopram? You should consider the risk of QT prolongation with citalopram 60 mg per day to be in the same range as that with any dose of ziprasidone. That is to say, citalopram can and should be used, even at doses higher than 40 mg per day, if the benefits outweigh the potential risks.
Alternatively, an option may be to switch to a different SSRI—at this point, apparently all of which are considered to be safe from a cardiac standpoint. Two good alternatives would be sertraline or escitalopram, both of which have good side effect profiles and are unlikely to cause drug interactions.