(Supplement)-Concomitant use of anxiolytic or sedative-hypnotic agents with selective serotonin reuptake inhibitors
By Gary M. Levin, PharmD, BCPP
Albany College of Pharmacy
Capital District Psychiatric Center
Albany, NY
Introduction
The selective serotonin reuptake inhibitors (SSRIs) have become one of the most frequently prescribed classes of psychotropic medications. When fluoxetine (Prozac) was introduced as the first drug in this class to be marketed, it was perceived to be without side effects. The perception continued as more drugs in this class were introduced. While it is believed that SSRIs do not cause some of the side effects (e.g., anticholinergic and cardiac effects) associated with the older, tricyclic antidepressants, they do have their own side-effect profile. For example, fluoxetine is considered to be more activating than the tricyclic antidepressants.
The SSRIs as a class may also be associated with various extra-pyramidal side effects. Furthermore, paroxetine has an affinity for muscarinic receptors and therefore is associated with anticholinergic side effects, albeit to a lesser degree than are the tricyclic antidepressants.
The fluoxetine product information reports that insomnia, anxiety, and nervousness occur in 13.8%, 9.4%, and 14.9% of patients, respectively; however, the figures may be higher in patients prescribed more than 20 mg daily. Patients prescribed larger doses (i.e., greater than 20 mg) are recommended to take them in a divided regimen; this means that a dosage taken later in the day, which might further contribute to insomnia. Patients with obsessive-compulsive disorder, for example, are often prescribed up to 80 mg daily.
Such side effects lead to the use of additional medications, for example, benzodiazepines, chloral hydrate, meprobamate, or sedating antidepressants (trazodone, amitriptyline), to help a patient relax or sleep. The use of such agents concomitantly to treat side effects creates the potential of adverse events via pharmacokinetic and/or pharmacodynamic drug-drug interactions.
This study's primary goals were to determine the rate of concomitant anxiolytic and/or sedative-hypnotic use in patients prescribed SSRIs and to identify differences in such concomitant drug use among specific SSRIs. A secondary aim was to identify differences in dosing strategies.
Methodology
The New York State Office of Mental Health Pharmakon database was used to identify psychiatric inpatients receiving SSRIs throughout the state. A comparison group of venlafaxine patients also was identified. Venlaxafine was chosen because it has a mechanism of action (inhibition of the reuptake of serotonin and norepinephrine) and a side-effect profile (nausea and other gastrointestinal effects, nervousness, etc.) similar to the SSRIs. Choosing a comparative agent with a similar mechanism of action and side-effect profile as the SSRIs would potentially limit the confounders that might have been seen if, for example, the comparative agent was associated with a high amount of sedation.
Each identified patient's medication profile was reviewed for the following: scheduled anxiolytics, including benzodiazepines, buspirone, or hydroxyzine; "as needed" anxiolytics (same agents); and scheduled bedtime hypnotics, including benzodiazepines, subtherapeutic sedating antidepressants (e.g. trazodone 50 to 150 mg), or sedating antihistamines such as diphenhydramine.
Dosing strategies were compared to determine differences in the way SSRIs were scheduled (i.e., once-daily dosing vs. multiple daily dosing). Chi-square analysis was done to determine if differences existed among the SSRIs and, additionally, between the SSRIs and the control group.
Results
A total of 871 SSRI and 40 control inpatients were identified from the 7,659 patients in the database (see table). No differences were detected in the use of either anxiolytics or sedative-hypnotics (scheduled or "as needed") among the different antidepressants studied. While there were no statistical differences, it does appear that there are subtle differences. Paroxetine was associated with a slightly lower use of scheduled hypnotics, which might be expected, since it is associated with a greater amount of sedation compared with the other SSRIs. Fluvoxamine appears to be associated with a slightly greater use of scheduled anxiolytics, which might be unexpected, since it is approved only for treating an anxiety disorder (obsessive-compulsive disorder). Therefore, it could be considered an anxiolytic itself.
| Rates of Concomitant Agent Use and Dosing Strategies for SSRIs | |||||
| Sertraline | Fluoxetine | Paroxetine | Fluvoxamine | Vanlaxafine | |
| Total (n) | 347 | 250 | 213 | 61 | 40 |
| Scheduled anxiolytic | |||||
| 23% | 21% | 24% | 33% | 28% | |
| Scheduled hypnotic | |||||
| 15% | 19% | 16% | 11% | 25% | |
| "As needed" anxiolytic | |||||
| 6% | 8% | 7% | 13% | 3% | |
| Once-daily dosing | |||||
| 79% | 92% | 64% | 48% | NA | |
| All bedtime dosing* | |||||
| 16% | 3% | 12% | 48% | NA | |
| * p < 0.0001 | |||||
| NA references pertain to drugs always dosed 2-3 times daily. | |||||
Since all the SSRIs can be taken once daily, except for fluvoxamine (which is recommended as twice daily), another factor that was analyzed was the percentage of time that this dosing strategy actually was followed. It was discovered that 48% of fluvoxamine patients received their medication as a once-daily dose (in contrast to the product recommendation). Stratifying the fluvoxamine group further, it was shown that among those receiving the drug once a day, 48% received the drug as a bedtime dose. This was a significant difference compared with the other agents (p < 0.0001).
Conclusions
In the study population, there were no statistically significant differences in the use of anxiolytic or hypnotic agents among the different agents studied. It was not possible to make a comparison of all SSRIs combined vs. the control group because of the small size of the latter. Because of the vast differences in side effects, it would not have been feasible to develop a control group from patients taking tricyclic antidepressants.
One significant difference found was the relatively high percentage of fluvoxamine patients that received their entire dosage at bedtime. This was unexpected because insomnia is a well-known side effect of SSRIs. Because of this dosing deviation, it might be expected that the fluvoxamine group would use a higher percentage of concomitant sedative-hypnotic agents; however, this was not shown. The patients receiving fluvoxamine did not use sedative hypnotic agents to any greater extent than did patients receiving other SSRIs, regardless of dosing strategy. That alternatively might lead one to believe that insomnia is not associated with fluvoxamine as strongly as with the other SSRIs. Therefore, if insomnia is a concern in the treatment of a specific patient receiving an SSRI, then fluvoxamine may warrant special consideration.
Our observational analysis did not show a significant difference in the use of concomitant anxiolytic or sedative-hypnotic use among the SSRIs. Therefore, in clinical practice, it should not be assumed that any specific SSRI will cause a greater amount of anxiety, nervousness, or insomnia as compared with any other similar agent.
In addition, with regard to once-daily dosing, our results indicate that if compliance issues exist and once-daily bedtime dosing is warranted, then fluvoxamine might be considered the agent of choice. Studies of larger samples, with stratification according to different disease states or other patient-specific demographics are warranted.
[For more details, contact Gary M. Levin at (518) 445-7266.]
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