Second Generation Antipsychotics for Bipolar Disorder
This study revealed several core findings. First, SGA use for bipolar disorder is increasing within VA medical centers, with an average of about 6,000 new SGA initiations each year. Time trends suggest that this growth rate was remarkably steady from 2004 to 2010, with no year seeing fewer than 5,000 or more than 7,000 new initiations. Given a roughly parallel increase in the overall bipolar population treated within VA, the proportion of individuals with bipolar disorder receiving an SGA prescription in a given year rose from 59% in 2003 to 75% in 2008 with a slight decrease to 72% in 2010. These increases in use may have in part been driven by recent treatment guidelines that suggest SGAs as potential first-line treatments for multiple phases of bipolar disorder. This decrease in overall use after 2008 may in part reflect effects of toxicity warnings on prescribing practices from the middle 2000's. Regarding specific SGAs, use of aripiprazole, quetiapine, and ziprasidone increased over time while use of olanzapine and risperidone declined. Among providers with prescription privileges treating patients with bipolar disorder, the proportion using SGAs shrunk somewhat over the course of the study (from 90% to 86%), though still encompasses the vast majority of potential prescribers.
A novel innovation in these analyses is the use of GLM techniques to investigate factors that affect provider decision-making on a month-by-month basis, to focus on clinical data available to prescribing clinicians. These analyses revealed that, while the number of new initiators each year remained relatively steady, the odds of initiating an SGA actually decreased slightly over the course of the study (OR = .988 annually). Additionally, two related factors emerged as key in predicting initiation of SGAs. First, SGA initiation was more common overall for patients who appeared more clinically complex. Second, over time SGA use appeared to be spreading to those with less complex clinical profiles.
Providers were more likely to initiate SGAs for patients who were generally more psychiatrically ill at the time of their prescription (i.e. more likely to have a history of psychiatric hospitalization, recent psychotic features, or recent sleep disorder diagnosis); this is consistent with our finding that those who received an SGA also—at some time during the study period—received another antimanic (Table 1). However, on a month-by-month basis, prescriptions of other antimanics were less likely prior to initiation of SGAs. One interpretation is that those not receiving SGAs were already effectively controlled by a non-SGA medication. However, it is also possible that SGAs are being increasingly utilized as first-line treatments, bypassing other medications. Definitive answer awaits finer-grained treatment trajectory analyses.
Time trend analyses indicate that, even though SGA initiation was more common for more complex cases as above, there was a broadening over time of the use of SGAs to include less clinically complex populations. Specifically, variable-by-time interaction terms indicated that SGA initiation became increasingly common for those with bipolar type II/NOS, those with no concurrent antimanic prescription, and those with no prior psychiatric hospitalization. This suggests that over time VA providers may have become increasingly comfortable prescribing SGAs for less severe portions of the bipolar population, though more provider-specific quantitative or qualitative data will be needed to draw firm conclusions.
Most patient demographic covariates showed only modest associations with SGA initiation. African American patients were somewhat more likely to be given an initial SGA prescription during the study period compared to Whites, which is broadly in line with another VA study which found slightly but nonsignificantly higher rates of SGA use among African Americans (52%) compared to others (44%) with bipolar disorder. Given evidence from previous studies that racial differences in SGA prescriptions may be closing, future studies should consider including race by time interaction terms in their statistical analyses.
The effects of medical comorbidities on SGA initiation appeared relatively small when results for all SGAs were combined, which makes intuitive sense given the heterogeneity of cardiometabolic risk profiles among the SGAs we studied. As expected, certain medical comorbidities were associated with substantial differences in prescribing practices for specific SGAs. Notably, individuals with preexisting diabetes, obesity, or hyperlipidemia were less likely to receive those SGAs with more prominent cardiometabolic effects (olanzapine, quetiapine and risperidone). Patients with substance abuse, in contrast, were more likely to receive these drugs: the sedating effects of these SGAs may be seen as desirable in treating patients with substance abuse disorders in whom benzodiazepines are considered inadvisable. Contrary to expectations, quetiapine was not statistically more likely to be prescribed than aripiprazole for individuals with sleep disorders. It should be noted, however, that providers would only be likely to provide a sleep disorder diagnosis if a patient's sleep troubles occurred independently of their bipolar condition (e.g. sleep apnea), which may reflect a complex population in whom sedating drugs would be avoided.
Regional variation in SGA initiation after controlling for covariates was marked by higher rates of SGA use in the South. Veterans in this region of the country have lower self-reported mental and physical quality of life than other regions, perhaps reflecting poorer clinical course or sociodemographic differences. However, analyses both in this bipolar population and among veterans with PTSD indicate prominent regional variation despite extensive control for demographic and clinical characteristics. This finding may thus reflect regional differences in provider practice patterns, commonly reported across many health domains.
Although administrative data provided a very large sample (n > 125,000 patients), it has the disadvantage of relying upon clinicians' diagnostic coding accuracy. Some conditions (e.g. obesity, sleep disturbance) may have been present and influenced treatment decisions and yet not been coded by clinicians. Similarly, codes for bipolar mixed episodes were not reliably utilized, although patients suffering mixed manic and depressive symptoms may be more responsive to SGAs than to other antimanic medications. Furthermore, we could not include data on non-VA prescribing. In addition, we opted to approach these analyses primarily as class analyses, although we secondarily conducted a priori analyses on specific SGAs and specific clinical correlates. Our current analyses did not include data on provider variables (e.g. demographics, academic affiliation, training background), but this is a clear direction for future research. Finally, our primary comparison was between patients initiating SGAs and those not initiating SGAs; we did not conduct additional analyses with different comparison groups (e.g. patients initiating lithium or other antimanics). Future research on SGA initiation exploring provider-level variables and using these other comparison groups would help shed further light on prescribers' initial medication decision for bipolar disorder.
Discussion
This study revealed several core findings. First, SGA use for bipolar disorder is increasing within VA medical centers, with an average of about 6,000 new SGA initiations each year. Time trends suggest that this growth rate was remarkably steady from 2004 to 2010, with no year seeing fewer than 5,000 or more than 7,000 new initiations. Given a roughly parallel increase in the overall bipolar population treated within VA, the proportion of individuals with bipolar disorder receiving an SGA prescription in a given year rose from 59% in 2003 to 75% in 2008 with a slight decrease to 72% in 2010. These increases in use may have in part been driven by recent treatment guidelines that suggest SGAs as potential first-line treatments for multiple phases of bipolar disorder. This decrease in overall use after 2008 may in part reflect effects of toxicity warnings on prescribing practices from the middle 2000's. Regarding specific SGAs, use of aripiprazole, quetiapine, and ziprasidone increased over time while use of olanzapine and risperidone declined. Among providers with prescription privileges treating patients with bipolar disorder, the proportion using SGAs shrunk somewhat over the course of the study (from 90% to 86%), though still encompasses the vast majority of potential prescribers.
A novel innovation in these analyses is the use of GLM techniques to investigate factors that affect provider decision-making on a month-by-month basis, to focus on clinical data available to prescribing clinicians. These analyses revealed that, while the number of new initiators each year remained relatively steady, the odds of initiating an SGA actually decreased slightly over the course of the study (OR = .988 annually). Additionally, two related factors emerged as key in predicting initiation of SGAs. First, SGA initiation was more common overall for patients who appeared more clinically complex. Second, over time SGA use appeared to be spreading to those with less complex clinical profiles.
SGA Initiation More Common for Clinically Complex Patients
Providers were more likely to initiate SGAs for patients who were generally more psychiatrically ill at the time of their prescription (i.e. more likely to have a history of psychiatric hospitalization, recent psychotic features, or recent sleep disorder diagnosis); this is consistent with our finding that those who received an SGA also—at some time during the study period—received another antimanic (Table 1). However, on a month-by-month basis, prescriptions of other antimanics were less likely prior to initiation of SGAs. One interpretation is that those not receiving SGAs were already effectively controlled by a non-SGA medication. However, it is also possible that SGAs are being increasingly utilized as first-line treatments, bypassing other medications. Definitive answer awaits finer-grained treatment trajectory analyses.
SGA Initiation Spreading to Less Clinically Complex Cases
Time trend analyses indicate that, even though SGA initiation was more common for more complex cases as above, there was a broadening over time of the use of SGAs to include less clinically complex populations. Specifically, variable-by-time interaction terms indicated that SGA initiation became increasingly common for those with bipolar type II/NOS, those with no concurrent antimanic prescription, and those with no prior psychiatric hospitalization. This suggests that over time VA providers may have become increasingly comfortable prescribing SGAs for less severe portions of the bipolar population, though more provider-specific quantitative or qualitative data will be needed to draw firm conclusions.
Other Factors Related to SGA Initiation
Most patient demographic covariates showed only modest associations with SGA initiation. African American patients were somewhat more likely to be given an initial SGA prescription during the study period compared to Whites, which is broadly in line with another VA study which found slightly but nonsignificantly higher rates of SGA use among African Americans (52%) compared to others (44%) with bipolar disorder. Given evidence from previous studies that racial differences in SGA prescriptions may be closing, future studies should consider including race by time interaction terms in their statistical analyses.
The effects of medical comorbidities on SGA initiation appeared relatively small when results for all SGAs were combined, which makes intuitive sense given the heterogeneity of cardiometabolic risk profiles among the SGAs we studied. As expected, certain medical comorbidities were associated with substantial differences in prescribing practices for specific SGAs. Notably, individuals with preexisting diabetes, obesity, or hyperlipidemia were less likely to receive those SGAs with more prominent cardiometabolic effects (olanzapine, quetiapine and risperidone). Patients with substance abuse, in contrast, were more likely to receive these drugs: the sedating effects of these SGAs may be seen as desirable in treating patients with substance abuse disorders in whom benzodiazepines are considered inadvisable. Contrary to expectations, quetiapine was not statistically more likely to be prescribed than aripiprazole for individuals with sleep disorders. It should be noted, however, that providers would only be likely to provide a sleep disorder diagnosis if a patient's sleep troubles occurred independently of their bipolar condition (e.g. sleep apnea), which may reflect a complex population in whom sedating drugs would be avoided.
Regional variation in SGA initiation after controlling for covariates was marked by higher rates of SGA use in the South. Veterans in this region of the country have lower self-reported mental and physical quality of life than other regions, perhaps reflecting poorer clinical course or sociodemographic differences. However, analyses both in this bipolar population and among veterans with PTSD indicate prominent regional variation despite extensive control for demographic and clinical characteristics. This finding may thus reflect regional differences in provider practice patterns, commonly reported across many health domains.
Limitations
Although administrative data provided a very large sample (n > 125,000 patients), it has the disadvantage of relying upon clinicians' diagnostic coding accuracy. Some conditions (e.g. obesity, sleep disturbance) may have been present and influenced treatment decisions and yet not been coded by clinicians. Similarly, codes for bipolar mixed episodes were not reliably utilized, although patients suffering mixed manic and depressive symptoms may be more responsive to SGAs than to other antimanic medications. Furthermore, we could not include data on non-VA prescribing. In addition, we opted to approach these analyses primarily as class analyses, although we secondarily conducted a priori analyses on specific SGAs and specific clinical correlates. Our current analyses did not include data on provider variables (e.g. demographics, academic affiliation, training background), but this is a clear direction for future research. Finally, our primary comparison was between patients initiating SGAs and those not initiating SGAs; we did not conduct additional analyses with different comparison groups (e.g. patients initiating lithium or other antimanics). Future research on SGA initiation exploring provider-level variables and using these other comparison groups would help shed further light on prescribers' initial medication decision for bipolar disorder.