The present study found that schizophrenia patients receiving olanzapine showed a significant increase in PPI over time (the other two groups did not), and greater PPI compared to patients receiving risperidone after 8 weeks of treatment. There were no effects of medication or time, despite equivalent baseline scores, on either startle habituation or startle reactivity.
These findings are mainly consistent with prior studies examining effects of antipsychotic medication on PPI in schizophrenia patients. Several uncontrolled studies have reported improvement in PPI with atypical antipsychotic medications, showing superiority of atypical vs. conventional medication in reversing PPI deficits or showing atypicals normalizing PPI compared to normal controls. However, to date only two of these studies utilized a randomized design. Quednow et al. (2006)
, utilizing a longitudinal, double-blind design, showed that both amisulpride and olanzapine improved PPI in schizophrenia patients, with no difference in PPI between the two medication groups, providing support that D2/D3 antagonists reverse schizophrenia-related PPI deficits. However, the “improvement” in PPI was seen only in comparison to normal controls, whose PPI habituated across test sessions. For the schizophrenia patients, there was very little change in PPI in either medication group. However, Mackeprang et al. (2002)
, utilizing a randomized but not double-blind design, found no differences in PPI in patients randomized to either conventional or atypical antipsychotics, with both groups showing lower PPI compared to normal controls.
Our results are also consistent with findings in animal models of disrupted PPI. These animal studies show that both conventional and atypical antipsychotic medications reverse apomorphine-induced deficits in PPI (Swerdlow et al., 1994
). In contrast, olanzapine (but not risperidone or haloperidol) is highly effective at reversing NMDA antagonist-induced PPI deficits, mostly in rodent models (Bakshi & Geyer, 1995
; Duncan et al., 2000
; Geyer et al., 2001
). In general, rodent model studies show that NMDA antagonist-induced PPI deficits are selectively reversed by second- vs. first-generation antipsychotic medications (Bubenikova et al., 2005
; Geyer & Ellenbroek, 2003
; Geyer et al., 2001
). The results from the current study are consistent with this animal literature in NMDA models. However, the specific mechanisms for such differences in PPI effects remain unknown. Also, despite the moderate to high level of homology between rodents and humans, key differences make inferences based on animal model studies of the NMDA system challenging. For example, the glutamate antagonist ketamine has been observed to increase PPI in normal human subjects, which is opposite from what would be predicted based on the animal literature (for discussion see Braff et al., 2001b
The study merits a few caveats: First, the study did not include healthy controls, so we cannot compare PPI in the patients at baseline to controls, and do not know if antipsychotic medication restored PPI to normal levels. However, it appears that the schizophrenia patients are within the range of “normal” PPI by week 8, based on the reported means from normal controls in previous reports (e.g., Braff et al., 2001a
; Quednow et al., 2006
; Swerdlow et al., in press
). Second, there were fewer subjects in the haloperidol group, and few who completed testing, compared to the other two randomization groups, potentially limiting the conclusions about the effectiveness of haloperidol in improving PPI. Future studies will need to ensure that adequate numbers of subjects are included in each group.
Third, smoking was not controlled in this study (and almost all similar studies). It has been demonstrated that nicotine administration briefly enhances PPI in normal controls (Duncan et al., 2001
; Kumari et al., 1996
; Postma et al., 2006
). Furthermore, it has been demonstrated that schizophrenia patients who smoked immediately prior to a PPI session (< 5 minutes) produced greater PPI compared to patients who did not smoke within an hour of testing (Kumari et al., 2001
). Although smoking might have influenced the results, it is probable that randomization would have equalized this factor across groups. Future longitudinal studies should more rigorously control for smoking (e.g., Swerdlow et al., 2006
). Fourth, menstural cycle phase (i.e., follicular vs. luteal phase) was not measured in women who were menstruating. It has been shown that women in the luteal phase, but not the follicular phase, show lower PPI than men (Jovanovic et al., 2004
; Swerdlow et al., 1997
). It is possible that women who were menstruating and in the luteal phase may have shown lower PPI thus affecting the results of the current study. Future studies will need to control for menstrual cycle phase in women.
Fifth, the olanzapine group showed a trend to have a relatively larger proportion of Caucasians compared to the other two groups. While no study to our knowledge has examined differences in PPI or startle between Caucasians and African Americans, it is possible that racial differences exist. Importantly, there were no differences in PPI (or startle amplitude) between African American and Caucasian schizophrenia patients at baseline, consistent with the observation of non-significant racial effects in PPI for normal Caucasians and Asian Americans (Swerdlow et al., 2005
). In addition, ongoing studies of PPI as one endophenotype in the Consortium on the Genetics of Schizophrenia (COGS) should ultimately clarify these racial results (Braff et al., 2007
; Turetsky et al., 2007
). Another consideration is that the study used fixed doses of antipsychotic medication. The doses of medications used in the current study were chosen to approximate modal doses for Veterans Administration Health Services patients at the time of study initiation. It is possible that different doses of risperidone or haloperidol might have resulted in improvements in PPI, particularly since it has been suggested that “effective” doses of conventional medications may also enhance PPI (Weike et al., 2000
). Further controlled studies should examine the effects of dose response curves of these medications on PPI in schizophrenia patients. A final caveat is the relatively short duration of the current study. It is possible that significant PPI improvements could be seen with risperidone or haloperidol given a longer study period.
In conclusion, this study found that olanzapine significantly improved PPI in schizophrenia patients, expanding upon past findings from schizophrenia patients and rodent models delineating the effects and mechanism of action of antipsychotic medications on PPI. This is the first longitudinal randomized, double-blind controlled trial of three commonly prescribed antipsychotic medications that examine PPI in schizophrenia patients. The broader implications of medication-induced changes in PPI are not known, but may have functional and endophenotypic/genetic implications based on a recent report of an association between higher levels of PPI and higher global functioning (Swerdlow et al., 2006
). In addition, understanding pharmacogenetic factors that influence PPI response to medications may be complementary to information being gained about the genetic architecture underlying PPI (Braff et al., 2007