To our knowledge this is the first study to report that medication delivery mode (LAI versus oral) has a significant differential effect on any brain volume variable. During this treatment trial, RLAI seems to promote myelination and stabilize frontal lobe WM volume compared to the decrease observed with RisO ( and ). A considerable part of the observed changes in WM represent a myelination-driven shift of the GM/WM boundary into or out of the cortex. This is most clearly demonstrated by examining the RisO data that show the decrease in WM volume to be accompanied by an increase in GM volume (). Given that frontal lobe volume did not show a meaningful volume change, the most plausible explanation is that the changes in WM and GM detected by the myelin-sensitive IR images represent a shift of the GM/WM boundary (see and ).
The antipsychotic medication exposure at the time of the baseline and end point assessments likely influenced the absolute values of WM change. In a recent cross-sectional study of SZ (Bartzokis et al, 2011
), we examined a wide range of medication exposure durations to oral
antipsychotics (2.3 to 273 months) and observed that frontal lobe myelination was affected by treatment duration. The myelination trajectory was significantly quadratic, reaching a peak at one year of antipsychotic treatment followed by a decline that was markedly accelerated compared to healthy subjects who do not decline until after the fifth decade of life () (Bartzokis et al, 2001
; Bartzokis et al, 2011
). In the current study our assessment points spanned this peak in antipsychotic treatment-associated myelination (baseline assessment at 7.2 months with the follow up at 14.9 months). The decline in WM volume observed in the RisO group ( and ) is therefore consistent with the trajectory of decline that occurs after the first year of treatment. Furthermore, the non-significant increase in WM volume observed with RLAI suggests that the trajectory defined by oral antipsychotic treatment may be modifiable with RLAI. This modification in the trajectory seems to be primarily driven by the superior adherence to medication achieved with RLAI since both treatment arms received the same antipsychotic medication and only differed in delivery mode.
The change in frontal lobe WM volume was positively associated with reaction time performance specifically on subtests involving higher-order executive functioning of working memory and mental flexibility functions (). These functions are mediated by frontal lobe systems. This suggests that increased frontal lobe WM volume is associated with improved performance on cognitive measures. This relationship may be domain specific, as other measures from the Cogstate battery that capture simple reaction time involving response to stimuli or choosing between two stimuli without higher-level working memory demands were not associated with WM change. As explained above, the WM increase seems to be primarily due to an increase in myelination of the lower layers of the cortex that shifts the GM/WM border into the cortex, and therefore we observed essentially opposite and counterintuitive associations (better performance with decreased GM volumes).
An antipsychotic-induced increase in WM is also supported by our prior cross-sectional study which showed that, very early in treatment, both typical and atypical antipsychotics increase WM above that of healthy controls (Bartzokis et al, 2007
). This was recently confirmed by our second cross-sectional study, showing the antipsychotic medication exposure-related quadratic trajectory of WM volume described above (Bartzokis et al, 2011
). Although the WM increase may be greater with atypicals, this common
effect of typical and atypical antipsychotics on myelination is consistent with the shared ability of all known antipsychotics to block dopamine 2 receptors and the striking correlation between their affinity to this receptor and the clinically effective dose (Seeman, 2010
). The mechanism underlying an antipsychotic-induced myelination is likely indirect and may involve dopamine receptor blockade promoting increased intracortical myelination (reviewed in Bartzokis, 2011
). The current data suggests that consistent medication levels achievable with LAI may have an advantage in achieving and maintaining a higher WM volume.
The increased intracortical myelin early in treatment is also consistent with the observation from a non-human primate study where adherence to antipsychotic treatment was experimentally controlled. The study revealed that non-human primates exposed to either typical or atypical antipsychotics for six months had an increased
glial density (with unchanged neuronal density) (Selemon et al, 1999
). In that same study, risperidone was the only antipsychotic associated with a decline in cortical neuron density. Greater intracortical myelination reduces fixation-associated cortical shrinkage, and could thus account for this risperidone-associated decline in neuronal density (Bartzokis and Altshuler, 2005
; Bartzokis and Altshuler, 2003
). In addition, several rodent models suggest that exposure to antipsychotics may promote oligodendrocyte differentiation and myelin repair (Wang et al, 2010
; Xu et al, 2010
). On the other hand, another study using non-human primates showed that a loss
of glia may occur with oral antipsychotics when administered over much longer exposure times (17–27 months) (Konopaske et al, 2008
). Loss of oligodendrocytes and myelin is also observed at post mortem of older chronic SZ subjects after many years of treatment with oral antipsychotics (reviewed in Bartzokis, 2011
Adherence to medication treatment has been a chronic problem in the treatment of psychiatric disorders such as schizophrenia. Atypical antipsychotics are associated with lower risk of acute and chronic extrapyramidal side-effects, which may contribute to the better acceptance of both oral and LAI formulations (reviewed in Keith, 2009
). The improved clinical outcomes, decreased hospitalizations, and significant healthcare cost savings associated with RLAI (Lindenmayer et al, 2009
; Olivares et al, 2009b
; Velligan et al, 2009
; Willis et al) (reviewed in Keith, 2009
) have spurred efforts to develop additional LAI treatments. However, these treatments remain underutilized, in part because of lack of clear biological evidence for benefits on disease progression and concerns about metabolic side-effects (reviewed in Keith, 2009
; Lindenmayer et al, 2009
). The current study suggests that the improved outcomes may be due to superior ability of RLAI to maintain frontal lobe myelination and supports the hypothesis that a promyelination effect may be a mechanism of action of antipsychotics (Bartzokis, 2002
; Bartzokis et al, 2011
) (reviewed in Bartzokis, 2011
Strengths of this study included the use of imaging sequences that optimally track the process of myelination (), excellent scoring reliability, prospective design, and a young cohort of first-episode SZ subjects randomly assigned to the two treatment arms. The study has several important limitations. The sample sizes of the treatment groups were small and not matched for race. Despite this limitation, treatment differences were apparent and remained significant when race was covaried ( and ). Complete cognitive data were available only at the follow-up time point, precluding the examination of change in cognitive scores against change in WM volume. The absence of matched subjects with very minimal pre-randomization antipsychotic exposure precluded assessment of very early medication-related changes in WM and, although all subjects were placed on RisO for at least 10 weeks before randomization, treatment occurring prior to study entry was not standardized. The availability of only two time-points limits our ability to define trajectories of change that our cross-sectional oral treatment data suggest is quadratic and peaks at approximately one year of antipsychotic treatment (Bartzokis et al, 2011
). Finally, our data suggest that antipsychotics may primarily change intracortical myelination () (Bartzokis et al, 2009
) (reviewed in Bartzokis, 2011
). To more fully define how LAI medications change the myelination trajectory beyond the first year of treatment, prospective randomized studies, over longer durations, and with multiple time points that also include measures of intracortical myelin are needed.
The advent of in vivo
neuroimaging methods that can dissect subtle differences in brain tissue characteristics may help clarify disease pathophysiology as well as the mechanisms of action of antipsychotic treatments. These methods can examine clinical as well as treatment response endophenotypes and thus improve targeting of treatment interventions. By modifying adherence, RLAI may differentially impact myelination and account for the better long-term outcomes of RLAI compared to the oral treatments. Improved treatment decisions and early intervention may make it possible to increase effectiveness of antipsychotic treatments and thus provide an opportunity to mitigate the biologic and clinical trajectories of decline into chronic/refractory states of disease (Bartzokis et al, 2011
; Lieberman, 2006