In this large longitudinal cohort of patients with schizophrenia (211 patients with 674 MRI scans) who were in their first episode and had received minimal treatment at the time of entry into the study, we examined the independent effects of 4 variables on progressive brain change during an extended period: illness duration, antipsychotic treatment, illness severity, and substance misuse. We found that longer follow-up was associated with a greater decrease in brain tissue volumes. Antipsychotic treatment also had a significant influence on brain volumes even after accounting for the potential confounds of the other 3 variables. More antipsychotic treatment was associated both with generalized tissue volume reduction involving multiple subregions and with a specific increase in putamen. The other 2 variables, severity of illness and substance abuse, had minimal or no effects. Progressive brain volume changes during the lifelong course of schizophrenia, including GM and WM volume reductions, CSF volume expansions, and basal ganglia volume enlargements, appeared in part to be related to antipsychotics. These findings may potentially have clinical implications for the use of long-term antipsychotic treatment.
The plausibility of long-term antipsychotic treatment leading to global brain volume reductions is further supported by recent controlled studies in macaque monkeys.19–21
Animal studies provide an additional perspective on possible causative links because they permit postmortem neuropathological examination of the brain. Dorph-Petersen et al19
administered haloperidol, olanzapine, or sham medication to macaque monkeys in doses that produced plasma levels equivalent to those observed in treatment of schizophrenia patients. After 17 to 27 months of treatment, both haloperidol- and olanzapine-treated monkeys had an equivalent and highly significant 8% to 11% decrease in fresh brain weight and volume when compared with the sham group. These decreases affected all major brain regions but were most robust in frontal and parietal lobes. The neuropathological manifestations of antipsychotic-related frontoparietal volume reductions in macaque monkeys involves decreased astrocyte numbers, decreased dendritic arborization, decreased dendritic spine density, and increased neuronal density with no neuronal loss.20,21
Although there have been some conflicting findings in the nonhuman primate literature (eg, studies by Lidow et al41
and Sweet et al42
), these neuropathological changes are strikingly similar to those described in the schizophrenia postmortem literature (eg, studies by Pakkenberg43
and Selemon et al44
These findings are also consistent with previous MRI studies suggesting that antipsychotics produce changes in the human brain that are measurable by in vivo neuroimaging techniques. The earliest work with morphometric MRI found increased basal ganglia size in schizophrenia patients, typically in the putamen.45,46
Subsequent studies have shown that this may be a medication effect and that typical antipsychotics in particular play a causal role in basal ganglia enlargement.47–51
Positron emission tomography studies measure cerebral blood flow and, by inference, cellular metabolism. Previous positron emission tomography studies conducted by our group52–54
confirm that both typical and atypical antipsychotics increase putamen cerebral blood flow. In addition, antipsychotics reduce frontal cerebral blood flow, suggesting that chronic frontal hypoperfusion could be a mechanism underlying smaller brain tissue volumes. However, the available studies that have used morphometric MRI to examine the effects of antipsychotics on cortical GM have yielded ambiguous results,10,55–57
possibly due to small sample sizes, differing duration of treatment assessment, variation in brain regions measured, and discrepant measurement techniques.
In the present study, WM but not GM volumes showed significant time × antipsychotic treatment interaction effects. Although higher antipsychotic doses were associated with a decrease in GM volumes, this relationship did not appear to change during the course of longitudinal follow-up in our study. A change in WM volume trajectories, on the other hand, was associated with antipsychotic treatment. As illustrated by the extreme tertile treatment group comparisons, patients in the most-treatment group had longitudinal WM volume reductions. As a group, patients with the least treatment showed WM volume increases over time that would be expected of individuals during their third and fourth decades of life.58
Bartzokis and colleagues59
previously found that patients with schizophrenia do not show the normal age-related WM volume expansion during early to mid-adulthood. Thus, the treatment × time interaction effects in the present study suggest that WM volume deficits in schizophrenia may, in part, be related to antipsychotic treatment. Our study found that all 3 classes of antipsychotics (ie, typical, nonclozapine atypical, and clozapine) were associated with deceases in GM brain volumes. The only differential effects on brain volumes between typical and nonclozapine atypical antipsychotics were in parietal WM and caudate measures. These typical-atypical differential effects on brain volumes in our study differ somewhat from a recent randomized treatment study.10
Lieberman and colleagues found that haloperidol treatment was associated with progressive GM volume reductions during that 2-year study. In contrast, olanzapine-treated patients did not show GM volume decrement. This raises concerns regarding the possibility of typical antipsychotic-associated neurotoxic effects. Our study suggests that atypical antipsychotic treatment may mitigate parietal WM volume loss in patients with schizophrenia; this finding needs to be interpreted with caution and will require support from additional well-designed clinical trials in first-episode patients.
Our results must be interpreted in the context of additional limitations. Identifying an association does not necessarily indicate a causal relationship. Furthermore, observational studies involving long durations such as ours inevitably preclude use of the “gold standard”: a random-assignment controlled trial. The current study could have been strengthened by having control groups, eg, schizophrenia patients assigned to deferred or no antipsychotic treatment or healthy volunteers treated with antipsychotics for comparable periods. However, ethical standards in human subject research prohibit such comparison groups. The small number of schizophrenia patients in our sample who received no antipsychotic treatment did not allow for meaningful statistical analyses. Illness severity and antipsychotic dosages were modestly correlated (Spearman r=−0.21), and patients who received the most treatment had smaller baseline cerebral tissue volumes. Associations between smaller brain tissue volumes and more antipsychotic treatment may still be moderated via illness severity despite our inclusion of illness severity as a covariate and obtaining similar results from different measures of illness severity. Even with the most sophisticated statistical methods, we may not be able to fully distinguish the potential confounding influences that illness severity or other sources of unmeasured variance could still have on the relationships between progressive brain volume reductions and antipsychotic treatment. Last, although our Talairach atlas–based lobar measures have well-established reliability and validity, these cerebral brain volumes lack precision to delineate abnormalities within smaller subregions implicated in schizophrenia (eg, superior temporal gyrus and prefrontal cortex).
Findings from the present study raise several clinical questions. Are antipsychotic-associated GM and WM volume reductions “bad” for patients? The implicit assumption is that brain volume reductions are probably undesirable because patients with schizophrenia already have diffuse brain volume deficits at the time of illness onset. Schizophrenia patients with poor outcomes are also more likely to have smaller brain volumes. However, the neurobiological changes that underlie MRI measurements of antipsychotic-associated brain volume decrement remain poorly understood. Some studies indicate that antipsychotic-induced changes mimic the neuropathologycal changes of schizophrenia,20,21
while others suggest otherwise.41,42
If antipsychotics do indeed result in deleterious brain tissue volume reductions, how does this influence the risk-benefit ratio of antipsychotic treatment? Given that these medications have substantially improved the long-term prognosis of schizophrenia and that schizophrenia is a disease with significant morbidity, continued use of antipsychotics is clearly still necessary. However, our findings point toward the importance of prescribing the lowest doses necessary to control symptoms. They also imply the need for rethinking the underlying pathological processes in schizophrenia,47,48
the target at which treatment is aimed, and the possibility that antipsychotic treatment may improve psychotic symptoms but also contribute to progressive brain tissue volume deficits. Antipsychotics were designed for the purpose indicated by their name, ie, to arrest psychosis. Not only is it probable that antipsychotics do not treat the fundamental pathophysiologic mechanism of schizophrenia (ie, the brain disease), but we perhaps must also entertain the possibility that they might have potentially undesirable effects of brain tissue volume reductions. In conjunction with neuroscientists and clinical investigators, pharmaceutical companies must continue the vigorous search for agents that are genuinely neuroprotective.
The second-generation antipsychotics are also now widely used for people who do not have schizophrenia, including children, the elderly, and patients with bipolar disorder or depressive disorders.27–30
They are also used in adolescents who have been identified to be at high risk for schizophrenia. Our findings may lead to heightened concerns regarding potential brain volume changes associated with the sharp rise in atypical antipsychotic use in non-schizophrenia psychiatric disorders. Even though no studies have assessed the long-term effects of antipsychotics on brain volumes in nonschizophrenia patients, our results suggest that antipsychotics should still be used with caution in these patient groups after careful risk-benefit assessment. Because typical antipsychotics are off patent and less expensive than atypical ones, there is also a growing trend to prescribe them preferentially for patients with schizophrenia. Given that these older medications carry a greater risk of producing extrapyramidal adverse effects and tardive dyskinesia, such a shift in clinical practice may produce deleterious effects on the primary diseased organ in schizophrenia: the brain.