17 June 2010. New findings challenge the prevailing view that first-generation antipsychotic drugs, such as haloperidol, only enlarge structures in the basal ganglia. Heike Tost, of the University of Heidelberg in Mannheim, Germany, and colleagues found that a single infusion of haloperidol quickly, but reversibly, shrank striatal regions in healthy men. Their study, published online in Nature Neuroscience on June 6, ties striatal volume loss to extra-pyramidal symptoms, which may reflect an uncoupling of key brain regions involved in movement. The researchers suggest that dopamine D2 receptors, a target of all antipsychotic drugs, mediate short-term neural plasticity and that striatal volume loss may serve as marker for extra-pyramidal side effects.
Any antipsychotic drug can cause tremors, muscle rigidity, involuntary muscle contractions, slowed movement, physical restlessness, or other extra-pyramidal symptoms. These side effects can hinder patients’ work, social interactions, and treatment adherence (see Haddad and Dursun, 2008).
The striatum, a region of interest in schizophrenia (see SRF related news story; SRF news story), serves as a hub for integrating cortical function with movement (for an overview, see Tisch et al., 2004). When antipsychotic drugs block too high a percentage of striatal D2 receptors, they increase the risk of extra-pyramidal symptoms (see Wong et al., 2007). Because these drugs can trigger gene expression changes in rodents within 15 minutes (Kovács et al., 2001), Tost, colleague Dieter Braus at the University of Heidelberg, and others examined the short-term effects of antipsychotic drug administration on human brain structures. Specifically, they looked at the so-called “typical” antipsychotic haloperidol, known to confer a high risk of extra-pyramidal symptoms (see SRF related news story and SRF news story).
Too little teamwork in the brain
A sample of seven men, ages 22 to 27, who had no history of mental illness or antipsychotic drug use, received haloperidol intravenously. All underwent neuroimaging before they received the drug, one to two hours after the infusion, and 24 hours later, a time corresponding to the drug’s half-life.
High-resolution structural magnetic resonance imaging showed a loss of gray matter in the striatum, particularly in the ventral putamen, from baseline to an hour or two after the infusion. The striatum lost more volume than any other brain region, but regained some of it within 24 hours. To assess extra-pyramidal symptoms, the study used a reaction time task that required subjects to press a computer key whenever they saw a certain stimulus. The greater the early striatal volume loss, the worse subjects did on this task.
Covariance analysis showed that, within two hours of infusion, a structural disconnect appeared between the ventral putamen and other regions important for movement—specifically, the dorsal putamen, thalamus, and motor cortices. This trend later reversed, in line with haloperidol’s pharmacokinetics.
Function seemed to echo structure. As subjects performed a finger-tapping task, an indicator of short-term motor control, functional magnetic resonance imaging revealed an unyoking of the motor pathways between the striatum and the motor cortex one to two hours after drug administration. In all but one subject, the functional ties normalized by the end of the study. The early striatal volume loss explained 67 percent of the variance in the functional uncoupling. In turn, the latter accounted for 74 percent of the variance in motor impairment.
The changes seen in these subjects did not appear in unmedicated, but otherwise matched, control subjects, bolstering the case that they reflect drug effects. As for the mechanisms behind the findings, Tost and colleagues think that the time course rules out changes in blood flow or cell number as an explanation. They noted that, over the long haul, D2 receptor blockers may foster remodeling at synapses, but on an acute basis, they may actually do the opposite. “Although previous work in humans has reported structural changes on a timescale of days to months, the drug-induced remodeling that we found suggests that dopamine D2 receptors have a role in short-term human neural plasticity,” they wrote. They suspect that brain-derived neurotrophic factor (BDNF) might be involved.
What to make of it?
If replicated, this study will need to be reconciled with prior findings that first-generation antipsychotics bulk up striatal structures, including the caudate and the putamen, over weeks or months of treatment (for related reviews, see Brandt and Bonelli, 2008; Smieskova et al., 2009; Navari and Dazzan, 2009). It leaves unresolved the issue of whether second-generation antipsychotics would produce the same effect, but some prior studies (e.g., McClure et al., 2008) hint that these drugs leave striatal volume relatively unchanged after weeks or months.
Since the study looked only at healthy subjects, its ramifications for schizophrenia have yet to crystallize. Other questions that need answering include whether the findings will hold up in larger samples (that include female subjects), in subjects who receive haloperidol orally, and in those exposed to antipsychotic drugs other than haloperidol. Clarifying the short- and long-term effects of antipsychotic drugs on striatal structures could keep researchers busy for some time!—Victoria L. Wilcox.
Tost H, Braus DF, Hakimi S, Ruf M, Vollmert C, Hohn F, Meyer-Lindenberg A. Acute D(2) receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci. 2010 Jun 6. Abstract