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Exploring Mechanisms for the Bad Behavior of Atypical Antipsychotics

24 August 2012. Up to three quarters of schizophrenia patients taking antipsychotics discontinue their treatment because they find the drug isn’t effective at treating their symptoms or because the side effects, such as sedation and weight gain, are intolerable (Lieberman et al., 2005). Three recent studies have identified potential mechanisms underlying some of these undesirable consequences of both atypical and typical antipsychotics.

A study published online August 5 in Nature Neuroscience by Javier González-Maeso, of New York’s Mount Sinai School of Medicine, and colleagues suggests that clozapine’s decrease of metabotropic glutamate 2 (mGlu2) receptor transcription through an increased binding of HDAC2 to the mGlu2 promoter region may explain why atypicals don’t work for some patients. The researchers also implicated serotonergic signaling, as the HDAC2 effects were serotonin 2A (5HT2A) receptor dependent. Interestingly, they also show that an HDAC inhibitor prevented these mGlu2 promoter region changes and enhanced the effects of antipsychotics in vitro and in behavioral tests, resurrecting the idea that histone deacetylase (HDAC) inhibitors, for example, valproate, could be effective as adjunctive therapy to atypical antipsychotics in treatment-resistant schizophrenia. However, the challenge for this new insight is that valproate and similar drugs have indeed been tested in schizophrenia, and have not distinguished themselves as effective against primary symptoms in well-constructed clinical trials (reviewed in Citrome, 2009).

Two recent papers in Neuropsychopharmacology also examine a role for serotonin in the sedation of atypicals. In a study appearing in the September issue, led by Amelia Gallitano of the University of Arizona College of Medicine in Phoenix—also a coauthor on the González-Maeso Nature Neuroscience paper—researchers suggest that 5HT2A receptors, but not histamine H1 receptors as previously thought, are responsible for clozapine’s suppression of locomotion in mice, thought to model the sedative properties of atypicals in humans. Another study by Caitlin McOmish of Columbia University in New York, published online August 8, provides additional evidence that 5HT2A receptor antagonism underlies this locomotor suppression, but shows that it alone does not account for the reduction in extrapyramidal symptoms (EPS) seen with atypicals compared to typical antipsychotics.

Connecting mGlu2, HDAC2, and 5HT2A
González-Maeso’s group has previously reported that treatment with atypical antipsychotics decreases mGlu2 expression in mouse frontal cortex (González-Maeso et al., 2008). Since alterations in glutamatergic neurotransmission have been implicated in schizophrenia (see SRF Hypothesis), and agonists of mGlu2 receptors have been in serious development as antipsychotic agents (see SRF related news story), the researchers wondered if the lowered mGlu2 expression might diminish the effects of atypicals. If so, this might explain why approximately 30 percent of schizophrenia patients do not respond to antipsychotic treatment (Lieberman et al., 2005).

First author Mitsumasa Kurita and colleagues suspected that chromatin remodeling might be a potential mechanism for the downregulation of mGlu2 following atypical antipsychotic treatment, since this epigenetic process has recently been implicated in the response to antipsychotic treatment (Dong et al., 2008). To investigate this possibility, the researchers quantified the modifications of histones, the proteins around which DNA is wound, at the promoter region of the mGlu2 gene in mouse frontal cortex after treatment with clozapine, and found a decrease in transcriptional-activating histone H3 acetylation. Similar results were obtained using postmortem prefrontal cortex (PFC) tissue from schizophrenia subjects treated with atypical antipsychotics (but not those who were antipsychotic naïve).

Given the observed reduction in histone acetylation, the authors examined the effect of chronic atypical antipsychotic treatment on levels of HDACs—the gene-repressing enzymes responsible for the deacetylation of lysine residues on histones. Clozapine increased both the mRNA and protein levels of HDAC2, but not other HDACs, in mouse frontal cortex, and similar increases were observed in postmortem PFC tissue of individuals treated with atypicals. The upregulation of HDAC2 by clozapine was serotonin 2A (5HT2A) receptor dependent, as it was absent in 5HT2A-null mutant mice, consistent with the known high affinity of clozapine for these receptors. Clozapine treatment increased the binding of HDAC2 to the mGlu2 promoter region, a process that was also 5HT2A dependent.

The researchers then showed that the HDAC inhibitor SAHA was able to increase mGlu2 mRNA expression and H3 histone acetylation at the mGlu2 promoter in mouse frontal cortex in vivo, and to reverse the downregulation of mGlu2 expression after clozapine treatment, suggesting that the drug is able to prevent the repressive epigenetic changes induced by the atypical antipsychotic. Behavioral experiments also demonstrated that SAHA is able to augment the responses to mGlu2-dependent behaviors. Neither SAHA nor a low dose of the mGlu2/3 agonist alone was able to reduce MK801-induced locomotor hyperactivity, but both drugs combined did produce a significant effect. In addition, both SAHA and the mGlu2/3 agonist were able to attenuate the MK801-induced prepulse inhibition deficits to a similar degree.

According to the authors, their data suggest a reason why some patients don’t respond to antipsychotics. “We propose that atypical antipsychotic drugs induce a selective upregulation of HDAC2 in frontal cortex of individuals with schizophrenia, which alters the chromatin state of the mGlu2 promoter and thereby limits the therapeutic effects of these agents.”

5HT2A’s role in side effects
Gallitano and colleagues have previously studied mice deficient in early growth response 3 (Egr3), which exhibit locomotor hyperactivity. Clozapine can reverse this hyperactivity, but at a dose that impairs the locomotor activity of wild-type animals (which, the researchers say, is analogous to clozapine’s sedating effects in humans). Thus, Egr3-deficient mice are relatively resistant to the locomotor-suppressing effects of clozapine. In the current study, the researchers used a pharmacological dissection approach to identify the receptors in clozapine’s binding profile that may underlie this resistance and thus shed light on the mechanisms underlying the sedative properties of clozapine.

Though these sedative properties of clozapine have previously been attributed to histamine H1 receptors and α-adrenergic receptors (Casey, 1997), antagonists of these receptors showed similar levels of locomotor suppression in wild-type and Egr3-deficient mice, indicating that neither was responsible for the resistance of Egr3-deficient mice to clozapine-induced locomotor suppression. Given that atypicals, but not typical antipsychotics, display a high affinity for 5HT2A receptors, the authors next hypothesized that these receptors may be responsible. Consistent with this idea, two different 5HT2A receptor antagonists produced a similar effect as clozapine, suppressing locomotion in wild-type but not Egr3-deficient mice. In addition, the researchers observed an almost 70 percent reduction in 5HT2A receptor expression in the prefrontal cortex, and a reduced behavioral response to a 5HT2A-dependent behavior (the head-twitch response) in Egr3-deficient mice.

In a second study, McOmish and colleagues report that 5HT2A knockout mice also show a resistance to the locomotor suppression induced by clozapine compared to wild-type animals. In contrast, 5HT2C knockout mice do not display this response. Adding 5HT2A receptor expression back into cortical and hippocampal glutamate neurons of 5HT2A knockout mice restored clozapine’s suppression of locomotion. This effect was not observed when the same approach was used to restore 5HT2A expression on dopamine neurons. Thus, clozapine’s suppression of locomotion was driven by 5HT2A receptors located in forebrain glutamatergic neurons.

McOmish and colleagues also examined the claim that the added 5HT2A receptor antagonism of atypicals may account for the reduction in EPS associated with these drugs compared to typical antipsychotics (Meltzer and Massey, 2011). EPS include a variety of movement disorders such as akathisia and dystonia, and can be assessed in the mouse using catalepsy behavior (muscular rigidity and fixed posture). If 5HT2A receptor antagonism underlies the fewer EPS symptoms reported with atypicals, the researchers hypothesized that administering the typical antipsychotic haloperidol in combination with a 5HT2A antagonist or to a 5HT2A knockout mouse would diminish EPS. In contrast, they found that catalepsy after haloperidol was not affected in 5HT2A knockout mice. However, there was some attenuation of catalepsy in mice treated with a combination of 5HT2A and 5HT2C antagonists. Thus, 5HT2A receptor antagonism alone does not seem to underlie the reduction in extrapyramidal symptoms observed with atypical compared to typical antipsychotics.—Allison A. Curley.

Kurita M, Holloway T, García-Bea A, Kozlenkov A, Friedman AK, Moreno JL, Heshmati M, Golden SA, Kennedy PJ, Takahashi N, Dietz DM, Mocci G, Gabilondo AM, Hanks J, Umali A, Callado LF, Gallitano AL, Neve RL, Shen L, Buxbaum JD, Han MH, Nestler EJ, Meana JJ, Russo SJ, González-Maeso J. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci . 2012 Aug 5. Abstract

McOmish CE, Lira A, Hanks JB, Gingrich JA. Clozapine-Induced Locomotor Suppression is Mediated by 5-HT(2A) Receptors in the Forebrain. Neuropsychopharmacology . 2012 Aug 8. Abstract

Williams AA, Ingram WM, Levine S, Resnik J, Kamel CM, Lish JR, Elizalde DI, Janowski SA, Shoker J, Kozlenkov A, González-Maeso J, Gallitano AL. Reduced Levels of Serotonin 2A Receptors Underlie Resistance of Egr3-Deficient Mice to Locomotor Suppression by Clozapine. Neuropsychopharmacology . 2012 Sep ; 37(10):2285-98. Abstract

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