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Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
Copyright © 2017 Elsevier B.V. All rights reserved.
Little is known about chromosomal loopings involving proximal promoter and distal enhancer elements regulating GABAergic gene expression, including changes in schizophrenia and other psychiatric conditions linked to altered inhibition. Here, we map in human chromosome 2q31 the 3D configuration of 200 kb of linear sequence encompassing the GAD1 GABA synthesis enzyme gene locus, and we describe a loop formation involving the GAD1 transcription start site and intergenic noncoding DNA elements facilitating reporter gene expression. The GAD1-TSS(-50kbLoop) was enriched with nucleosomes epigenetically decorated with the transcriptional mark, histone H3 trimethylated at lysine 4, and was weak or absent in skin fibroblasts and pluripotent stem cells compared with neuronal cultures differentiated from them. In the prefrontal cortex of subjects with schizophrenia, GAD1-TSS(-50kbLoop) was decreased compared with controls, in conjunction with downregulated GAD1 expression. We generated transgenic mice expressing Gad2 promoter-driven green fluorescent protein-conjugated histone H2B and confirmed that Gad1-TSS(-55kbLoop), the murine homolog to GAD1-TSS(-50kbLoop), is a chromosomal conformation specific for GABAergic neurons. In primary neuronal culture, Gad1-TSS(-55kbLoop) and Gad1 expression became upregulated when neuronal activity was increased. We conclude that 3D genome architectures, including chromosomal loopings for promoter-enhancer interactions involved in the regulation of GABAergic gene expression, are conserved between the rodent and primate brain, and subject to developmental and activity-dependent regulation, and disordered in some cases with schizophrenia. More broadly, the findings presented here draw a connection between noncoding DNA, spatial genome architecture, and neuronal plasticity in development and disease.
Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague-Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition. The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.
Dopamine and other G protein-coupled receptors (GPCRs) represent the major target of antipsychotic drugs. GPCRs undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Arrestins and GRKs are major regulators of GPCR signaling. We elucidated changes in expression of two arrestins and four GRKs following chronic (21 days) treatment with haloperidol (1 mg/kg i.p.) or clozapine (20 mg/kg i.p.) 2 or 24 h after the last injection in 11 brain regions. Haloperidol decreased GRK3 in ventrolateral caudate-putamen and transiently down-regulated GRK5 in globus pallidus and caudal caudate-putamen. Clozapine also caused a short-term suppression of the GRK5 expression in the caudal caudate-putamen and globus pallidus, but, unlike haloperidol, elevated GRK5 in the caudal caudate-putamen after 24 h. Unlike haloperidol, clozapine decreased arrestin2 and GRK3 in hippocampus and GRK3 in globus pallidus but increased arrestin2 in the core of nucleus accumbens and ventrolateral caudate-putamen and GRK2 in prefrontal cortex. Clozapine, but not haloperidol, induced long-term activation of extracellular signal-regulated kinase (ERK) 2 in ventrolateral caudate-putamen and transient in prefrontal cortex. The data demonstrate that haloperidol and clozapine differentially affect the expression of arrestins and GRKs and ERK activity, which may play a role in determining their clinical profile.
Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia.
Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.
OBJECTIVE - To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.
RESEARCH METHODS AND PROCEDURES - Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.
RESULTS - Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.
DISCUSSION - A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.
Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17-0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.