The influence of clozapine treatment and other antipsychotics on the 18 kDa translocator protein, formerly named the peripheral-type benzodiazepine receptor, and steroid production

Danovich, Lena; Veenman, Leo; Leschiner, Svetlana; Lahav, Michal; Shuster, Vered; Weizman, Abraham; Gavish, Moshe

doi:10.1016/j.euroneuro.2007.04.005

Cited by 34 publications

(20 citation statements)

References 54 publications

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“…Indeed, it has been shown in vitro that TSPO expression is reduced in cell lines treated with most atypical antipsychotics, apart from clozapine, which tended to increase TSPO expression. 21 In the present study, no significant differences between patients on or off antipsychotics were found, but subgroups were small. Future studies may be able to address this issue by examining antipsychotic naive patients, which so far has only been performed in ultra-high-risk individuals.…”

Section: Discussioncontrasting

confidence: 62%

In vivo (R)-[11C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis

et al. 2016

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Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various in vivo and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer (R)-[11C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis in vivo at an early stage of the disease. (R)-[11C]PK11195 binding potential (BPND) was measured in 19 patients with recent onset psychosis and 17 age and gender-matched healthy controls. Total gray matter, as well as five gray matter regions of interest (frontal cortex, temporal cortex, parietal cortex, striatum, and thalamus) were defined a priori. PET data were analysed using a reference tissue approach and a supervised cluster analysis algorithm to identify the reference region. No significant difference in (R)-[11C]PK11195 BPND between patients and controls was found in total gray matter, nor one of the regions of interest. These findings suggest that microglia activation is not present in recent onset psychosis or that it is a subtle phenomenon that could not be detected using the design of the present study.

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Section: Discussioncontrasting

confidence: 62%

In vivo (R)-[11C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis

et al. 2016

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“…Furthermore, we have determined earlier that clozapine markedly elevates pregnenolone levels in rat hippocampus and serum to a greater degree than other second-generation antipsychotics at doses producing comparable striatal D 2 receptor occupancies, representing a candidate mechanism for its superior efficacy (Marx et al , 2006a). Recent evidence that clozapine enhances the binding of the translocator protein involved in the rate-limiting step leading to pregnenolone formation from cholesterol (formerly referred to as the peripheral-type benzodiazepine receptor, (Lacapere and Papadopoulos, 2003)) supports a role for this neurosteroid in clozapine mechanisms of action (Danovich et al , 2008). In addition, pregnenolone is present in human brain tissue at physiologically relevant concentrations in the nanomolar range that are greater than 10-fold higher than those frequently observed in serum or plasma (Marx et al , 2006c) and known to positively impact learning and memory (Flood et al , 1992).…”

Section: Discussionmentioning

confidence: 99%

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

Marx

Keefe

Boyer

et al. 2009

Neuropsychopharmacol

163

158

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The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

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“…These include ethanol, etifoxine, gamma-hydroxybutyrate, and clinically-used psychotropic medications, including the antidepressant fluoxetine and the antipsychotics clozapine and olanzepine [27–29]. It remains unclear whether neurosteroids contribute to actions of the latter agents, although sedating and anxiolytic effects could result from this mechanism.…”

Section: Neurosteroid Synthesis and Cns Effectsmentioning

confidence: 99%

The sticky issue of neurosteroids and GABAA receptors

Chisari

Eisenman

Covey

et al. 2010

Trends in Neurosciences

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Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABA A receptors. Thus, they are of physiological and clinical relevance for their ability to modulate inhibitory function in the central nervous system. Despite their importance, fundamental issues of neurosteroid actions remain unresolved. Recent evidence suggests that glutamatergic principal neurons, rather than glia, are major sources of neurosteroid synthesis. Other recent studies have identified putative neurosteroid binding sites on GABA A receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane domain binding sites within GABA A receptors. This has implications for the design of future neuroactive steroids, since the lipid solubility and related accessibility properties of the ligand may be key determinants of receptor modulation. OverviewEndogenous neurosteroids and their synthetic analogues (neuroactive steroids) are among the most potent and effective modulators of γ-aminobutyric acid-A (GABA A ) receptors known [1]. Although a role for neurosteroids as endogenous modulators has been postulated for nearly thirty years, fundamental issues of neurosteroid actions on circuits, cells, and receptors remain unresolved. For instance, which cells in the CNS synthesize neurosteroids? Once synthesized, how, where, and at what concentrations do these modulators reach their target receptors? Recent evidence suggests that principal neurons, rather than glia, may dominate CNS neurosteroid synthesis. Other studies have identified putative neurosteroid binding sites on GABA A receptors. Parallel pharmacological approaches have implied a non-classical interaction between neurosteroid ligands and GABA A receptors, involving a membrane route of access and a low-affinity receptor interaction for neurosteroids. Here, we discuss our opinion

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The influence of clozapine treatment and other antipsychotics on the 18 kDa translocator protein, formerly named the peripheral-type benzodiazepine receptor, and steroid production

Cited by 34 publications

References 54 publications

In vivo (R)-[11C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis

In vivo (R)-[11C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

The sticky issue of neurosteroids and GABAA receptors

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