Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Estrogen exerts profound effects on mood, mental state and memory by acting on both "classical" monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine2 (D2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome. and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated by way of 5-HT2A receptors. 3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains "social" or "olfactory" memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined. 4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as "Nature's" psychoprotectant.
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PMID:Estrogen control of central neurotransmission: effect on mood, mental state, and memory. 881

Estrogen is considered to play an important role in neuropsychiatric disorders and the estrogen receptors mediate the action of the hormone. In the present study, the messenger RNA expression pattern of the estrogen receptor alpha subtype was identified in the post mortem human brain. High stringent in situ hybridization histochemistry was performed using a riboprobe specific for the estrogen receptor alpha subtype. The human brain was mainly characterized by abundant estrogen receptor alpha messenger RNA expression in the amygdala and hypothalamus, but labeling (lower) was also found in the extended sublenticular amygdala, cerebral cortex, and hippocampus. In the amygdala, the estrogen receptor alpha messenger RNA was preferentially expressed in medially-localized nuclei suggesting that estrogen regulates distinct human amygdala-mediated functions. The Cynomologous monkey brain was also examined in the present study and a similar distribution of the estrogen receptor alpha messenger RNA signal was observed in the human and monkey brain. However, the primate expression pattern differed in part from the known distribution in the rat. The current results show that estrogen receptor alpha messenger RNA is expressed in discrete areas of the human brain not only related to neuroendocrine function, but also emotion, memory, and cognition, which is consistent with the hypothesized involvement of estrogen in schizophrenia, affective disorders, and Alzheimers disease.
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PMID:The human forebrain has discrete estrogen receptor alpha messenger RNA expression: high levels in the amygdaloid complex. 1065 12

This review highlights recent evidence from clinical and basic science studies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may also enhance recovery from traumatic neurological injury such as stroke. Recent basic science studies show that not only does exogenous estradiol decrease the response to various forms of insult, but the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Thus, our view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission and enhanced neurogenesis. Some of the mechanisms underlying these effects are independent of the classically defined nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the classical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades through direct interactions with protein kinases or that estrogen receptor signaling may converge with signaling by other trophic molecules to confer resistance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include the optimal ligand and doses that can be used clinically to confer benefit without undue risk, modulation of neurotrophin and neurotrophin receptor expression, interaction of estrogen with regulated cofactors and coactivators that couple estrogen receptors to basal transcriptional machinery, interactions of estrogen with other survival and regeneration promoting factors, potential estrogenic effects on neuronal replenishment, and modulation of phenotypic choices by neural stem cells.
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PMID:Neuroprotection by estradiol. 1104 Apr 17

Estrogen has been shown in animal studies to modulate both the dopamine and serotonin neurotransmitter systems - the main neurotransmitters implicated in the pathogenesis of schizophrenia. A double blind, 28 day, placebo-controlled study was conducted with three groups of women of child-bearing age (N=12 in each group) who received standardized antipsychotic medication plus 50mcg transdermal estradiol or 100mcg transdermal estradiol or transdermal placebo. Analyses show that women receiving 100mcg of estradiol made greater improvements in the symptoms of schizophrenia than both the 50mcg estradiol and placebo groups. Women receiving 50mcg estradiol had more improvement in their symptoms compared with the placebo group. The 100mcg estradiol group had significantly lower mean lutenizing hormone (LH) and higher mean prolactin levels across the study period compared with both the 50mcg and placebo groups. The addition of 100mcg adjunctive transdermal estrogen significantly enhanced the treatment of acute, severe psychotic symptoms in women with schizophrenia. The differential response of adding 50mcg versus 100mcg estradiol on the types of symptom affected may be related to the estrogen effect on LH and prolactin. The positive impact of estrogen treatment on psychotic symptoms by a direct effect on dopamine and serotonin systems or via an indirect prolactin-mediated effect may be very useful in the overall treatment of women with schizophrenia.
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PMID:Estrogen - a potential treatment for schizophrenia. 1127 60

Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor alpha (ERalpha) and the thyroid hormone receptor alpha (TRalpha) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance (all coding exons and flanking splice junctions) of the ERalpha and TRalpha genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ERalpha gene and 1.16 megabases of the TRalpha gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ERalpha gene, while only four silent mutations were present in the TRalpha gene. Two of the missense mutations in ERalpha are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ERalpha and TRalpha genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases.
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PMID:Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene. 1137 52

Tardive dyskinesia (TD) is an involuntary movement disorder induced by long-term antipsychotic treatments. Estrogen is suggested to modulate dopamine receptors in the central nervous system and may decrease the incidence and/or relieve the symptoms of TD. In this study, 118 schizophrenia patients with antipsychotic-induced TD and 128 sex- and age-matched non-TD schizophrenia patients were recruited. All patients were assessed by the Abnormal Involuntary Movement Scale and genotyped for the polymorphisms of estrogen receptor-alpha gene (ESR 1). There was a marginal association of the genotypes determined by PVU II between TD and non-TD patients (p = 0.057), but not of the genotypes determined by XBA I (p = 0.896). However, further studies on other polymorphisms of ESR 1 or other estrogen receptors are necessary to clarify the role of estrogen in the pathogenesis of TD.
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PMID:Association study of the estrogen receptor polymorphisms with tardive dyskinesia in schizophrenia. 1256 32

This article presents a systematic review of pharmacological treatment for negative symptoms of schizophrenia, based on MEDLINE searches from 1995 to September 2002 to identify pertinent clinical trials. The pharmacotherapy of negative symptoms in schizophrenia includes novel/atypical antipsychotics and classical antipsychotics, as well as antidepressants, glutamatergic compounds, antiepileptic drugs and estrogens. In the assessment of therapy for negative symptoms of schizophrenia, it is imperative that better studies of sound methodology are performed. In such studies, some important aspects to be considered include an accurate definition and assessment of negative symptoms (including well designed, valid and reliable rating scales), the differentiation between primary and secondary negative symptoms, an appropriate selection of standard comparators, adequate dosages of comparators (e.g. haloperidol dosages) and an overall optimal study design. Most of the available studies on treating negative symptoms in schizophrenia have focused on the atypical antipsychotics, while other potential candidates, mostly in the context of add-on therapy, have not been so intensively investigated. Atypical antipsychotics have been proven in placebo-controlled trials to be effective in treating negative symptoms of acute schizophrenic episodes. In many of the comparator studies, they showed efficacy in treating negative symptoms that was superior to that of typical antipsychotics. Data on stable, predominant negative symptoms in subchronic or chronic cases of schizophrenia, although limited, have demonstrated the efficacy of atypical antipsychotics. If the beneficial tolerability profile with respect to extrapyramidal symptoms is also taken into account during clinical decision making, the atypical antipsychotics should be preferred for the treatment of negative symptoms. It is also worth noting that the traditional antipsychotics have the risk of inducing negative symptoms in the context of akinesia. The benefits of add-on therapy with SSRIs or a glutamatergic compound are well documented. Estrogen add-on therapy seems promising. Other traditionally suggested approaches, such as comedication with an antiepileptic drug, lithium or beta-adrenoceptor antagonist, cannot generally be recommended on the basis of the available data.
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PMID:Management of the negative symptoms of schizophrenia: new treatment options. 1292 92

The estrogen hypothesis of schizophrenia postulates that estrogen exerts a protective effect against schizophrenia and that this partly explains the observed sex differences in premorbid adjustment, onset age, treatment response, and illness course. It has been suggested that estrogen supplementation can augment the treatment effects of antipsychotics. The purpose of the present investigation was to access the efficacy of ethinyl estradiol as an adjuvant agent in the treatment of premenopausal women with chronic schizophrenia in an 8-week, double-blind, and placebo-controlled trial. Eligible participants in the study were 32 women of childbearing age with schizophrenia. All patients were inpatients, in the active phase of illness, and met DSM-IV criteria for chronic schizophrenia. Patients were allocated in a random fashion, 16 to haloperidol 15 mg/day plus ethinyl estradiol 0.05 mg/day and 16 to haloperidol 15 mg/day plus placebo for an 8-week, double-blind, placebo-controlled study. Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of haloperidol and ethinyl estradiol showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms as well as Positive and Negative Syndrome Scale (PANSS) total scores. Although the means Extrapyramidal Symptoms Rating Scale (ESRS) for the placebo group were higher than ethinyl estradiol group, the differences were not significant over the trial. A significant difference was observed between the overall mean biperiden dosages in the two groups. The results of this study suggest that estrogen may be an effective adjuvant agent in the management of women of childbearing age with chronic schizophrenia. Nevertheless, results of larger controlled trials are needed before recommendation for a broad clinical application can be made.
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PMID:Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. 1449 18

The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT1A) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT(1A) receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.
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PMID:Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women. 1623 86

There is a wealth of historical and circumstantial evidence to suggest that female patients with schizophrenia may suffer from a deficit in estrogenic function. The prolactin-inducing properties of most antipsychotic drugs, and subsequent negative feedback on estrogen levels, is in keeping with this. The functions of estrogen, its complex receptor organization and its numerous actions are the focus of ongoing research activity. Of particular interest are its neuroprotective properties, particularly with regard to cognitive impairment, and its involvement with neurotransmitter systems, which are the substrate for psychotropic drugs. Estrogen has now been used as an adjunct to standard antipsychotic medication in quite a few studies of female schizophrenia patients. However, most of these are not double-blind, randomized, controlled trials. Only two relatively small double-blind, randomized clinical trials returned positive results: one long-term study that selected for hypoestrogenism reported negative findings. Furthermore, recent evidence of the risks of long-term hormone replacement therapy is of concern. The advent of specific estrogen receptor modulators, which may avoid excess risks of cancer and cardiovascular events, will have little to add to schizophrenia treatment if estrogen is, essentially, devoid of any specific antipsychotic or adjuvant mechanism of action relevant to the pathophysiology of this disorder.
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PMID:Relationship between estrogen and schizophrenia. 1718 96


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