The influence of risperidone on cognitive functions in schizophrenia

Introduction of the antipsychotics of the second generation (SGA) into the therapy of schizophrenia roused expectations that, finally, the cognitive dysfunction in schizophrenia could be eliminated by psychopharmacological therapy. The purpose of the study was to verify the effect of atypical antipsychotic risperidone on cognitive functions in schizophrenic patients. The study was carried out upon 48 male schizophrenic patients aged 21-47 years who were switched from the antipsychotics of the first generation (FGA) to the antipsychotic risperidone, due to intolerance, during the treatment. Intelligence, abstract and concrete thinking and mental speed, attention, and short-term non-verbal memory prior to the switch, one month after the switch, and three months after the switch to risperidone, were evaluated. One month after the switch the number of subjects with severe impairment of intellectual abilities decreased significantly from 62% to 15% and after three months the number was even lower-8%. The impairment of concrete and abstract thinking and mental speed also showed the same tendencies of decrease. The improvement of the cognitive functioning after the switch from the antipsychotics of the first generation to the antipsychotic risperidone is explained by removal of the antipsychotics of the first generation from the therapy and the consequential disinhibition of secondary cognitive impairments and by decreased average dose of anticholinergic and decreased number of patients who need anticholinergic therapy beside risperidone. The possibility of clear pro-cognitive effect of risperidone is suggested and its verification is proposed with strict control of other factors that improve cognitive functioning of schizophrenic patients during the treatment.     

Impaired mitophagosome–lysosome fusion mediates olanzapine-induced aging

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome–lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome–lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.     

Antipsychotic drugs differentially modulate apolipoprotein D in rat brain

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.     

奥氮平联合重复经颅磁刺激或改良电休克治疗精神分裂症的疗效分析

目的:比较抗精神病药物奥氮平联合复经颅磁刺激(rTMS)或改良电休克(MECT)治疗精神分裂症的疗效。方法:将84例精神分裂症患者随机分为rTMS组(42例)与MECT组(42例),两组分别在奥氮平的基础上联合MECT或rTMS进行治疗。在治疗2、4、8周末后,采用阳性症状和阴性症状量表PANSS、治疗时出现症状量表TESS评估临床治疗效果及不良反应,同时采用修订韦氏记忆量表(WMS-RC)和威斯康星卡片分类测验(WCST)评定认知功能。结果:治疗后,两组总有效率比较无统计学差异(P0.05)。两组治疗后PANSS总分、阳性症状、阴性症状和一般病理分值均显著低于治疗前(P0.05,P0.01),但组间比较无统计学差异(P0.05)。两组TESS评分及不良反应的发生情况比较无统计学差异(P0.05)。与治疗前相比,两组患者治疗后认知功能均显著改善(P0.05,P0.01),且rTMS联合组在改善患者记忆功能、执行能力方面效果优于MTCT组(P0.05)。结论:奥氮平联合MECT或rTMS对精神分裂症状的疗效相当,但联合rTMS可更显著改善患者的认知功能。     

Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects

Antipsychotic drugs have various neuropharmacological properties as a result of their structural diversity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tardive dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structure-activity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H(1) receptors may significantly advance schizophrenia therapy.     

Extended treatment with typical and atypical antipsychotic drugs differential effects on the densities of dopamine D2-like and GABAA receptors in rat striatum

In situ radioligand binding and quantitative autoradiography have been used to measure the density of striatal D1-like, D2-like, and GABAA receptors in rats treated with haloperidol at 0.01 or 0.1 mg/kg/ day or chlorpromazine, olanzapine or clozapine at 0.1 or 1.0 mg/kg/day for 1, 3 or 7 months. [3H]SCH23390 binding to D1-like receptors was not changed by any drug treatments. There were significant increases in [3H]nemonapride binding to D2-like receptors at different time points due to treatment with haloperidol, chlorpromazine and olanzapine. By contrast, treatment with clozapine and olanzapine caused a time-dependent decrease in [3H]muscimol binding to the GABAA receptor. These data suggest that treatment with atypical antipsychotic drugs, but not typical antipsychotic drugs, affect striatal GABAergic neurons. In addition, it would appear that clozapine might be unique in that it does not increase dopamine-D2 like receptor density at doses which would be predicted to have antipsychotic effects in humans. The extent to which such changes are involved in the therapeutic effects of drugs such as olanzapine and clozapine remains to be determined.     

Antipsychotic treatment of acute paranoid schizophrenia patients with olanzapine results in altered glycosylation of serum glycoproteins

Atypical antipsychotic drugs, such as olanzapine, have been shown to alleviate the positive, negative and, to a lesser degree, the cognitive symptoms of schizophrenia in many patients. However, the detailed mechanisms of action of these drugs have yet to be elucidated. We have carried out the first investigation aimed at evaluating the effects of olanzapine treatment on the glycosylation of serum proteins in schizophrenia patients. Olanzapine treatment resulted in increased levels of a disialylated biantennary glycan and reduced levels of a number of disialylated bi- and triantennary glycans on whole serum glycoproteins. These changes were not observed on a low-abundance serum protein fraction. α1 acid glycoprotein was identified as a carrier of some of the detected altered oligosaccharides. In addition, glycan analysis of haptoglobin, transferrin, and α1 antitrypsin reported similar findings, although these changes did not reach significance. Exoglycosidase digestion analysis showed that olanzapine treatment increased galactosylation and sialylation of whole serum proteins, suggesting increased activity of specific galactosyltransferases and increased availability of galactose residues for sialylation. Taken together, these findings indicate that olanzapine treatment results in altered glycosylation of serum proteins.     

Differentiating the Cognitive Profile of Schizophrenia from That of Alzheimer Disease and Depression in Late Life

Background

To compare the cognitive profile of older patients with schizophrenia to those with other neuropsychiatric disorders assessed in a hospital-based memory clinic.

Methods

Demographic, clinical, and cognitive data of all patients referred to the memory clinic at the Centre for Addiction and Mental Health between April 1, 2006 and August 15, 2008 were reviewed. We then identified four groups of older patients with: (1) late-life schizophrenia (LLS) and no dementia or depression (DEP); (2) Alzheimer''s disease (AD); (3) DEP and no dementia or LLS; (4) normal cognition (NC) and no DEP or LLS.

Results

The four groups did not differ in demographic data except that patients with AD were about 12 years older than those with LLS. However, they differed on cognitive tests even after controlling for age. Patients with LLS were impaired on most cognitive tests in comparison with patients with NC but not on recalling newly learned verbal information at a short delay. They experienced equivalent performance on learning new verbal information in comparison with patients with AD, but better performance on all other tests of memory, including the ability to recall newly learned verbal information. Finally, they were more impaired than patients with DEP in overall memory.

Conclusions

Patients with LLS have a different cognitive profile than patients with AD or DEP. Particularly, memory impairment in LLS seems to be more pronounced in learning than recall. These findings suggest that cognitive and psychosocial interventions designed to compensate for learning deficits may be beneficial in LLS.     

Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study

Objective To compare the incidence of admissions to hospital for stroke among older adults with dementia receiving atypical or typical antipsychotics.Design Population based retrospective cohort study.Setting Ontario, Canada.Patients 32 710 older adults (≤ 65 years) with dementia (17 845 dispensed an atypical antipsychotic and 14 865 dispensed a typical antipsychotic).Main outcome measures Admission to hospital with the most responsible diagnosis (single most important condition responsible for the patient''s admission) of ischaemic stroke. Observation of patients until they were either admitted to hospital with ischaemic stroke, stopped taking antipsychotics, died, or the study ended.Results After adjustment for potential confounders, participants receiving atypical antipsychotics showed no significant increase in risk of ischaemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01, 95% confidence interval 0.81 to 1.26). This finding was consistent in a series of subgroup analyses, including ones of individual atypical antipsychotic drugs (risperidone, olanzapine, and quetiapine) and selected subpopulations of the main cohorts.Conclusion Older adults with dementia who take atypical antipsychotics have a similar risk of ischaemic stroke to those taking typical antipsychotics.     

Neuroprotective effect of atypical antipsychotics in cognitive and non-cognitive behavioral impairment in animal models

Antipsychotic drugs are divided into two groups: typical and atypical. Recent clinical studies show atypical antipsychotics have advantages over typical antipsychotics in a wide variety of neuropsychiatric conditions, in terms of greater efficacy for positive and negative symptoms, beneficial effects on cognitive functioning, and fewer extra pyramidal side effects in treating schizophrenia. As such, atypical antipsychotics may be effective in the treatment of depressive symptoms associated with psychotic and mood disorders, posttraumatic stress disorder and psychosis in Alzheimer disease. In this paper, we describe the effects and potential neurochemical mechanisms of action of atypical antipsychotics in several animal models showing memory impairments and/or non-cognitive behavioral changes. The data provide new insights into the mechanisms of action of atypical antipsychotics that may broaden their clinical applications.Key words: atypical antipsychotics, neuroprotective effect, memory, anxiety-like behavior, neurotoxicity     

Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic,PAOPA: Examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia

Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia.     

Correlation of cognitive functions with some aspects of illness, treatment and social functioning in recurrently hospitalized schizophrenic patients

Cognitive deficits are found to be contributors to poorer psychosocial functioning, rehabilitation outcome and lack of treatment success in schizophrenia. Aim of the study was to examine correlation of cognitive functions with some aspects of illness, treatment and social functioning in a group of recurrently hospitalized schizophrenic patients (N=60). Deficient results on psychomotor processing speed, verbal fluency and verbal learning correlated with the longer duration of illness, higher number of hospitalizations and shorter duration of regular antipsychotic treatment. Deficient results on verbal fluency correlated with the younger age of onset, poor functional autonomy and organizational skills, whereas deficient results on psychomotor processing and verbal learning correlated with poor organizational skills alone. Score on verbal fluency was predictive of social skills impairment, whereas score on psychomotor processing was predictive of functional autonomy and organizational skills impairment. Functioning of different cognitive domains could be predictive of functioning in different social domains. Interplay of specific cognitive deficit and social functioning could be responsible for recurrent hospitalizations and unfavorable treatment choices.     

Neuroprotective effect of atypical antipsychotics in cognitive and non-cognitive behavioral impairment in animal models

Antipsychotic drugs are divided into two groups: typical and atypical. Recent clinical studies show atypical antipsychotics have advantages over typical antipsychotics in a wide variety of neuropsychiatric conditions, in terms of greater efficacy for positive and negative symptoms, beneficial effects on cognitive functioning, and fewer extra pyramidal side effects in treating schizophrenia. As such, atypical antipsychotics may be effective in the treatment of depressive symptoms associated with psychotic and mood disorders, posttraumatic stress disorder, and psychosis in Alzheimer’s disease. In this paper, we describe the effects and potential neurochemical mechanisms of action of atypical antipsychotics in several animal models showing memory impairments and/or non-cognitive behavioral changes. The data provide new insights into the mechanisms of action of atypical antipsychotics that may broaden their clinical applications.     

Antipsychotic drugs scavenge radiation-induced hydroxyl radicals and intracellular ROS formation,and protect apoptosis in human lymphoma U937 cells

Antioxidant activity has been reported for some atypical antipsychotic drugs; however, the detailed mechanism is not well known. Here, we investigated the effects of atypical antipsychotic drugs on ^?OH radical formation, intracellular reactive oxygen species (ROS), and apoptosis induced by ionising radiation. The reaction rate constants with ^?OH radicals were determined for five antipsychotic drugs as follows, in descending order: olanzapine, aripiprazole, clozapine, haloperidol, and risperidone. Experiments with aminophenyl fluorescein, a fluorescent dye, showed that olanzapine and clozapine could scavenge intracellular ROS. However, experiments with hydroxyphenyl fluorescein showed that only olanzapine inhibited ROS generation. X-irradiation-induced apoptosis in human lymphoma U937 cells was inhibited by clozapine at relatively low concentrations and by olanzapine at higher concentrations. Clozapine inhibited caspase-8 and caspase-3 activation and prevented loss of mitochondrial membrane potential. In contrast, olanzapine inhibited X-irradiation-induced p-JNK activation. Although the atypical antipsychotic drugs used here have relatively high reaction rate constants with ^?OH radicals in aqueous solutions, inhibition of intracellular ROS was not due to ^?OH radical scavenging. In addition, suppression of X-irradiation-induced apoptosis was not directly linked with intracellular ROS scavenging. When apoptosis signalling pathways were studied, clozapine-mediated inhibition of apoptosis was dependent on caspase-3 and caspase-8. In contrast, olanzapine inhibited apoptosis via down regulation of X-irradiation-induced p-JNK. These results suggested that both olanzapine and clozapine have antioxidative and antiapoptotic activities via distinct pathways, and provide useful information for better understanding of drug characteristics.     

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis

Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.     

The effects of hormone therapy on cognition in breast cancer

The use of hormonal therapies for the treatment of breast cancer is common, yet few studies have examined the possible cognitive effects. Several regions of the brain, important in memory and cognition, are rich in oestrogen receptors. As a result, the long-term use of anti-oestrogens may have potential consequences for cognition. This project aims to establish whether significant cognitive deficit exists in women receiving hormone therapy for breast cancer and to develop a cognitive package that is sensitive to the potential effects of oestrogen deficiency on cognition. Cognitive assessments measured a range of memory and attention functions in patient and control groups to identify whether cognitive impairment, if apparent, occurs at a widespread or function specific level. Ninety-four patients from the anastrozole, tamoxifen and combined (ATAC) trial and 35 non-cancer controls were assessed. Groups did not differ significantly in age or estimated full-scale intelligence. The patient group did not differ from controls on measures of working memory, attention and visual memory but was significantly impaired compared to the control group on measures of verbal memory (P=0.026) and processing speed (P=0.032). Cognitive performance in the patient group was not significantly related to length of time on trial or measures of psychological morbidity. As more and more hormonal agents are used in clinical trials of both adjuvant and preventive settings it is of vital importance that any potentially deleterious effects on cognitive function are measured adequately. Preliminary results from this study suggest that anti-oestrogen therapy may cause a specific deficit in verbal memory that corroborates the links between oestrogen levels and verbal memory often reported in studies of the cognitive benefits of hormone replacement therapy.     

Schizophrenia and bipolar affective disorder: perspectives for the development of therapeutics

Schizophrenia and bipolar disorder remain two of the most severe and difficult to treat psychotic disorders hampered by our poor understanding of their pathologies. The development of typical antipsychotic drugs opened an avenue of investigation through the dopamine D2 receptor in schizophrenia. With the reintroduction of the atypical antipsychotic clozapine came the development of a new generation of atypical agents and hypotheses challenging the centrality of this receptor in explaining antipsychotic effects. Evaluation of these competing theories does not provide sufficient evidence to displace the importance of the dopamine D2 receptor in antipsychotic efficacy, but does raise limitations of it as an explanatory hypothesis. Further, the treatment of other symptom domains in schizophrenia remains relatively neglected and open for the development of novel therapies. Similar to schizophrenia, bipolar disorder presents a diversity of clinical states but unlike schizophrenia, its mainstay of treatment, lithium, has not had a clear receptor target impeding understanding of the disorder's pathology and treatment. This has pushed investigation into other domains emphasising a number of intracellular signalling pathways and glial-neuronal interactions. The heavy genetic loading of bipolar disorder has allowed linkage analyses to identify a number of putative regions, however, the diversity of phenotypes complicates such studies. Polymorphisms of candidate genes have yielded potential leads such as dopamine beta hydroxylase in mood disorder and the serotonin transporter for treatment response. It is anticipated that combiningthe above approaches may hold promise for the development of more effective treatments.     

How do glial-neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia?

Evidence is accumulating that the exclusive dopamine hypothesis of schizophrenia has to be abandoned. Instead, a more integrative approach combines different neurotransmitter systems, in which glutamatergic, GABAergic and dopaminergic pathways interact. This paradigm shift coincides with the recognition that, while typical and modern atypical antipsychotic drugs have efficiently controlled the dramatic psychotic symptoms of schizophrenia, their impact on negative and cognitive symptoms is negligible. Indeed, cognitive decline is now believed to represent the core of schizophrenic morbidity and in this context, impairment of glutamate and more specifically NMDA function is of major importance. Given that astrocytes are important in controlling glutamate homeostasis, it is necessary to assign a significant role to glial-neuronal interactions in the pathophysiology of schizophrenia. Indeed, recent data from several animal and human studies corroborate this notion. This review outlines current neurotransmitter hypotheses and evidence for glial impairment in schizophrenia. Furthermore, findings from recent studies of (13)C nuclear magnetic resonance spectroscopy in experimental models of schizophrenia and NMDA hypofunction are presented and their implications for future research on glial-neuronal interactions discussed.     

Subjective and psychopathological response in patients under different antipsychotic treatments: are there differences in real clinical practice?

The aim of this study is to investigate whether subjective well-being in patients under treatment with typical (ATPs) and atypical antipsychotic (ATPsA) compounds can be compared with the improvement of psychopathological state and to verify if both variables correlate to adherence to treatment. We assessed 106 consecutive patients receiving ATPs or ATPsA in the University Psychiatric Ward of L?Aquila, according to DSM-IV diagnosis of Schizophrenia and Bipolar Disorder. Psychopathological state was assessed by Brief Psychiatric Rating Scale-4.0 version (BPRS), adherence to treatment and subjective well-being was assessed by Drug Attitude Inventory (DAI-10) and Subjective Well-being under Neuroleptics (SWN), respectively. BPRS and DAI-10 were administered on admission (T0) and at the end of recovery (T1). The subjects enrolled in this study were divided into 2 groups according to ATP prescribed. We observed an improvement of BPRS and SWN total scores in each group, and increasing scores in DAI-10, from admission to discharge, both in total samples and in each group. There were statistical differences between the patients receiving ATPs and those receving ATPsA regardindg the SWN total score and its different dimensions. This study emphasizes that patients receiving ATPsA show better subjective response compared with patients undergoing ATP treatment, although the adherence to pharmacotherapy and clinical improvement do not differ between the groups.     

Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals

Gonadal hormones, particularly estrogens, have been suggested to influence memory and cognitive tasks that show sex differences. Previously, we reported that male-to-female (M-F) transsexuals undergoing estrogen treatment for sex re-assignment scored higher on verbal Paired Associate Learning (PAL) than a transsexual control group awaiting estrogen treatment. The present study used a more robust design to examine further associations between estrogen and cognition. We assessed additional aspects of memory, including visual, spatial, object and location memory, other cognitive abilities that show reliable sex differences, including verbal and visual-spatial abilities, and mood variables that could mediate associations between estrogen and cognition. In addition to comparing groups of individuals on and off estrogen, we used two repeated measures designs (AB and BA). The AB group was tested prior to hormone treatment and then again after treatment had begun; the BA group was tested while on estrogen treatment and then again when hormones had been withdrawn prior to surgery. Few changes in memory or cognition were observed, and changes that were observed were not consistent across study designs. The lack of significant effects did not relate to mood changes or to the sexual orientation of participants. These findings suggest that estrogen treatment associated with sex change for M-F transsexuals has little or no influence on sex-typed aspects of cognition or memory.