Biomedical subjects

Jeffrey A Lieberman

Publications and source records attributed to Jeffrey A Lieberman.

At least 19 recordsLinked to original sources

PubMed2021

High-impact rare genetic variants in severe schizophrenia.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Aged↗

PubMed2007

Schizophrenia: new pathological insights and therapies.

The neurodevelopmental hypothesis of schizophrenia posits an interaction between multiple susceptibility genes and one or more environmental insults in early life, resulting in altered brain development and the emergence of psychosis in early adulthood. Based on this framework, it has been argued that most neuropathological deficits observed in post mortem and neuroimaging studies of schizophrenia represent one or more lesions that originated in early life and remained static thereafter. However, recent longitudinal neuroimaging studies demonstrate a progressive component to the neuropathology of new-onset schizophrenia. This opens the possibility that the functional decline seen in many patients following the onset of illness may be halted or slowed. This review provides an update on developments in research on the neuropathology of schizophrenia and discusses recent advances in antipsychotic treatment and the potential impact on long-term outcomes.

Antipsychotic Agents↗

PubMed2006

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction.

Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1-/-) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (0.05, 0.1, and 0.2 mg/kg). The NR1-/- mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1+/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1-/- mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1-/- mice, but did reduce startle amplitude in the NR1+/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1+/+ and NR1-/- mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1+/+ and NR1-/- mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.

Animals↗

PubMed2006

Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response.

Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/- and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (-48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings.

Adult↗

PubMed2006

Attentional modulation of early-stage visual processing in schizophrenia.

This study shows that paying attention to the color of a visual stimulus is manifested by an early endogenous scalp-positive event-related brain potential (ERP) component, referred to as "selection positivity", that emerges within the first 100 ms after stimulus onset in healthy observers. In contrast, recently ill and chronically ill schizophrenia patients as well as patients at high risk for schizophrenia all failed to show this early ERP component while attending to color. These results suggest that a relatively early stage of visual-selective processing in posterior extrastriate cortex is disrupted in schizophrenia.

Adolescent↗

PubMed2006

Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.

BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

Aged↗

PubMed2006

The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease.

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.

Aged↗

PubMed2006

Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions.

Olanzapine and fluoxetine elevate the GABAergic neuroactive steroid allopregnanolone to physiologically relevant concentrations in rodent cerebral cortex. It is unknown if these agents also alter pregnenolone or deoxycorticosterone. Since olanzapine and fluoxetine in combination have clinical utility and may demonstrate synergistic effects, we investigated neuroactive steroid alterations following olanzapine, fluoxetine or coadministration. Male rats received IP vehicle, olanzapine, fluoxetine or the combination of both agents in higher-dose (0, 10, 20 or 10/20 mg/kg, respectively) and lower-dose (0, 5, 10 or 5/10 mg/kg, respectively) experiments. Pregnenolone and allopregnanolone levels in hippocampus were determined by gas chromatography/mass spectrometry. Peripheral deoxycorticosterone and other steroid levels were determined by radioimmunoassay. Olanzapine, fluoxetine or the combination increased hippocampal pregnenolone and serum deoxycorticosterone in both higher- and lower-dose experiments, and elevated hippocampal allopregnanolone in higher-dose conditions. No synergistic effects on pregnenolone or allopregnanolone were observed following olanzapine and fluoxetine coadministration compared to either compound alone. Pregnenolone and its sulfate enhance learning and memory in rodent models, and therefore pregnenolone elevations may be relevant to cognitive changes in psychotic and affective disorders. Since pregnenolone decreases have been linked to depression, it is possible that olanzapine- and fluoxetine-induced pregnenolone elevations may contribute to the antidepressant actions of these agents.

Animals↗

PubMed2006

Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy?

Clozapine demonstrates superior efficacy in patients with schizophrenia, but the precise mechanisms contributing to this clinical advantage are not clear. Clozapine and olanzapine increase the GABAergic neuroactive steroid (NS) allopregnanolone, and it has been hypothesized that NS induction may contribute to the therapeutic actions of these agents. Pregnenolone administration improves learning and memory in rodent models, and decreases in this NS have been associated with depressive symptoms in humans. These pregnenolone characteristics may be relevant to the actions of antipsychotics. We therefore investigated potential pregnenolone alterations in rat hippocampus and cerebral cortex following clozapine, olanzapine, and other second generation agents as a candidate NS mechanism contributing to antipsychotic efficacy. In the first set of experiments, intact, adrenalectomized, and sham-operated male rats received vehicle or clozapine (20 mg/kg) IP. In the second set, male rats received vehicle, olanzapine (5 mg/kg), quetiapine (20 mg/kg), ziprasidone (10 mg/kg) or aripiprazole (5 mg/kg) IP. Pregnenolone levels were determined by gas chromatography/mass spectrometry. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum; hippocampal levels were strongly correlated with serum levels (r=0.987). Olanzapine also elevates pregnenolone levels, but to a lesser degree than clozapine. Pregnenolone induction may contribute to the clinical actions of clozapine and olanzapine.

Adrenalectomy↗

PubMed2006

Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients.

Tardive dyskinesia (TD) is a side-effect of chronic antipsychotic medication. Abnormalities in dopaminergic activity in the nigrostriatal system have been most often suggested to be involved because the agents which cause TD share in common potent antagonism of dopamine D2 receptors (DRD2), that notably is not balanced by effects such as more potent serotonin (5-HT)2A antagonism. Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD. The most consistent findings have been found with the Ser9Gly polymorphism of the DRD3 gene. Although DRD2 has long been hypothesized to be the main target for antipsychotics, only a few polymorphisms in DRD2 have been investigated for their potential involvement in the aetiology of TD. In the present study, we investigated 12 polymorphisms spanning the DRD2 gene and their association with TD in our European Caucasian (n=202) and African-American (n=30) samples. Genotype frequencies for a functional polymorphism, C957T (Duan et al., 2003; Hirvonen et al., 2004), and the adjacent C939T polymorphism were found to be significantly associated with TD (p=0.013 and p=0.022 respectively). DRD2 genotypes were not significantly associated with TD severity as measured by AIMS (Abnormal Involuntary Movement Scale) with the exception of a trend for C939T (p=0.071). Both TD and total AIMS scores were found to be significantly associated with two-marker haplotypes containing C939T and C957T (p=0.021 and p=0.0087 respectively). Preliminary results indicated that C957T was also associated with TD in our African-American sample (p=0.047). Taken together, the present study suggests that DRD2 may be involved in TD in the Caucasian population, although further studies are warranted.

Adult↗

PubMed2006

Family and case-control association study of the tumor necrosis factor-alpha (TNF-alpha) gene with schizophrenia and response to antipsychotic medication.

BACKGROUND: Dysregulation of the immune system has been suggested to play a role in the etiology of schizophrenia (SCZ). In this context, the tumor necrosis factor-alpha (TNF-alpha) is considered an interesting candidate for genetic studies as overproduction of TNF-alpha, which may be genetically modulated, can influence neuron growth and proliferation. Moreover, the TNF-alpha gene is located on chromosome 6p21.3, a region that has been found to be associated with SCZ in numerous linkage studies. One functional polymorphism, G-308A, has been studied for association with SCZ yielding inconsistent findings. RESULTS AND DISCUSSIONS: In our study, we investigated the G-308A polymorphism with SCZ including 95 nuclear families and 149 pairs of cases/controls matched by age, gender, and ethnicity. Furthermore, we examined BPRS change scores (after 6 weeks, 3 months, and 6 months) and weight changes (after 6 weeks) with this polymorphism in 153 and 247 patients, respectively, after clozapine treatment. We did not observe biased transmission using family-based association test (P=0.752) or significant differences in case/control studies (P=0.839). However, patients with allele A showed significant improvement on BPRS change score after 3 months (t=2.000, P=0.049) and 6 months (t=2.481, P=0.015) of clozapine treatment when compared with patients without allele A. Moreover, trends were observed for genotype A/A with clinical improvement in BPRS change score after 6 months (F=2.834, P=0.065) using ANCOVA, and for allele G with weight gain (t=-1.702, P=0.091). CONCLUSION: Overall, the G-308A polymorphism of the TNF-alpha gene does not appear to play a major role in SCZ but might be involved in antipsychotic response.

Adult↗

PubMed2006

No evidence for parental imprinting of mouse 22q11 gene orthologs.

Non-Mendelian factors may influence central nervous system (CNS) phenotypes in patients with 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velocardiofacial Syndrome), and similar mechanisms may operate in mice carrying a deletion of one or more 22q11 gene orthologs. Accordingly, we examined the influence of parent of origin on expression of 25 murine 22q11 orthologs in the developing and mature CNS using single nucleotide polymorphism (SNP)-based analysis in interspecific crosses and quantification of mRNA in a murine model of 22q11DS. We found no evidence for absolute genomic imprinting or silencing. All 25 genes are biallelically expressed in the developing and adult brains. Furthermore, if more subtle forms of allelic biasing are present, they are very small in magnitude and most likely beyond the resolution of currently available quantitative approaches. Given the high degree of similarity of human 22q11 and the orthologous region of mmChr16, genomic imprinting most likely cannot explain apparent parent-of-origin effects in 22q11DS.

Alleles↗

PubMed2006

Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline.

UNLABELLED: Persons diagnosed with schizophrenia have higher morbidity and mortality rates from cardiovascular disease, yet often have limited access to appropriate primary care screening or treatment. Metabolic disorders such as diabetes, hyperlipidemia and hypertension are highly prevalent in populations with schizophrenia, exceeding 50% in some studies; however, there have been few published studies on treatment rates among schizophrenia patients screened for these disorders. METHODS: Using the baseline data from subjects (N=1460) recruited into the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, we examined the point prevalence of diabetes, hyperlipidemia and hypertension treatment at the time of enrollment for the entire cohort and those with fasting laboratory values obtained 8 or more hours since last meal. RESULTS: Rates of non-treatment ranged from 30.2% for diabetes, to 62.4% for hypertension, and 88.0% for dyslipidemia. Nonwhite men were more likely to be treated for DM and dyslipidemia than nonwhite women. CONCLUSIONS: These data indicate the high likelihood that metabolic disorders are untreated in patients with schizophrenia, with particularly high rates of non-treatment for hypertension and dyslipidemia. Nonwhite women may be especially vulnerable to undertreatment of dyslipidemia and diabetes compared to nonwhite men. The findings here support the need for increased attention to basic monitoring and treatment of cardiovascular risk factors in this vulnerable and often underserved psychiatric population.

Antihypertensive Agents↗

PubMed2006

Insight in first-episode psychosis.

BACKGROUND: We report here a study examining the relationships between insight and psychopathology, cognitive performance, brain volume and co-morbid depression in 251 patients experiencing a first episode of psychosis, who were then randomly assigned to 2 years of double-blind treatment with either olanzapine or haloperidol. METHOD: Repeated measures of insight were obtained at baseline and 12, 24, 52 and 104 weeks by the Insight and Treatment Attitudes Questionnaire (ITAQ). RESULTS: Older age, female gender and white ethnicity were associated with more insight. Higher total, positive, negative and general psychopathology scores on the Positive and Negative Syndromes Scale (PANSS) were associated with less insight. Higher depression scores were associated with more insight. Better neurocognitive function and large brain volumes were associated with more insight. More insight throughout the study was associated with longer time to medication non-adherence. However, baseline insight was not significantly related to the probability of discontinuing the study before 2 years. Insight improved significantly over the course of the study, but the improvement in insight was not significantly different between the two antipsychotic treatment groups. CONCLUSIONS: Multiple factors contribute to insight. Patients experiencing a first episode of psychosis who have little insight are at increased risk of discontinuing their medication.

Adolescent↗

PubMed2006

Baseline neurocognitive deficits in the CATIE schizophrenia trial.

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An 'all-comer' approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13-0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an 'all-comer' clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Adult↗

PubMed2006

Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics.

In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects.

Analysis of Variance↗

PubMed2006

Neonatal neurosteroid administration results in development-specific alterations in prepulse inhibition and locomotor activity: neurosteroids alter prepulse inhibition and locomotor activity.

RATIONALE: Early life exposure to stress and to GABAA receptor modulators have well-defined and persistent behavioral effects. A single neonatal injection of the GABAergic neurosteroid allopregnanolone (3alpha-hydroxy,5alpha-pregnane-20-one, 10 mg/kg, i.p.) alters the localization of prefrontal cortex (PFC) interneurons in adulthood. Such displacement could result in disinhibited behavior associated with impaired development of the mesocortical dopamine system. OBJECTIVES: To determine if there is a critical window in which allopregnanolone levels may impact the development and mature function of the mesocorticolimbic circuitry. METHODS: Behavioral measures, including prepulse inhibition (PPI) and total locomotor activity, after amphetamine exposure were assessed at postnatal day 20 (P20) (prepuberty), P40 (puberty), P60 (postpuberty), and P80 (adulthood) in animals previously exposed to allopregnanolone (10 mg/kg) on P2 and P5. PFC tyrosine hydroxylase immunoreactivity was stereologically measured. RESULTS: P2 administration of allopregnanolone resulted in an increased locomotor response to amphetamine (14, 28% on P20 and P80, respectively) and reduced PPI (28, 22% on P20 and P80, respectively) at P20 and P80, whereas allopregnanolone administration on P5 increased locomotor response to amphetamine (20%) and reduced PPI (37%) at P80. Clozapine (7.5 mg/kg) pretreatment reversed the PPI deficit in P2-exposed animals. The total length of tyrosine hydroxylase immunopositive fibers in PFC was not altered by neonatal neurosteroid exposure, but more fibers were located in layers V/VI vs I-III. CONCLUSIONS: Altering neonatal allopregnanolone levels disrupts PFC-dependent behavior, indicating that allopregnanolone might be important for normal PFC circuitry development. The temporal exposure differences (P2 vs P5) and ontological-dependent effects (P20 and P80, but not P40 or P60) suggest critical windows of vulnerability to neurosteroid insult across development.

Amphetamine↗

PubMed2006

Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode.

BACKGROUND: Many patients recovering from a first psychotic episode will discontinue medication against medical advice, even before a 1-year treatment course is completed. Factors associated with treatment adherence in patients with chronic schizophrenia include beliefs about severity of illness and need for treatment, treatment with typical versus atypical antipsychotic and medication side effects. METHOD: In this 2-year prospective study of 254 patients recovering from a first episode of schizophrenia, schizophreniform, or schizoaffective disorder we examined the relationship between antipsychotic medication non-adherence and patient beliefs about: need for treatment, antipsychotic medication benefits, and negative aspects of antipsychotic medication treatment. We also examined the relationship between medication non-adherence and treatment with either haloperidol or olanzapine, and objective measures of symptom response and side effects. RESULTS: The likelihood of becoming medication non-adherent for 1 week or longer was greater in subjects whose belief in need for treatment was less (HR=1.75, 95% CI 1.16, 2.65, p=0.0077) or who believed medications were of low benefit (HR=2.88, 95 CI 1.79-4.65, p<0.0001). Subjects randomized to haloperidol were more likely to become medication non-adherent for >or=1 week than subjects randomized to olanzapine (HR-1.51, 95% CI 1.01, 2.27, p=0.045). CONCLUSION: Beliefs about need for treatment and the benefits of antipsychotic medication may be intervention targets to improve likelihood of long-term medication adherence in patients recovering from a first episode of schizophrenia, schizoaffective, or schizophreniform disorder.

Adult↗