Emerging data suggest that second-generation antipsychotics such as aripiprazole may be effective in the treatment of post-traumatic stress disorder (PTSD). However, few clinical trials have used aripiprazole in PTSD, and data are limited on its use in Veterans with PTSD. The objective of this pilot trial was to investigate the safety and efficacy of aripiprazole in Veterans with PTSD. Ten individuals (five men and five women) meeting the Diagnostic and statistical manual of mental disorders, 4th ed., PTSD criteria participated in this 12-week, open-label, flexibly dosed monotherapy trial. The dose range of aripiprazole was 5-30 mg/day, titrated to tolerability and clinical response. The primary outcome measure was the Clinician-Administered PTSD Scale. Additional outcomes included the Short PTSD Rating Interview, the Treatment Outcome PTSD Scale (Top-8), the Davidson Trauma Scale, the Positive and Negative Syndrome Scale, the Beck Depression Inventory-Fast Screen, and Clinical Global Impressions-Improvement. Eight participants completed the study, and aripiprazole was generally well tolerated and associated with a significant improvement in PTSD symptoms, as measured by the Clinician-Administered PTSD Scale (primary outcome measure) and by the Short PTSD Rating Interview, the Treatment Outcome PTSD Scale, and the Davidson Trauma Scale. An improvement was also observed on all three Positive and Negative Syndrome Scale subscales and the Beck Depression Inventory-Fast Screen, and the average Clinical Global Impressions-Improvement ratings indicated that patients were 'much improved'. These promising initial results merit further investigation in a larger, randomized-controlled trial.

BACKGROUND It has been suggested that obstructive sleep apnea (OSA) may result in symptoms similar to those experienced in attention-deficit/hyperactivity disorder (ADHD). Because this may have important public health implications, we reviewed the literature regarding this association, with a focus on interventional studies examining the effect of OSA treatment on change in ADHD symptoms. METHODS We performed a systematic literature search of PubMed, along with other major databases, for interventional studies published between January 1966 and June 2010 that examined the effect of OSA treatment on ADHD, which resulted in 6 studies. The literature on the prevalence of ADHD symptoms in OSA and vice versa was also reviewed. RESULTS Attentional deficits have been reported in up to 95% of OSA patients. In full syndromal ADHD, a high incidence (20% to 30%) of OSA has been shown. All 6 interventional studies reported improvements in behavior, inattention, and overall ADHD after treatment of OSA. CONCLUSIONS OSA may contribute to ADHD symptomatology in a subset of patients diagnosed with ADHD (DSM-IV criteria). Treatment of OSA appears to have favorable effects on ADHD symptoms. Controlled trials and epidemiologic investigations will be required to better understand these relationships, as well as their diagnostic and prognostic implications.

The neuroactive steroid allopregnanolone is a potent gamma-aminobutyric acid type A (GABA(A)) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.

Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

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.

OBJECTIVE: People with serious mental illness have higher mortality rates than the general population, and this difference is not explained by such causes as suicide or accidents. This study therefore examined access and barriers to medical care among persons with serious mental illness. METHODS: Using a nationally representative sample, the authors examined access and barriers to medical care among individuals reporting psychotic and mood disorders. The National Health Interview Survey (NHIS) and NHIS-Disability Component for 1994 and 1995 were merged to provide a sample of 156,475 people over age 18. Individuals with psychotic disorders, bipolar disorder, or major depression were compared with persons without mental disorders on the following outcomes: having a primary care physician, being unable to get needed medical care, being unable to get a needed prescription medication, and delaying medical care because of cost. RESULTS: Persons with psychotic disorders (odds ratio [OR]=.55, 95% confidence interval [CI]=.44-.69) and bipolar disorder (OR=.74, CI=.56-.98) had significantly reduced odds of having a primary care physician compared with people without mental disorders. For any barriers to care, persons with psychotic disorders, bipolar disorder, or major depressive disorder had greatly increased odds (ORs=2.5-7.0) of reporting difficulties in accessing care. CONCLUSIONS: Persons with psychotic disorders and bipolar disorder reported markedly more difficulty in obtaining a primary care physician and greater barriers to care than the general population. Interventions are needed to improve provision of primary medical care to this population.

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.

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 (r(s)=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline pregnenolone (r(s)=-0.76, p=0.037), pregnenolone sulfate (r(s)=-0.83, p=0.015), and allopregnanolone levels (r(s)=-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 (r(s)=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Objective: It is currently unknown if cerebrospinal fluid (CSF) neurosteroid levels are related to brain neurosteroid levels in humans. CSF and brain dehydroepiandrosterone (DHEA) levels are elevated in patients with Alzheimer's disease (AD), but it is unclear if CSF DHEA levels are correlated with brain DHEA levels within the same subject cohort. We therefore determined DHEA and pregnenolone levels in AD patients (n = 25) and cognitively intact control subjects (n = 16) in both CSF and temporal cortex. Design: DHEA and pregnenolone levels were determined by gas chromatography/mass spectrometry preceded by high performance liquid chromatography. Frozen CSF and temporal cortex specimens were provided by the Alzheimer's Disease Research Center at Duke University Medical Center. Data were analyzed by Mann-Whitney U test statistic and Spearman correlational analyses. Results: CSF DHEA levels are positively correlated with temporal cortex DHEA levels (r = 0.59, P < 0.0001) and neuropathological disease stage (Braak and Braak)[r = 0.42, P = 0.007]. CSF pregnenolone levels are also positively correlated with temporal cortex pregnenolone levels (r = 0.57, P < 0.0001), and tend to be correlated with neuropathological disease stage (Braak)[r = 0.30, P = 0.06]. CSF DHEA levels are elevated (P = 0.032) and pregnenolone levels tend to be elevated (P = 0.10) in patients with AD compared to cognitively intact control subjects. Conclusions: These findings indicate that CSF DHEA and pregnenolone levels are correlated with temporal cortex brain levels of these neurosteroids, and that CSF DHEA is elevated in AD and related to neuropathological disease stage. Neurosteroids may thus be relevant to the pathophysiology of AD.

Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n=14-15 per group, 59-60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABA(A) and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.Neuropsychopharmacology advance online publication, 23 November 2005; doi:10.1038/sj.npp.1300952.

OBJECTIVE: This study examined the association of lifetime traumatic stress with psychiatric diagnostic status and symptom severity in veterans serving in the US military after 9/11/01. METHOD: Data from 356 US military veterans were analyzed. Measures included a standardized clinical interview measure of psychiatric disorders, and paper-and-pencil assessments of trauma history, demographic variables, intellectual functioning, posttraumatic stress disorder (PTSD) symptoms, depression, alcohol misuse, and global distress. RESULTS: Ninety-four percent of respondents reported at least one traumatic stressor meeting DSM-IV criterion A for PTSD (i.e., life threatening event to which the person responded with fear, helplessness or horror), with a mean of four criterion A traumas. Seventy-one percent reported serving in a war-zone, with 50% reporting occurrence of an event meeting criterion A. The rate of current psychiatric disorder in this sample was: 30% PTSD, 20% major depressive disorder, 6% substance abuse or dependence and 10% for the presence of other Axis I psychiatric disorders. After accounting for demographic covariates and combat exposure, childhood physical assault and accident/disasters were most consistently associated with increased likelihood of PTSD. However, PTSD with no comorbid major depressive disorder or substance use disorder was predicted only by combat exposure and adult physical assault. Medical/unexpected-death trauma and adult physical assault were most consistently associated with more severe symptomatology. CONCLUSIONS: Particular categories of trauma were differentially associated with the risk of psychiatric diagnosis and current symptom severity. These findings underscore the importance of conducting thorough assessment of multiple trauma exposures when evaluating recently post-deployed veterans.

Primary hyperparathyroidism is a disorder of calcium homeostasis that occurs most commonly in older adults. Resultant hypercalcemia may be accompanied by neuropsychiatric symptoms, ranging from mild depression and cognitive changes to extreme agitation and psychosis. Surgical intervention almost invariably reverses these symptoms. The authors reviewed the importance of considering this diagnosis in the setting of neuropsychiatric symptoms in the elderly and reported on a 63-year-old man with mild hypercalcemia and a new onset of psychosis.