Daniel W. Bradford

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

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

Access to Medical Care Among Persons With Psychotic and Major Affective Disorders

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.

Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence

Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

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.

Diagnostic Accuracy of Spanish Language Depression-Screening Instruments

PURPOSE To make decisions about implementing systematic depression screening, primary care physicians who serve Spanish-speaking populations need to know whether Spanish language depression-screening instruments are accurate. We aimed to review systematically the evidence regarding diagnostic accuracy of depression-screening instruments in Spanish-speaking primary care populations. METHODS We searched PubMed, PsycINFO, CINAHL, EMBASE, and Cochrane Libraries from inception to May 28, 2008, for studies examining the diagnostic accuracy of Spanish language depression case-finding instrument(s) administered to primary-care outpatients. Two authors independently assessed studies for inclusion and quality. RESULTS Twelve studies met inclusion criteria. In general primary care screening, the Spanish language version of the Center for Epidemiologic Studies-Depression scale (CES-D) had sensitivities ranging from 76% to 92% and specificities ranging from 70% to 74%. We found no US study reporting the accuracy of the Primary Care Evaluation of Mental Disorders (PRIME-MD-9) or the Patient Health Questionnaire (PHQ-9) depression module in Spanish-speakers. One fair-quality European study and 1 poor-quality study conducted in Honduras found the 9-item PRIME-MD had sensitivities ranging from 72% to 77% and specificities ranging from 86% to 100%. The 2-item PRIME-MD was 92% sensitive, but only 44% specific for depression in 1 US study. In geriatric outpatients, the 15-item Spanish language version of the Geriatric Depression Scale (GDS) had sensitivities ranging from 76% to 82%, and specificities ranging from 64% to 98%. In postpartum women, the Spanish language version of the Edinburgh Postnatal Depression Scale (EPDS) was 72% to 89% sensitive and 86% to 95% specific for major depression (2 non-US studies). The Spanish language version of the Postpartum Depression Screening Scale (PDSS) was 78% sensitive and 85% specific for combined major/minor depression (1 US study). CONCLUSIONS For depression screening in Spanish-speaking outpatients, fair evidence supports the diagnostic accuracy of the CES-D and PRIME-MD-9 in general primary care, the GDS-15-Spanish for geriatric patients, and the Spanish language versions of the EPDS or PDSS for postpartum patients. The ultrashort 2-item version of PRIME-MD may lack specificity in US Spanish-speakers.

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.

Healthcare barriers among severely mentally ill homeless adults: evidence from the five-site health and risk study.

AbstractFew studies have examined barriers to physical and mental healthcare among homeless mentally adults. Methods This study examined physical and mental healthcare barriers reported by 154 recently homeless mentally ill persons. Results Practical concerns (e.g. transportation and cost) were key components of barriers to accessing general medical care among uninsured men with poorer overall mental health, PTSD, and STD infections. Perceived stigma was an important component of mental healthcare barriers reported most frequently by those with greater psychiatric symptoms. Conclusion Focusing on individual characteristics underlying barriers to healthcare may lead to better interventions for improving access to needed care.

Pharmacological Management of First-Episode Schizophrenia and Related Nonaffective Psychoses

Schizophrenia is a severe mental illness characterised by abnormalities of thought and perception that affects 1–2% of the population. Patients who experience a first episode of schizophrenia should be treated early and optimally with antipsychotic agents to lessen the morbidity of the initial episode and possibly improve the course of the illness. Positive psychotic symptoms remit in the majority of patients who are treated with adequate trials of antipsychotic medications, but most relapse within 1 year. Non-adherence is strongly related to the likelihood of recurrence of symptoms. Innovative programmes that integrate early intervention, psychosocial treatments and atypical antipsychotic pharmacotherapy show promise in improving outcomes.The available research supports the use of antipsychotic medications early in the first-episode of schizophrenia and for at least 1 year after remission of positive symptoms. Antidepressants, benzodiazepines and mood stabilisers have roles in the acute and maintenance phases of treatment for some patients. Atypical antipsychotics represent a great advance in the treatment of first-episode schizophrenia with strong evidence for greater tolerability with equal or better therapeutic efficacy. Future research will further define their roles in treatment and hopefully identify targets for prevention of first-episode schizophrenia.

Issues in defining and measuring veteran community reintegration: proceedings of the Working Group on Community Reintegration, VA Rehabilitation Outcomes Conference, Miami, Florida.

In January 2010, the Department of Veterans Affairs (VA) Rehabilitation Research and Development Service convened a State of the Art (SOTA) conference to advance the field of outcome measurement for rehabilitation-related studies. This article reports on the proceedings of the SOTA Working Group on Community Reintegration. We explored the use of the International Classification of Health, Disability, and Functioning as a theoretical framework for measuring community reintegration; identified key dimensions of community reintegration that could and/or should be measured; discussed challenges in measuring community reintegration; suggested steps to enhance community reintegration measurement; proposed future research that focuses on outcomes measures for community reintegration and the study of community reintegration outcomes; and made policy recommendations that would facilitate community reintegration research within the VA.

An evidence synthesis of care models to improve general medical outcomes for individuals with serious mental illness: A systematic review

OBJECTIVE To conduct a systematic review of studies of interventions that integrated medical and mental health care to improve general medical outcomes in individuals with serious mental illness. DATA SOURCES English-language publications in MEDLINE (via PubMed), EMBASE, PsycINFO, and the Cochrane Library, from database inception through January 18, 2013, were searched using terms for our diagnoses of interest, a broad set of terms for care models, and a set of terms for randomized controlled trials (RCTs) or quasi-experimental design. Bibliographies of included articles were examined for additional sources. ClinicalTrials.gov was searched using the terms for our diagnoses of interest (serious mental illness,SMI,bipolar disorder,schizophrenia,orschizoaffective disorder) to assess for evidence of publication bias and ongoing studies. STUDY SELECTION 4 RCTs were included from 1,729 articles reviewed. Inclusion criteria were RCT or quasi-experimental design; adult outpatient population with 25% or greater carrying a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder; intervention with a stated goal to improve medical outcomes through integration of care, using a comparator of usual care or other quality improvement strategy; and outcomes assessing process of care, clinical outcomes, or physical functioning. DATA EXTRACTION A trained researcher abstracted the following data from the included articles: study design, funding source, setting, population characteristics, eligibility and exclusion criteria, number of subjects and providers, intervention(s), comparison(s), length of follow-up, and outcome(s). These abstracted data were then overread by a second reviewer. RESULTS Of the 4 studies reviewed, 2 good-quality studies (according to the guidelines of the Agency for Healthcare Research and Quality) that evaluated processes of preventive and chronic disease care demonstrated positive effects of integrated care. Specifically, integrated care interventions were associated with increased rates of immunization and screening. All 4 RCTs evaluated changes in physical functioning, with mixed results: 2 studies demonstrated small improvements in the physical health component of the 36-Item Short-Form Health Survey (SF-36) and the 12-Item Short-Form Health Survey, and 2 studies demonstrated no significant difference in SF-36 scores. No studies reported on clinical outcomes related to preventive care or chronic medical care. CONCLUSIONS Integrated care models have positive effects on processes of preventive and chronic disease care but have inconsistent effects on physical functioning for individuals with serious mental illness. The relatively small number of trials and limited range of treatment models tested and outcomes reported point to the need for additional study in this important area.