Misreporting of Results of Research in Psychiatry.

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.

Using the NIH Research, Condition and Disease Categorization Database for research advocacy: Schizophrenia research at NIMH as an example.

In 2008 the National Institutes of Health established the Research, Condition and Disease Categorization Database (RCDC) that reports the amount spent by NIH institutes for each disease. Its goal is to allow the public "to know how the NIH spends their tax dollars," but it has been little used. The RCDC for 2018 was used to assess 428 schizophrenia-related research projects funded by the National Institute of Mental Health. Three senior psychiatrists independently rated each on its likelihood ("likely", "possible", "very unlikely") of improving the symptoms and/or quality of life for individuals with schizophrenia within 20 years. At least one reviewer rated 386 (90%), and all three reviewers rated 302 (71%), of the research projects as very unlikely to provide clinical improvement within 20 years. Reviewer agreement for the "very unlikely" category was good; for the "possible" category was intermediate; and for the "likely" category was poor. At least one reviewer rated 30 (7%) of the research projects as likely to provide clinical improvement within 20 years. The cost of the 30 projects was 5.5% of the total NIMH schizophrenia-related portfolio or 0.6% of the total NIMH budget. Study results confirm previous 2016 criticisms that the NIMH schizophrenia-related research portfolio disproportionately underfunds clinical research that might help people currently affected. Although the results are preliminary, since the RCDC database has not previously been used in this manner and because of the subjective nature of the assessment, the database would appear to be a useful tool for disease advocates who wish to ascertain how NIH spends its public funds.

Zonisamide for bipolar disorder, mania or mixed states: a randomized, double blind, placebo-controlled adjunctive trial.

OBJECTIVE: This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar mania or mixed state. EXPERIMENTAL DESIGN: One hundred four patients with Bipolar Disorder, Type I, II or NOS, in a manic, hypomanic or mixed state of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases: a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. The primary outcome variable for manic and hypomanic patients was the Young Mania Rating Scale (YMRS) both the YMRS and Montgomery Asberg Depression Rating Scale (MADRS) served as primary outcome variables for patients in mixed states. Secondary outcome measures included the Clinical Global Impression for Bipolar Disorder (CGI-BP), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also analyzed. Side effects were measured using the SAFTEE. PRINCIPAL OBSERVATIONS: There were no statistically significant differences for any of the primary or secondary outcome measures between zonisamide and placebo-treated patients. CONCLUSIONS: In contrast to previous studies that suggested efficacy of adjunctive zonisamide in bipolar mania or mixed state, these results were not confirmed in this double blind controlled study.

Zonisamide for Bipolar Depression: A Randomized, Double Blind, Placebo-Controlled, Adjunctive Trial.

OBJECTIVE: This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar depression. EXPERIMENTAL DESIGN: One hundred two patients with bipolar disorder, type I or II in the depressed phase of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases, a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. MADRS score was the primary outcome variable. Secondary outcome measures included the YMRS, CGI-S, CGI-I, Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also evaluated. Side effects were measured using the SAFTEE. PRINCIPAL OBSERVATIONS: There were no statistically significant differences in response between subjects treated with adjunctive zonisamide vs. placebo controls for the primary or secondary outcome measures. There were also no differences between the groups with regard to response rate or remission rate. CONCLUSIONS: In contrast to preliminary open label studies that suggested a role for zonisamide in bipolar depression, we could not confirm these results in a large double blind controlled study.

Putative psychosis genes in the prefrontal cortex: combined analysis of gene expression microarrays.

BACKGROUND: Recent studies have shown similarities between schizophrenia and bipolar disorder in phenotypes and in genotypes, and those studies have contributed to an ongoing re-evaluation of the traditional dichotomy between schizophrenia and bipolar disorder. Bipolar disorder with psychotic features may be closely related to schizophrenia and therefore, psychosis may be an alternative phenotype compared to the traditional diagnosis categories. METHODS: We performed a cross-study analysis of 7 gene expression microarrays that include both psychosis and non-psychosis subjects. These studies include over 400 microarray samples (163 individual subjects) on 3 different Affymetrix microarray platforms. RESULTS: We found that 110 transcripts are differentially regulated (p < 0.001) in psychosis after adjusting for confounding variables with a multiple regression model. Using a quantitative PCR, we validated a set of genes such as up-regulated metallothioneins (MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3) and down-regulated neuropeptides (SST, TAC1 and NPY) in the dorsolateral prefrontal cortex of psychosis patients. CONCLUSION: This study demonstrates the advantages of cross-study analysis in detecting consensus changes in gene expression across multiple microarray studies. Differential gene expression between individuals with and without psychosis suggests that psychosis may be a useful phenotypic variable to complement the traditional diagnosis categories.

Meta-analysis of 12 genomic studies in bipolar disorder.

Multiple genome-wide expression studies of bipolar disorder have been published. However, a unified picture of the genomic basis for the disease has not yet emerged. Genes identified in one study often fail to be identified in other studies, prompting the question of whether microarray studies in the brain are inherently unreliable. To answer this question, we performed a meta-analysis of 12 microarray studies of bipolar disorder. These studies included >500 individual array samples, on a range of microarray platforms and brain regions. Although we confirmed that individual studies showed some differences in results, clear and striking regulation patterns emerged across the studies. These patterns were found at the individual gene level, at the functional level, and at the broader pathway level. The patterns were generally found to be reproducible across platform and region, and were highly statistically significant. We show that the seeming discordance between the studies was primarily a result of the following factors, which are also typical for other brain array studies: (1) Sample sizes were, in retrospect, too small; (2) criteria were at once too restrictive (generally focusing on fold changes >1.5) and too broad (generally using p < 0.05 or p < 0.01 as criteria for significance); and (3) statistical adjustments were not consistently applied for confounders. In addition to these general conclusions, we also summarize the primary biological findings of the meta-analysis, focusing on areas that confirm previous research and also on novel findings.

A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia.

Dopamine D1 receptors play an important role in memory and cognition in non-human primates. Dopamine D1 agonists have been shown to reverse performance deficits in both aged non-human primates and in primates with lesions to dopamine systems. This study explored whether a single dose of the first full D1 agonist dihydrexidine (DAR-0100) would cause changes in brain activity (perfusion) in dopamine-rich brain regions. We used a new gadolinium-contrast magnetic resonance perfusion scanning technique to measure brain activity. A within-subject cross-over double-blind randomized design was used in 20 adults with SCID-diagnosed schizophrenia. Each morning at 0800 h, they were scanned on a 3.0 T MRI scanner for perfusion. They then received either 20 mg of dihydrexidine, or placebo, subcutaneously over 15 min. Over the next 45 min, they had intermittent MRI scans. Two days later, they had a repeat of the Day 1 schedule, but received the opposite treatment from that given on the first day. Within-day, as well as between-day, comparisons were made to test for perfusion effects of dihydrexidine. Analysis revealed that dihydrexidine induced a significant increase in both prefrontal and non-prefrontal perfusion compared to placebo. The greatest increases occurred approximately 20 min after dihydrexidine infusion, consistent with the short pharmacokinetic half-life of dihydrexidine. These data are consistent with the hypothesis formulated from studies of non-human primates that dihydrexidine and other D1 agonists may be able to modulate prefrontal dopaminergic function.

A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia.

The potential of dopamine D(1) receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D(1) agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D(1)-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.

Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts.

BACKGROUND: Hippocampal dentate granule neurons are altered in schizophrenia, but it is unknown if their gene expressions change in schizophrenia or other psychiatric diseases. METHODS: Laser-captured dentate granule neurons from two groups of schizophrenia and control cases and from major depression and bipolar disease cases were examined for alterations in gene expression using complementary DNA (cDNA) microarrays and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with 24 control cases, the 22 schizophrenia patients in both groups revealed decreases in clusters of genes that encode for protein turnover (proteasome subunits and ubiquitin), mitochondrial oxidative energy metabolism (isocitrate, lactate, malate, nicotinamide adenine dinucleotide [NADH], and succinate dehydrogenases; cytochrome C oxidase; adenosine triphosphate [ATP] synthase), and genes associated with neurite outgrowth, cytoskeletal proteins, and synapse plasticity. These changes were not obtained in 9 bipolar cases or 10 major depression cases and were not associated with age, sex, brain weight, body weight, postmortem interval, or drug history. Brain pH contributed to the variance of some genes but was mostly independent of the disease effect. CONCLUSIONS: Decreases in hippocampal neuron gene expression are consistent with brain imaging and microarray studies of the frontal cortex in schizophrenia. A mitochondrial and ubiquitin-proteasome hypofunctioning of dentate granule neurons may contribute to the deficits of schizophrenia.

Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains.

BACKGROUND: Previous studies of postmortem neurochemical markers in severe psychiatric disorders have been carried out on different brain collections, making it difficult to compare results. METHODS: One hundred RNA, protein, and other neurochemical markers were assessed in a single set of 60 postmortem brains (15 each with schizophrenia, bipolar disorder, major depression without psychosis, and unaffected control subjects) in relation to seven neurochemical systems. Quantitative measures of continuous variables for prefrontal, hippocampus, anterior cingulate, superior temporal cortex, or a combination of these were analyzed from published and unpublished studies by 56 research groups. RESULTS: Before correcting for multiple comparisons, 23% of markers (23/100) were abnormal in one or more regions, with most indicating decreased expression. The largest percentage were associated with the developmental/synaptic (10/22) and gamma-aminobutyric acid (GABA; 3/7) systems. Bipolar disorder (20) and schizophrenia (19) had the most abnormalities, with a 65% overlap. When all brain areas were considered together and corrected for multiple comparisons, reelin, parvalbumin, and GAD67 were the most abnormal. CONCLUSIONS: Confirming other studies, the GABA and developmental/synaptic neurochemical systems are promising areas for research on schizophrenia and bipolar disorder. Research should include tissue from both diseases, and additional brain areas should be assessed.

Secretin for refractory schizophrenia.

In preliminary uncontrolled studies, intravenous injection of the gastrointestinal peptide secretin produced improvements in the symptoms of autism. Because of the phenotypic overlap between autism and some aspects of schizophrenia, we performed a pilot study of secretin for treatment refractory schizophrenia. Twenty-two patients were randomized to a single intravenous dose of porcine secretin or placebo. Patients were evaluated with the Positive and Negative Symptom Scale for Schizophrenia (PANSS) and the Clinical Global Impression Scale (CGI) at baseline, 2 days after secretin infusion and weekly for 4 weeks. There were no statistically significant differences between drug- and placebo-treated patients with repeated measures analysis of variance (ANOVA). However, several patients treated with secretin experienced clinically meaningful, but transient, reductions in symptoms and a greater percentage of patients treated with secretin were rated as improved with the CGI. Further study of brain hypocretins and molecules affecting this system are warranted in schizophrenia.

Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium.

Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors.

Central muscarinic acetylcholine receptor availability in patients treated with clozapine.

Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D(2) receptor blockade as well as high serotonin 5HT(2) receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age- and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275+/-88 mg/day), these differences were highly significant (p <0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.

In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia.

OBJECTIVE: Postmortem studies have implicated the central muscarinic acetylcholine system in schizophrenia. However, central muscarinic receptor availability has not previously been studied in vivo. Using [I-123]iodoquinuclidinyl benzilate ([(123)I]IQNB) single photon emission computed tomography (SPECT), the authors sought to compare the muscarinic receptor availability in vivo in unmedicated patients with schizophrenia and normal subjects. METHOD: Twelve medication-free patients with schizophrenia underwent an [(123)I]IQNB SPECT scan during approximate-equilibrium conditions. A group of 10 age- and gender-matched normal comparison subjects were given the same kind of scan under similar conditions. Regions of interest were analyzed in the cortex, basal ganglia, thalamus, and pons. Binding data were analyzed as nCi/ml tissue per mCi injected dose. RESULTS: Muscarinic receptor availability was significantly less in patients with schizophrenia than in normal subjects in all regions of interest except the pons. Reductions ranged from -33% in the caudate to -20% in the occipital cortex. Positive symptoms of schizophrenia correlated negatively with muscarinic receptor availability in the striatum and the frontal cortex. CONCLUSIONS: These results indicate a reduction in muscarinic acetylcholine receptor availability in vivo in unmedicated patients with schizophrenia, confirming results from postmortem studies and adding further evidence that the muscarinic system is involved in the pathophysiology of schizophrenia.

Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series.

We used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited.

Controlled trial of hydroxychloroquine in schizophrenia.

Hydroxychloroquine is widely employed for the treatment of rheumatological diseases. A preliminary pilot study suggested that hydroxychloroquine may be a useful adjunct for the treatment of schizophrenia, which has been associated with abnormalities in several proinflammatory cytokines. Sixty-one patients were randomized to receive 200 mg/ day hydroxychloroquine or placebo in addition to standard typical antipsychotic treatment. After 8 weeks of double-blind treatment, there was no significant interaction between treatment status and length of treatment for positive, negative, or general symptoms according to the Positive and Negative Syndrome Scale, despite a hydroxychloroquine-associated decrease in serum interferon-gamma levels. After completion of the 8-week study, all participants were offered open treatment with hydroxychloroquine for an additional 12 weeks. Open treatment produced no further improvement in Positive and Negative Syndrome Scale scores at weeks 12, 16, and 20. Further study will be required to determine the role of anti-inflammatory treatments for schizophrenia.

Test-retest stability of the Repeatable Battery for the Assessment of Neuropsychological Status in schizophrenia.

OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was designed as a cognitive screening test, providing both a total scale score and five specific cognitive ability index scores. This study examined the test-retest stability of the RBANS in individual patients with schizophrenia relative to a healthy comparison group. METHOD: A total of 181 patients with schizophrenia or schizoaffective disorder were recruited from three clinical settings. Healthy comparison subjects were recruited as part of the RBANS standardization. Participants were administered one form of the RBANS on one occasion and another form at a later date, with intervals ranging from 1 to 134 days. RESULTS: Intraclass correlation coefficients for the RBANS total scale were 0.84 for the patients with schizophrenia and 0.77 for the healthy comparison subjects. Confidence intervals and percentile data for the total scale change scores were similar for both groups. CONCLUSIONS: The RBANS demonstrated reasonable intraclass correlation coefficient test-retest reliability for both schizophrenia patients and healthy comparison subjects. Confidence intervals are comparable to those previously published for the WAIS-R and Wechsler Memory Scale-Revised, suggesting that retest measurement error is not dramatically increased in the RBANS, despite the brevity of the test. These data may serve as an informative guide for using the RBANS to evaluate neuropsychological change on the level of the individual subject.