Duration of untreated psychosis and response to treatment: an analysis of response in the OPTiMiSE cohort.

Some, but not all, studies have found longer duration of untreated psychosis (DUP) to be associated with poor response to treatment and more severe negative symptoms in schizophrenia. The aim of the current analysis was to investigate these parameters in a large cohort of patients in their first psychotic episode. The OPTiMiSE cohort included 446 patients with DUP up to two years, who were administered amisulpride for 4 weeks (Phase I). Patients who did not meet Andreasen remission criteria were randomized to double-blind continuation of amisulpride or olanzapine for 6 additional weeks in a blinded study (Phase II). Analyses showed that shorter DUP was associated with lower baseline CGI scores (p<0.001, r = 0.184), PANSS total (p = 0.025, r = 0.106) and PANSS negative subscale scores (p = 0.023, r = 0.107). Remitters had a significantly shorter mean DUP compared to non-remitters both in Phase I (24.5 weeks ±24.3 vs. 35 weeks ± 32.2, p = 0.01, t=-2.521) and in Phase II (24.3 weeks ± 26.4 vs. 38.3 weeks ± 31.3, p = 0.031, t=-2.194). Logistic regression analyses showed a significant effect of DUP on treatment response both in phase I (p = 0.008) and phase II (p = 0.041). Linear regression analyses found that DUP significantly affects PANSS Total change at the end of phase I (p = 0.028) but not at the end of phase II (p = 0.236). Based on these findings, it is possible to conclude that shorter DUP is associated with better response to treatment, particularly during the first weeks after treatment initiation. These findings highlight the need for early identification of the first psychotic episode.

Understanding the association between advanced paternal age and schizophrenia and bipolar disorder.

BACKGROUND: Previous studies reported an association between advanced paternal age at birth and increased risk for schizophrenia and bipolar disorder. While some hypothesize that this association is caused by de-novo mutations in paternal spermatozoa, others cite factors associated with psycho-social characteristics of fathers who have children at a late age. This study aims to test these hypotheses. METHODS: A historical-prospective, population-based cohort study, performed by linking the Israeli Draft Board Registry and the Israeli National Psychiatric Hospitalization Registry (N = 916 439; 4488 with schizophrenia, 883 with bipolar disorder). Odds ratios (OR) and two-sided 95% confidence intervals (CI) were calculated by logistic regression models, using paternal age as predictor and risk for later hospitalizations for schizophrenia or bipolar disorder as outcome measure. Models were first fitted unadjusted, then adjusted for paternal age at birth of the first child. RESULTS: In the unadjusted model, offspring of fathers aged 45 and above at birth had increased risk of schizophrenia (OR = 1.71, 95% CI 1.49-1.99) and bipolar disorder (OR = 1.63, 95% CI 1.16-2.24). However, taking into account paternal age at birth of first child, advanced paternal age was no longer associated with increased risk of schizophrenia (OR = 0.60, 95% CI 0.48-0.79) or bipolar disorder (OR = 1.03, 95% CI 0.56-1.90). CONCLUSIONS: Controlling for paternal age at birth of the first offspring, advanced paternal age does not predict increased risk for schizophrenia or bipolar disorder. These data indicate that the association between advanced paternal age and having an offspring with schizophrenia and bipolar disorder is likely due to psychos-social factors, or common genetic variation associated with delayed initial fatherhood.

Effect of Adjunctive Estradiol on Schizophrenia Among Women of Childbearing Age: A Randomized Clinical Trial.

Importance: Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated. Objective: To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age. Design, Setting, and Participants: An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5. Intervention: Patients were randomized to receive a 200-µg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment. Main Outcomes and Measures: The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis. Results: A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (-0.94; 95% CI, -1.64 to -0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, -1.98 points on the PANSS positive subscale; 95% CI, -2.94 to -1.02; P < .001). Younger participants did not benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI, -0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group). Conclusions and Relevance: The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males. Trial Registration: ClinicalTrials.gov identifier: NCT03848234.

The effect of minocycline on symptoms in schizophrenia: Results from a randomized controlled trial.

BACKGROUND: Studies have hypothesized that immunological abnormalities might contribute to schizophrenia, and basic science studies, as well as several clinical trials suggest that minocycline could be efficacious in ameliorating both positive and negative symptoms of schizophrenia. In this study we examined the effect of minocycline on schizophrenia in a large randomized controlled trial. METHODS: We performed a 16-week, multi-center, double-blind, randomized, placebo-controlled study on 200 subjects with schizophrenia or schizoaffective disorder randomized to receive either minocycline (200 mg/day, n = 100), or placebo (n = 100) as an add-on to anti-psychotic treatment. The primary outcome measure was the PANSS total score. RESULTS: Mixed models for repeated measures showed no significant difference between minocycline and placebo for total PANSS (p = 0.862), PANSS subscales, CGI or BACS. CONCLUSIONS: Minocycline did not improve symptoms or cognition in schizophrenia.

A Population-Based Longitudinal Study of Symptoms and Signs Before the Onset of Psychosis.

OBJECTIVE: The authors sought to characterize the symptoms of patients later hospitalized for psychotic disorders in primary mental health outpatient settings, and to investigate whether these symptoms can be used to predict later onset of psychotic illness. METHOD: This was a population-based historical prospective cohort study using national registers of clinical psychiatric services. The sample (N=114,983) comprised 18- to 21-year-olds serving in the Israeli military and examined in military mental health outpatient clinics across 72 consecutive months. RESULTS: Overall, 1,092 individuals (0.95%) not diagnosed with a psychotic disorder at the time of examination were hospitalized for nonaffective psychotic disorder up to 9 years after the index examination. A principal components analysis of symptoms presented at index examination found that a symptom cluster of thought disorder, perceptual abnormalities, poor orientation, and suicidality was associated with an increased risk for hospitalization for nonaffective psychotic disorder within 14 days after examination (hazard ratio=45.80, 95% CI=22.87-91.73), 15-111 days after examination, (hazard ratio=19.59, 95% CI=13.08-29.33), 112-365 days after examination (hazard ratio=4.94, 95% CI=2.59-9.40), and 1-3.5 years after examination (hazard ratio=3.42, 95% CI=2.21-5.28), but not for hospitalization 3.5 years or more after examination (hazard ratio=1.57, 95% CI=0.91-2.71). Despite the increased risk, the positive predictive values of this symptom cluster were low, ranging from 0.54% to 1.99%. CONCLUSIONS: In 18- to 21-year-olds, the presence of psychotic symptoms was associated with later hospitalization for a nonaffective psychotic disorder. However, the low positive predictive values of symptoms elicited in primary mental health care settings suggest that symptoms alone are not useful in predicting later hospitalization for nonaffective psychotic disorder.

Raloxifene Plus Antipsychotics Versus Placebo Plus Antipsychotics in Severely Ill Decompensated Postmenopausal Women With Schizophrenia or Schizoaffective Disorder: A Randomized Controlled Trial.

OBJECTIVE: Several single-center studies have found raloxifene, an estrogen agonist, to be effective in ameliorating symptoms of schizophrenia in stable patients as augmentation of antipsychotics. This multicenter study assessed whether raloxifene plus antipsychotic treatment, in comparison to placebo plus antipsychotics, improves symptoms or cognition in severely ill decompensated schizophrenia patients. METHODS: In this 16-week, double-blind, randomized, placebo-controlled study, 200 severely ill, decompensated postmenopausal women who met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder were recruited from January 2011 to December 2012 and were randomized to receive either raloxifene 120 mg/d plus antipsychotics or placebo plus antipsychotics. The primary outcome measure was Positive and Negative Syndrome Scale (PANSS) total score at the end of the trial. RESULTS: The placebo plus antipsychotics group experienced statistically significant improvement in PANSS total score (P < .001) compared to the raloxifene plus antipsychotics group, using mixed models for repeated measures, with results favoring placebo by 4.5 points (95% CI, 2.3-6.7). These results were clearly outside the 95% confidence interval. This negative effect was more pronounced in patients who had more frequent relapses and in those with baseline PANSS scores of 100 or higher. There were no differences between groups in Clinical Global Impression Scale-Severity scores or Composite Brief Assessment of Cognition in Schizophrenia scores at 16 weeks (P > .3). Baseline follicle-stimulating hormone and estradiol levels did not alter the drug-placebo differences. CONCLUSIONS: Individuals in the active treatment arm showed worse outcome than those in the placebo arm, most likely as a result of chance variation, but the results unequivocally show no benefit of antipsychotics plus raloxifene versus antipsychotics plus placebo in this large randomized, double-blind, placebo-controlled trial in postmenopausal women. These data do not support the use of raloxifene in severely decompensated schizophrenia patients until reliable research identifies what subgroup of patients or domain of outcome is benefited. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01280305.

The association between premorbid cognitive ability and social functioning and suicide among young men: A historical-prospective cohort study.

Previous studies have found associations between low cognitive ability and later completed suicide. The aim of this study was to examine the association between cognitive ability and social functioning in adolescence, and later completed suicide in a large population-based longitudinal study. Data from the Israeli Draft Board Register for 634,655 Israeli male adolescents aged 16 and 17 was linked to a causes-of-death data registry, with a mean follow-up of 10.6 years for completed suicide. Our results show that in males without a psychiatric diagnosis, both low (adjusted HR=1.51, 95% CI: 1.19-1.92) and high (adjusted HR=1.36, 95% CI: 1.04-1.77) cognitive ability, and very poor (adjusted HR=2.30, 95% CI: 1.34-3.95) and poor (adjusted HR=1.64, 95% CI: 1.34-2.07) social functioning were associated with increased risk for later completed suicide; however positive predictive values were low (PPVs=0.09% and 0.10%, for low cognitive ability and very poor or poor social functioning, respectively). No association between cognitive ability or social functioning and risk for suicide was found in males with a psychiatric diagnosis. These data do not support the clinical utility of screening for such potential predictors.

PTSD treatment in light of DSM-5 and the "golden hours" concept.

One of the main changes in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was the separation of Stress Related Disorders from the Anxiety chapter. This separation paves the way to examine the unique characteristics of posttraumatic stress disorder (PTSD) (ie, identifiable onset, memory processes, etc) and related neural mechanisms. The time that elapses between the traumatic event and the manifestation of the disorder may also be addressed as the "golden hours," or the window of opportunity in which critical processes take place and relevant interventions may be administrated.

The 4th Schizophrenia International Research Society Conference, 5-9 April 2014, Florence, Italy: a summary of topics and trends.

The 4th Schizophrenia International Research Society Conference was held in Florence, Italy, April 5-9, 2014 and this year had as its emphasis, "Fostering Collaboration in Schizophrenia Research". Student travel awardees served as rapporteurs for each oral session, summarized the important contributions of each session and then each report was integrated into a final summary of data discussed at the entire conference by topic. It is hoped that by combining data from different presentations, patterns of interest will emerge and thus lead to new progress for the future. In addition, the following report provides an overview of the conference for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

Allopurinol for mania: a randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder.

OBJECTIVE: An emerging body of evidence supports a role for dysfunctional purinergic neurotransmission in mood disorders. Adenosine agonists have been shown to have properties similar to those of dopamine antagonists; there is a well-characterized interaction between adenosine and dopamine receptors in the ventral striatum, and increasing adenosinergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol increases adenosine levels in the brain, and hence is hypothesized to reduce the symptoms of mania. Two randomized, placebo-controlled trials administering add-on allopurinol to manic patients showed significantly greater improvements in Young Mania Rating Scale (YMRS) scores for drug compared to placebo, while a more recent, relatively small, add-on study showed negative results. Based on these data, our objective was to examine the efficacy of allopurinol as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. METHODS: We performed a large, well-powered, multicenter, six-week, randomized, placebo-controlled trial of allopurinol added to mood stabilizers and/or antipsychotic agents in 180 patients with bipolar disorder in an acute manic episode. RESULTS: Both groups showed improvement on the YMRS (effect size of 1.5 for placebo and 1.6 for allopurinol), with no difference observed between groups on YMRS scores (t = 0.28, p = 0.78). There was no difference in the proportion of patients who responded to treatment (defined as showing at least 50% improvement in YMRS score) between the two groups (p = 0.92), or in dropout rates (p = 0.84). LIMITATIONS: None of our patients received lithium. However, the side effects of lithium and its narrow therapeutic index made the use of lithium less common and, therefore, our study results reflect common current clinical practice. In the present study, we used a variety of antipsychotic and/or mood stabilizing treatments, to which we added allopurinol; one might hypothesize that add-on allopurinol has a different effect in combination with different antipsychotic agents or mood stabilizers. CONCLUSIONS: The findings of this large, well-powered study do not support add-on allopurinol as a treatment for acute mania. This study did not test the efficacy of allopurinol as monotherapy.

Is single umbilical artery an independent risk factor for perinatal mortality?

OBJECTIVE: To evaluate perinatal outcome of fetuses with isolated single umbilical artery (SUA), and specifically to examine whether an isolated SUA is an independent risk factor for perinatal mortality. METHODS: A population-based study was conducted, comparing pregnancies of women with and without SUA. Deliveries occurred between the years 1988-2006, in a tertiary medical center. Multiple gestations, chromosomal abnormalities and malformations were excluded from the analysis. Stratified analysis was performed using multiple logistic regression models to evaluate the association between SUA and perinatal mortality, while controlling for confounders. RESULTS: Out of 194,809 deliveries, 243 (0.1%) were of fetuses with isolated SUA. Fetuses with SUA were smaller (2,844 ± 733 vs. 3,197 ± 530 g, P < 0.001), and were delivered at an earlier gestational age (38.3 ± 3.0 vs. 39.3 ± 2.1 weeks, P < 0.001), when compared with fetuses with normal umbilical vessels. Mothers to fetuses with isolated SUA tended to have a history of infertility treatments (4.5 vs. 1.7%; P = 0.001) when compared with the comparison group. Fetuses with SUA had more complications, including fetal growth restriction (FGR 9.5 vs. 1.9%, P < 0.001), polyhydramnios (11.5 vs. 3.7%; P < 0.001) and oligohydramnios (6.6 vs. 2.2%; P < 0.001). Deliveries of SUA fetuses had higher rates of placental abruption (3.3 vs. 0.7%; P < 0.001), placenta previa (1.2 vs. 0.4%; P = 0.03) and cord prolapse (2.9 vs. 0.4%; P < 0.001). Higher rates of cesarean deliveries were noted in this group (23.9 vs. 12.2%; P < 0.001). SUA newborns had higher rates of low Apgar scores (<7) in one (11.8 vs. 3.7%; P < 0.001) and 5 min (3.5 vs. 0.4%; P < 0.001). Higher rates of perinatal mortality were noted in the SUA group, as compared to fetuses with normal umbilical vessels (6.6 vs. 0.9%, OR 7.78; 95% CI 4.7-13.0; P < 0.001). Using a multiple logistic regression model, controlling for possible confounders, such as FGR, oligohydramnios, polyhydramnios, prolapse of cord, maternal hypertension and diabetes mellitus, isolated SUA remained an independent risk factor for perinatal mortality (adjusted OR = 3.91, 95% CI 2.06-7.43; P < 0.001). CONCLUSION: Isolated SUA in our population was noted as an independent risk factor for perinatal mortality.