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Saturday, August 8, 2015

August 2015

Specific SSRIs and birth defects: bayesian analysis to interpret

new data in the context of previous reports 



To follow up on previously reported associations between periconceptional use of selective serotonin
reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects Prevention Study.

Bayesian analysis combining results from independent published analyses with data from a multicenter
population based case-control study of birth defects.

17952 mothers of infants with birth defects and 9857 mothers of infants without birth defects, identified
through birth certificates or birth hospitals, with estimated dates of delivery between 1997 and 2009.

Citalopram, escitalopram, fluoxetine, paroxetine, or sertraline use in the month before through the third
month of pregnancy. Posterior odds ratio estimates were adjusted to account for maternal race/ethnicity, education, smoking, and prepregnancy obesity.

Main outcome measure
14 birth defects categories that had associations with SSRIs reported in the literature.

Sertraline was the most commonly reported SSRI, but none of the five previously reported birth defects associations with sertraline was confirmed. For nine previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association. High posterior odds ratios excluding the null value were observed for five birth defects with paroxetine (anencephaly 3.2, 95% credible interval 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0).

These data provide reassuring evidence for some SSRIs but suggest that some birth defects occur 2-3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset

Translational of Psychiatry


Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86–0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71–0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82–0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.

Sparse whole-genome sequencing identifies two loci for major depressive disorder



Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide1, poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified2, despite analysis of more than 9,000 cases3. Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 × 10−10), the other in an intron of the LHPP gene (P = 6.45 × 10−12). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

Risk of intracranial haemorrhage linked to co-treatment with antidepressants and NSAIDs



The linked paper by Shin and colleagues (doi:10.1136/bmj.h3517) offers important new evidence about the relation between antidepressant drugs, non-steroidal anti-inflammatory drugs (NSAIDs), and the incidence of intracranial haemorrhage.1 Although NSAIDs and antidepressants are both associated with an increased risk of gastrointestinal bleeding, previous evidence has not shown clear links between intracranial haemorrhage and either type of drug when used alone. The new study, however, set out to define the risk of such bleeds when the two classes of drugs are combined, and the results give some cause for concern. In a retrospective population cohort study of more than four million people in Korea, the authors found that the combination of antidepressants and NSAIDs was associated with a substantially increased risk of intracranial haemorrhage, compared with antidepressant treatment alone.

Antidepressants are widely prescribed globally, and their use is increasing.2 3 4 In England, almost 40 million antidepressant prescriptions were issued in 2012, compared with just under 15 million in 1998.4 NSAIDs are also widely used, often without prescription and in non-pharmacy settings. Oral analgesics accounted for 739 million items in …

US FDA approves brexpiprazole to treat schizophrenia and aS an add on to an antidepressant to treat major depressive disorder

FDA News Release

The U.S. Food and Drug Administration approved Rexulti (brexpiprazole) tablets to treat adults with schizophrenia and as an add-on treatment to an antidepressant medication to treat adults with major depressive disorder (MDD).

Schizophrenia is a chronic, severe, and disabling brain disorder affecting about one percent of Americans. Typically, symptoms are first seen in adults younger than 30 years of age and include hearing voices; believing other people are reading their minds or controlling their thoughts; and being suspicious or withdrawn.

MDD, commonly referred to as depression, is also a severe and disabling brain disorder characterized by mood changes and other symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Episodes of depression often recur throughout a person's lifetime, although some may experience a single occurrence. Other signs and symptoms of MDD include loss of interest in usual activities; significant change in weight or appetite; insomnia or excessive sleeping (hypersomnia); restlessness/pacing (psychomotor agitation); increased fatigue; feelings of guilt or worthlessness; slowed thinking or impaired concentration; and suicide attempts or thoughts of suicide. Not all people with MDD experience the same symptoms.

“Schizophrenia and major depressive disorder can be disabling and can greatly disrupt day-to-day activities,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Medications affect everyone differently so it is important to have a variety of treatment options available for patients with mental illnesses.”

The effectiveness of Rexulti in treating schizophrenia was evaluated in 1,310 participants in two 6-week clinical trials. Rexulti was shown to reduce the occurrence of symptoms of schizophrenia compared to placebo (inactive tablet).

The effectiveness of Rexulti as an add-on treatment for MDD was evaluated in two 6-week trials that compared Rexulti plus an antidepressant to placebo plus an antidepressant in 1,046 participants for whom an antidepressant alone did not adequately treat their symptoms. The participants taking Rexulti reported fewer symptoms of depression than those taking the placebo. 

Rexulti and other drugs used to treat schizophrenia have a Boxed Warning alerting health care professionals about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

The Boxed Warning also alerts health care professionals and patients to an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be monitored for worsening and emergence of suicidal thoughts and behaviors. Rexulti must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. 

The most common side effects reported by participants taking Rexulti in clinical trials included weight gain and an inner sense of restlessness, such as feeling the need to move.

Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease

JAMA Neurology


Importance  Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD).

To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation–carrying and noncarrying children with ADAD.

Design, Setting, and Participants  
Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012.

Main Outcomes and Measures  
All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding–dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD.

Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task–related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were −0.590 [0.50] for noncarriers and −0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons).

Conclusions and Relevance  
Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.


Depression and Anxiety Journal


Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo.

Thirty-six adults with PTSD were randomized to 24 weeks of double-blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models.

The combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26–.63). Both treatments were well-tolerated, with significantly increased appetite but not weight gain in the combined treatment group.

Findings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI.

A2BP1 gene polymorphisms association with olanzapine-induced weight gain

Pharmacological Research


The ataxin-2 binding protein 1 (A2BP1) gene is reported to be one of the susceptibility genes in schizophrenia, autism, and obesity. The aim of this study was to explore the association of A2BP1 gene polymorphisms with antipsychotic induced weight gain (AIWG) in Chinese Han population. Three hundred and twenty-eight patients with schizophrenia were followed-up for an 8-week period of treatment with olanzapine. The fasting weights of 328 patients were measured before and after the 8-week course of treatment. Four single nucleotide polymorphisms (SNPs: rs8048076, rs1478697, rs10500331, and rs4786847) of the A2BP1 gene were genotyped by polymerase chain reaction (PCR). We analyzed putative association of A2BP1 polymorphisms with AIWG of olanzapine using linear regression analysis and found that SNP rs1478697 was significantly associated with AIWG caused by olanzapine (p = 0.0012; Bonferroni corrected p = 0.0048). The association was replicated in another independent sample including 208 first-episode and drug-naïve patients presenting with schizophrenia after a 4-week treatment with olanzapine (p = 0.0092; Bonferroni corrected p = 0.0368; meta p = 5.33 × 10−5). To explore the biological plausibility of A2BP1 in the pathogenesis of AIWG, we made expression analyses and eQTL analyses; these analyses showed that A2BP1 was highly expressed in whole brain tissues using the HBT database, and that rs1478697 has an expression quantitative trait locus effect in human cerebellar cortex tissues using the BRAINEAC database (p = 2.50E−04). In conclusion, the rs1478697 in A2BP1 may be associated with AIWG induced by 8-week treatment with olanzapine.

Evidence for serotonin function as a neurochemical difference between fear and anxiety disorders in humans?

Journal of Psychopharmacology


The relationships between serotonin and fear and anxiety disorders have been much studied yet many important questions remain, despite selective serotonin reuptake inhibitors having been the primary treatments for these disorders for some time. In order to explore this issue we performed a pooled analysis of six of our studies in remitted patients with a fear/anxiety disorder who were exposed to syndrome-specific aversive stimulation under acute tryptophan depletion. We based our analysis on the hypothesis that the inconsistencies observed in the studies could be predicted by Deakin and Graeff’s theory about the dual role of serotonin in responses to threats, whereby serotonin is critical to prevent fear (panic) but not anxiety. In accordance with this view, our results give support to a dissociation of the disorders traditionally grouped under fear and anxiety-related disorders in terms of different roles of serotonin in modulation of responses to aversive stimulation. Implications for future studies and psychiatric nosology are discussed.

Autoimmune Encephalitis in Postpartum Psychosis

The American Journal of Psychiatry


Significant immunological alterations have been observed in women with first-onset affective psychosis during the postpartum period. Recent studies have highlighted the possibility that a subset of patients with first-onset severe psychiatric episodes might suffer from undiagnosed autoimmune encephalitis. Therefore, the authors performed a three-step immunohistochemistry-based screening for CNS autoantibodies in a large cohort of patients with postpartum psychosis and matched postpartum comparison subjects.

Ninety-six consecutive patients with postpartum psychosis and 64 healthy postpartum women were included. Screening for antibodies in patient serum was performed using immunohistochemistry. Samples showing any staining were further examined by immunocytochemistry using live hippocampal neurons and cell-based assays to test for anti-N-methyl-d-aspartate (NMDA) receptor antibodies. Cell-based assays for all other known CNS antigens were performed in those samples with immunocytochemistry labeling but negative for NMDA receptor antibodies.

Four patients (4%) with neuropil labeling suggestive for extracellular antigen reactivity were identified. Serum samples from all four patients showed clear extracellular labeling of live hippocampal neurons. Two women had the specific staining pattern characteristic for anti-NMDA receptor antibody positivity, which was confirmed by cell-based assays. Neither patient with anti-NMDA receptor antibody positivity had evidence of an ovarian teratoma. The other two patients tested negative by cell-based assays for all known CNS antigens. None of the matched postpartum comparison subjects had confirmed neuronal surface antibodies. The two patients with anti-NMDA receptor antibodies both showed extrapyramidal symptoms following initiation of treatment with low-dose haloperidol.

In patients with acute psychosis during the postpartum period, systematic screening for anti-NMDA receptor autoantibodies should be considered. The acute onset of severe atypical psychiatric symptoms in young female patients should raise the index of suspicion for anti-NMDA receptor encephalitis, particularly in the setting of neurological symptoms, including extrapyramidal side effects of antipsychotic treatment.

Online Journals:

Biological Psychiatry - Volume 78, Issue 5, September 2015

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