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Biological Psychiatry

Monday, March 4, 2019

March 2019

The neuroactive potential of the human gut microbiota in quality of life and depression

Nature Microbiology


The relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research. Bidirectional microbiota–gut–brain communication has mostly been explored in animal models, with human research lagging behind. Large-scale metagenomics studies could facilitate the translational process, but their interpretation is hampered by a lack of dedicated reference databases and tools to study the microbial neuroactive potential. Surveying a large microbiome population cohort (Flemish Gut Flora Project, n = 1,054) with validation in independent data sets (ntotal = 1,070), we studied how microbiome features correlate with host quality of life and depression. Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Together with Dialister, Coprococcus spp. were also depleted in depression, even after correcting for the confounding effects of antidepressants. Using a module-based analytical framework, we assembled a catalogue of neuroactive potential of sequenced gut prokaryotes. Gut–brain module analysis of faecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as correlating positively with mental quality of life and indicated a potential role of microbial γ-aminobutyric acid production in depression. Our results provide population-scale evidence for microbiome links to mental health, while emphasizing confounder importance. 

Tamoxifen for bipolar disorder: Systematic review and meta-analysis

Journal of Psychopharmacology

Tamoxifen is an oral medication that has been proposed as a potential treatment for bipolar disorder. Tamoxifen acts to inhibit the intracellular action of protein kinase C, which is also an action of well-established treatments such as lithium and valproate. Here we aimed to identify randomised controlled trials (RCTs) of tamoxifen in the treatment of bipolar disorder and synthesise their results using meta-analysis.

RCTs were identified by searching of electronic databases and from discussion with experts in the field. Data were extracted, and meta-analyses performed in R.

Five placebo-controlled RCTs of tamoxifen in the treatment of acute mania were identified. There were no trials in the treatment of episodes of bipolar depression, or for relapse prevention. The studies of mania treatment were of between three and six weeks duration. Tamoxifen was studied either as monotherapy (two trials) or as augmentation of lithium or valproate (three trials). Change in mania scale scores favoured tamoxifen over placebo: SMD −2.14 (95% CI −3.39 to −0.89; 4 trials), as did endpoint mania scale scores SMD 1.23 (95% CI 0.60–1.87; 5 trials). Response rates were also higher: RR 4.35 (1.99–9.50; 4 trials). Acceptability was similar to placebo: RR 1.03 (0.94–1.13; 5 trials).

Tamoxifen appears to be a promising potential treatment for episodes of mania. Future studies could investigate its effects as an adjunct to dopamine antagonists for improved anti-manic efficacy, and establish its longer term effects on mood, particularly depression and relapse.

Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia

JAMA Psychiatry

The effectiveness of antipsychotic polypharmacy in schizophrenia relapse prevention is controversial, and use of multiple agents is generally believed to impair physical well-being.

To study the association of specific antipsychotic combinations with psychiatric rehospitalization.

Design, Setting, and Participants 
In this nationwide cohort study, the risk of psychiatric rehospitalization was used as a marker for relapse among 62 250 patients with schizophrenia during the use of 29 different antipsychotic monotherapy and polypharmacy types between January 1, 1996, and December 31, 2015, in a comprehensive, nationwide cohort in Finland. We conducted analysis of the data from April 24 to June 15, 2018. Rehospitalization risks were investigated by using within-individual analyses to minimize selection bias.

Main Outcomes and Measures 
Hazard ratio (HR) for psychiatric rehospitalization during use of polypharmacy vs during monotherapy within the same individual.

In the total cohort, including 62 250 patients, 31 257 individuals (50.2%) were men, and the median age was 45.6 (interquartile range, 34.6-57.9) years. The clozapine plus aripiprazole combination was associated with the lowest risk of psychiatric rehospitalization in the total cohort, being superior to clozapine, the monotherapy associated with the best outcomes, with a difference of 14% (HR, 0.86; 95% CI, 0.79-0.94) in the analysis including all polypharmacy periods, and 18% in the conservatively defined polypharmacy analysis excluding periods shorter than 90 days (HR, 0.82; 95% CI, 0.75-0.89; P < .001). Among patients with their first episode of schizophrenia, these differences between clozapine plus aripiprazole vs clozapine monotherapy were greater (difference, 22%; HR, 0.78; 95% CI, 0.63-0.96 in the analysis including all polypharmacy periods, and difference, 23%; HR, 0.77; 95% CI, 0.63-0.95 in the conservatively defined polypharmacy analysis). At the aggregate level, any antipsychotic polypharmacy was associated with a 7% to 13% lower risk of psychiatric rehospitalization compared with any monotherapy (ranging from HR, 0.87; 95% CI, 0.85-0.88, to HR, 0.93; 95% CI, 0.91-0.95; P < .001). Clozapine was the only monotherapy among the 10 best treatments. Results on all-cause and somatic hospitalization, mortality, and other sensitivity analyses were in line with the primary outcomes.

Conclusions and Relevance 
Combining aripiprazole with clozapine was associated with the lowest risk of rehospitalization, indicating that certain types of polypharmacy may be feasible in the treatment of schizophrenia. Because add-on treatments are started when monotherapy is no longer sufficient to control for worsening of symptoms, it is likely that the effect sizes for polypharmacy are underestimates. Although the results do not indicate that all types of polypharmacy are beneficial, the current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy in the maintenance treatment of schizophrenia.

Severity and Variability of Depression Symptoms Predicting Suicide Attempt in High-Risk Individuals

JAMA Psychiatry 


Predicting suicidal behavior continues to be among the most challenging tasks in psychiatry.

To examine the trajectories of clinical predictors of suicide attempt (specifically, depression symptoms, hopelessness, impulsivity, aggression, impulsive aggression, and irritability) for their ability to predict suicide attempt and to compute a risk score for suicide attempts.

Design, Setting, and Participants  
This is a longitudinal study of the offspring of parents (or probands) with mood disorders who were recruited from inpatient units at Western Psychiatric Institute and Clinic (Pittsburgh) and New York State Psychiatric Institute. Participants were recruited from July 15, 1997, to September 6, 2005, and were followed up through January 21, 2014. Probands and offspring (n = 663) were interviewed at baseline and at yearly follow-ups for 12 years. Lifetime and current psychiatric disorders were assessed, and self-reported questionnaires were administered. Model evaluation used 10-fold cross-validation, which split the entire data set into 10 equal parts, fit the model to 90% of the data (training set), and assessed it on the remaining 10% (test set) and repeated that process 10 times. Preliminary analyses were performed from July 20, 2015, to October 5, 2016. Additional analyses were conducted from July 26, 2017, to July 24, 2018.

Main Outcomes and Measures  
The broad definition of suicide attempt included actual, interrupted, and aborted attempts as well as suicidal ideation that prompted emergency referrals during the study. The narrow definition referred to actual attempt only.

The sample of offspring (n = 663) was almost equally distributed by sex (316 female [47.7%]) and had a mean (SD) age of 23.8 (8.5) years at the time of censored observations. Among the 663 offspring, 71 (10.7%) had suicide attempts over the course of the study. The trajectory of depression symptoms with the highest mean scores and variability over time was the only trajectory to predict suicide attempt (odds ratio [OR], 4.72; 95% CI, 1.47-15.21; P = .01). In addition, we identified the following predictors: younger age (OR, 0.82; 95% CI, 0.74-0.90; P < .001), lifetime history of unipolar disorder (OR, 4.71; 95% CI, 1.63-13.58; P = .004), lifetime history of bipolar disorder (OR, 3.4; 95% CI, 0.96-12.04; P = .06), history of childhood abuse (OR, 2.98; 95% CI, 1.40-6.38; P = .01), and proband actual attempt (OR, 2.24; 95% CI, 1.06-4.75; P = .04). Endorsing a score of 3 or higher on the risk score tool resulted in high sensitivity (87.3%) and moderate specificity (63%; area under the curve = 0.80).

Conclusions and Relevance  
The specific predictors of suicide attempt identified are those that clinicians already assess during routine psychiatric evaluations; monitoring and treating depression symptoms to reduce their severity and fluctuation may attenuate the risk for suicidal behavior.

Association of Fetal Growth With General and Specific Mental Health Conditions

JAMA Psychiatry


It is unclear if the associations between fetal growth and later mental health conditions remain after controlling for familial factors and psychiatric comorbidity.

To examine the associations between fetal growth and general and specific mental health conditions, controlling for familial factors.

Design, Setting, and Participants  
This register-based study conducted in Sweden analyzed 546 894 pairs of full siblings born between January 1, 1973, and December 31, 1998. Sibling pairs were followed up through December 31, 2013. First, population-based and within-sibling pair associations (which controlled for time-invariant familial confounders) between fetal growth and the outcomes were estimated. Second, exploratory factor analysis was applied to the outcomes to derive 1 general factor and 4 specific and independent factors. Third, the general and specific factors were regressed on fetal growth. Statistical analysis was performed from March 27, 2017, to October 27, 2018.

Main Outcome and Measures  
The outcomes were 11 psychiatric diagnoses (depression, anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, bipolar disorder, alcohol abuse, drug use, attention-deficit/hyperactivity disorder, autism, schizophrenia, and schizoaffective disorder) and court convictions of violent crimes. Birth weight (in kilograms) statistically adjusted for gestational age was the exposure.

The mean (SD) age of the 1 093 788 participants was 27.2 (6.8) years (range, 15.1-40.9 years) and 51.5% were male. Nine outcomes were significantly associated with birth weight in the population at large: depression (odds ratio [OR], 0.96; 95% CI, 0.95-0.98), anxiety (OR, 0.94; 95% CI, 0.92-0.95), posttraumatic stress disorder (OR, 0.91; 95% CI, 0.89-0.93), bipolar disorder (OR, 0.94; 95% CI, 0.89-1.00), alcohol abuse (OR, 0.89; 95% CI, 0.87-0.91), drug use (OR, 0.83; 95% CI, 0.80-0.85), violent crimes (OR, 0.85; 95% CI, 0.83-0.86), attention-deficit/hyperactivity disorder (OR, 0.88; 95% CI, 0.86-0.90), and autism (OR, 0.95; 95% CI, 0.92-0.97). Only depression (OR, 0.95; 95% CI 0.92-0.98), obsessive-compulsive disorder (OR, 0.93; 95% CI, 0.87-0.99), attention-deficit/hyperactivity disorder (OR, 0.86; 95% CI, 0.82-0.89), and autism (OR, 0.72; 95% CI, 0.69-0.76) remained significantly associated within sibling pairs. An exploratory factor analysis indicated that 1 general and 4 specific factors (capturing anxiety, externalizing, neurodevelopmental, and psychotic conditions) fit the outcomes well. Across almost all sensitivity analyses, an increase in birth weight by 1 kg significantly reduced the general (β, −0.047; 95% CI, −0.071 to −0.023) and the specific neurodevelopmental factors (β, −0.159; 95% CI, −0.190 to −0.128) within sibling pairs.

Conclusions and Relevance  
Controlling for familial confounders, reduced fetal growth was associated with a small but significant increase in the general factor of psychopathology and a moderate increase in a specific neurodevelopmental factor.

Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood

JAMA Psychiatry


Cannabis is the most commonly used drug of abuse by adolescents in the world. While the impact of adolescent cannabis use on the development of psychosis has been investigated in depth, little is known about the impact of cannabis use on mood and suicidality in young adulthood.

To provide a summary estimate of the extent to which cannabis use during adolescence is associated with the risk of developing subsequent major depression, anxiety, and suicidal behavior.

Data Sources  
Medline, Embase, CINAHL, PsycInfo, and Proquest Dissertations and Theses were searched from inception to January 2017.

Study Selection  
Longitudinal and prospective studies, assessing cannabis use in adolescents younger than 18 years (at least 1 assessment point) and then ascertaining development of depression in young adulthood (age 18 to 32 years) were selected, and odds ratios (OR) adjusted for the presence of baseline depression and/or anxiety and/or suicidality were extracted.

Data Extraction and Synthesis  
Study quality was assessed using the Research Triangle Institute item bank on risk of bias and precision of observational studies. Two reviewers conducted all review stages independently. Selected data were pooled using random-effects meta-analysis.

Main Outcomes and Measures  
The studies assessing cannabis use and depression at different points from adolescence to young adulthood and reporting the corresponding OR were included. In the studies selected, depression was diagnosed according to the third or fourth editions of Diagnostic and Statistical Manual of Mental Disorders or by using scales with predetermined cutoff points.

After screening 3142 articles, 269 articles were selected for full-text review, 35 were selected for further review, and 11 studies comprising 23 317 individuals were included in the quantitative analysis. The OR of developing depression for cannabis users in young adulthood compared with nonusers was 1.37 (95% CI, 1.16-1.62; I2 = 0%). The pooled OR for anxiety was not statistically significant: 1.18 (95% CI, 0.84-1.67; I2 = 42%). The pooled OR for suicidal ideation was 1.50 (95% CI, 1.11-2.03; I2 = 0%), and for suicidal attempt was 3.46 (95% CI, 1.53-7.84, I2 = 61.3%).

Conclusions and Relevance  
Although individual-level risk remains moderate to low and results from this study should be confirmed in future adequately powered prospective studies, the high prevalence of adolescents consuming cannabis generates a large number of young people who could develop depression and suicidality attributable to cannabis. This is an important public health problem and concern, which should be properly addressed by health care policy.

Parental Age and Differential Estimates of Risk for Neuropsychiatric Disorders

Child and Adolescent Psychiatry


Parental age at birth has been shown to affect the rates of a range of neurodevelopmental disorders, but the understanding of the mechanisms through which it mediates different outcomes is still lacking. We used a population-based cohort to assess differential effects of parental age on estimates of risk across pediatric-onset neuropsychiatric disorders: autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) and Tourette syndrome/chronic tic disorder (TS/CT).

Our study cohort included all singleton births in Denmark between 1980 and 2007 with full information on parental ages (N=1,490,745), followed through December 31, 2013. Cases of ASD, ADHD, OCD and TS/CT were identified in the Danish Psychiatric Central Register and the National Patient Register. Associations with parental age were modeled using a stratified Cox regression, allowing for changes in baseline diagnostic rates across time.

Younger parental age was significantly associated with increased estimates of risk for ADHD and TS/CT, while older parental age was associated with ASD and OCD. Except for OCD, we did not observe any evidence for differential effects of parental ages on male vs. female offspring.

We provide novel evidence for the association between age at parenthood and TS/CT and OCD, and show for the first time in a population-based sample that parental age confers differential risk rates for pediatric-onset psychiatric disorders. Our results are consistent with a model of both shared and unshared risk architecture for pediatric-onset neuropsychiatric conditions, highlighting unique contributions of maternal and paternal ages.



The U.S. Food and Drug Administration today approved Cassipa (buprenorphine and naloxone) sublingual film (applied under the tongue) for the maintenance treatment of opioid dependence. This action provides a new dosage strength (16 milligrams/4 milligrams) of buprenorphine and naloxone sublingual film, which is also approved in both brand name and generic versions and in various strengths.

“There’s an urgent need to ensure access to, and wider use and understanding of, medication-assisted treatment for opioid use disorder. The introduction of new treatment options has the potential to broaden access for patients. For example, the FDA recently described a streamlined approach to drug development for certain medication-assisted treatments that are based on buprenorphine. This streamlined approach can reduce drug development costs, so products may be offered at a lower price to patients and we can broaden access to treatment,” said FDA Commissioner Scott Gottlieb, M.D. “The FDA is committed to helping those with opioid use disorder transition to lives of sobriety. We’ve taken a number of steps to advance the development of new FDA-approved treatments for opioid dependence and encourage health care professionals to ensure patients are offered an adequate chance to benefit from these therapies. We’re also working to address the unfortunate stigma that’s sometimes associated with the use of opioid replacement therapy as one approach to the successful treatment of addiction. Despite what some may think, individuals who successfully transition onto medication-assisted treatment are not swapping one addiction for another. Opioid replacement therapy can be an important part of effective treatment. Opioid use disorder should be viewed similarly to any other chronic condition that is treated with medication.”

Medication-assisted treatment (MAT) is a comprehensive approach that combines FDA-approved medications (currently methadone, buprenorphine, or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder (OUD). Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use opioids, without causing the cycle of highs and lows associated with opioid misuse or abuse. At proper doses, buprenorphine also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for treatment of their OUD cut their risk of death from all causes in half.


PLOS Medicine


• Widespread use of organophosphate (OP) pesticides to control insects has resulted inubiquitous human exposures.
• High exposures to OP pesticides are responsible for poisonings and deaths, particularly in developing countries.
• Compelling evidence indicates that prenatal exposure at low levels is putting children atrisk for cognitive and behavioral deficits and for neurodevelopmental disorders.To protect children worldwide, we recommend the following:
• Governments phase out chlorpyrifos and other OP pesticides, monitor watersheds andother sources of human exposures, promote use of integrated pest management (IPM)through incentives and training in agroecology, and implement mandatory surveillanceof pesticide-related illness.
• Health professions implement curricula on the hazards from OP pesticides in nursingand medical schools and in continuing medical education courses and educate theirpatients and the public about these hazards.
• Agricultural entities accelerate the development of nontoxic approaches to pest controlthrough IPM and ensure the safety of workers through training and provision of protec-tive equipment when toxic chemicals are to be used.


Frontiers in Aging Neuroscience


Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD. Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia—are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD. It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD. Three other studies are described which directly relate to HSV1 and AD: they deal respectively with lysosomal changes in HSV1-infected cell cultures, with evidence for a role of human herpes virus type 6 and 7 (HHV6 and HHV7) in AD, and viral effects on host gene expression, and with the antiviral characteristics of beta amyloid (Aβ). Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia (FM), and with FM being associated with later development of SD. Studies on the link between epilepsy, AD and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-ε4, HHV6 and HSV1 in epilepsy. 


Online Journals:

Biological Psychiatry - Volume 85, Issue 6, March 2019

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