Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).

This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown.

We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models.

Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p < 0.001). By week 8, the response for benzodiazepines and SSRIs (p = 0.103) and SNRIs (p = 0.911) did not differ nor did SSRIs and SNRIs differ (p = 0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference − 12.42, CrI: −25.05 to −0.78, p = 0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4 weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders.

Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

Although antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines.

To delineate the effects of benzodiazepine-use during cariprazine treatment in acute schizophrenia.

Pooled data of cariprazine-treated (1.5-6mg/day) and placebo-treated patients from four short-term, randomised, double-blind trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) were analysed. Baseline characteristics (age, duration of illness) and efficacy outcome parameters (Total and Hostility Factor Score of the Positive and Negative Syndrome Scale [PANSS]) were compared in patients receiving benzodiazepines (for more ≥3 consecutive days) and not receiving benzodiazepines (<3 consecutive days).

Altogether, 36.7% and 40.7% of the CAR-treated and PBO-treated patients required BZDs. BZD-taking was associated with a higher age in both the CAR-treated (p=0.0002) and PBO-treated (p<0.0001) patients, and with longer illness-duration in both treatment groups (p<0.0001). PANSS Total Score at baseline was similar for BZD users and non-users (CAR: LS Mean=96.36 and 96.27; PBO: LS Mean=95.55 and 96.66). Change from baseline in the PANSS Total Score was greater for patients who did not use BZD vs those who did (CAR: LS Mean= -23.8 vs LS Mean 17.2, p<0.0001; PBO: LS Mean= -14.0 vs LS Mean 12.9, p=0.5776).

These findings may suggest that requiring benzodiazepines is a potential indicator of longer illness duration and poorer response in acute schizophrenia.

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Benzodiazepines and non-benzodiazepines have been linked to a variety of adverse effects including addiction. Long term use of these drugs has been associated with an increased risk of suicide.

We assessed if individuals in treatment with non-benzodiazepine (n-BZD) and benzodiazepine (BZD) had higher rates of suicide when compared to individuals not in treatment with these drugs.

We utilized a cohort design and national longitudinal data on all individuals aged 10 or above who lived in Denmark between 1995 and 2018. Treatment with either n-BZD or BZD was identified via the Danish National Prescription Registry and suicide deaths were identified in the national cause of death registries.

In a total of 6,494,206 individuals, 10,862 males and 4,214 females died by suicide. Of these, 1,220 (11.2%) males and 792 (18.8%) females had been in treatment with n-BZD, resulting in adjusted IRR for suicide of 4.2 (95% CI, 4.0 – 4.5) and 3.4 (95% CI, 3.1 – 3.7) for males and females, respectively, when compared to those not in treatment. In all, 529 (4.8%) males and 395 (9.3%) females who died by suicide had been in treatment with BZD. The IRRs for suicide were 2.4 (95% CI, 2.2 – 2.6) and 2.5 (95% CI, 2.3 – 2.8) for males and females, respectively, and compared to those not in treatment.

In this study we find that those in treatment experienced higher suicide rates than those not in treatment, this persisted when also adjusting for a large variety of covariates.

No significant relationships.

To examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalised for coronavirus disease 2019 (COVID-19).

A multicentre observational study was performed at Greater Paris University hospitals. The sample involved 14 381 patients hospitalised for COVID-19. A total of 686 (4.8%) inpatients received a BZRA at hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (standard deviation (s.d.) = 25.4). The study baseline was the date of admission, and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, medical comorbidities and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW).

Over a mean follow-up of 14.5 days (s.d. = 18.1), the primary endpoint occurred in 186 patients (27.1%) who received BZRAs and in 1134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (hazard ratio (HR) = 3.20; 95% confidence interval (CI) = 2.74–3.74; p < 0.01) and in the IPW analysis (HR = 1.61; 95% CI = 1.31–1.98, p < 0.01), with a significant dose-dependent relationship (HR = 1.55; 95% CI = 1.08–2.22; p = 0.02). This association remained significant in sensitivity analyses. Exploratory analyses indicate that most BZRAs may be associated with an increased mortality among patients hospitalised for COVID-19, except for diazepam, which may be associated with a reduced mortality compared with any other BZRA treatment.

BZRA use may be associated with an increased mortality among patients hospitalised for COVID-19, suggesting the potential benefit of decreasing dose or tapering off gradually these medications when possible.

Benzodiazepines (BZD) are widely used in patients with bipolar disorder (BD) and their effectiveness is well documented. Therefore, there are major risks associated with BZD use including abuse and dependence. Those risks can be related to the patients’chacteristics, the particularities of BD and the prescribers.

To determine the factors associated with chronic use of BZD in patients with BD.

We conducted a cross-sectional, descriptive and analytical study among a sample of patients with BD (DSM-5) followed in psychiatric outpatient of Hedi Chaker university hospital in Sfax. We used the Benzodiazepine Cognitive Attachment Scale (ECAB) to determine dependent patients

Among the 61 included patients, 50 (82%) had a chronic use of BZD (> 3 months). They had a mean age of 49.3 years (± 14.02 years) and a low socio-economic level in 44%. The type of BD was dominated by type II (66%). Initial episode type was depressive in 78%. The average number of depressive episodes was 2.92±2.3. A rate of 65.5% of patients have already attempted BZD withdrawal. Chronic BZD use was significantly correlated with BZD dependence (p=0.000), low socioeconomic level (p=0.04), depressive type of the initial episode (p=0.011), the depressive recurrence (p=0.000) and the absence of any attempt to discontinue BZD (p=0.011).

Chronic use of BZD in patients with BD is prevalent. In order to minimize this problem in this population, it is important to enhance programs to improve psychiatrist-prescribing behavior and to use cognitive-behavioral therapies in combination with medication to help withdrawal.

Benzodiazepines (BZD) are frequently prescribed to patients with bipolar disorder. The use of this medication can become problematic in some cases or even lead to dependence mainly in patients with personality disorders.

To assess different personality traits in BZD-dependent patients with bipolar disorder

A cross-sectional descriptive and analytical study was conducted on euthymic bipolar patients (DSM-5) attending the psychiatric outpatient in Hedi Chaker university hospital of Sfax. We used the Benzodiazepine Cognitive Attachment Scale (ECAB) to determine dependent patients and the Ten Item Personality Measure (TIPI) scale to assess the five personality traits.

Among the 61 included patients, 34 were BZD-dependents (55.7%). Their mean age was 52.12 ± 12.87 years. The sex ratio (M/F) was 0.54. A comorbid personality disorder was found in 18% of patients and the most frequent was histrionic personality (45.45%). According to TIPI, the highest scores of personality traits were conscientiousness, agreeableness and extraversion, with mean scores of 9.8 ± 2.78, 8.21 ± 3.15 and 7.98 ± 1.77 respectively. Having a comorbid personality disorder was not associated with BZD dependence. Regarding the dimensional approach using TIPI, the dimensions of extraversion, agreeableness and emotional stability were significantly negatively correlated with BZD-dependence (p 0.024; 0.006 and 0.01 respectively).

This study demonstrates that personality characterized by less extraversion, agreeableness, and emotional stability may increase the risk of BZD-dependence among bipolar patients. Such psychological factors should be taken into account in the risk-benefit assessment made in the planning of BZD treatment.

Benzodiazepine (BZD) prescription rates have increased over the past decade in the United States. Available literature indicates that sociodemographic factors may influence diagnostic patterns and/or prescription behaviour. Herein, the aim of this study is to determine whether the gender of the prescriber and/or patient influences BZD prescription.

Cross-sectional study using data from the Florida Medicaid Managed Medical Assistance Program from January 1, 2018 to December 31, 2018. Eligible recipients ages 18 to 64, inclusive, enrolled in the Florida Medicaid plan for at least 1 day, and were dually eligible. Recipients either had a serious mental illness (SMI), or non-SMI and anxiety.

Total 125 463 cases were identified (i.e., received BZD or non-BZD prescription). Main effect of patient and prescriber gender was significant F(1, 125 459) = 0.105, P = 0 .745, partial η2 < 0.001. Relative risk (RR) of male prescribers prescribing a BZD compared to female prescribers was 1.540, 95% confidence intervals (CI) [1.513, 1.567], whereas the RR of male patients being prescribed a BZD compared to female patients was 1.16, 95% CI [1.14, 1.18]. Main effects of patient and prescriber gender were statistically significant F(1, 125 459) = 188.232, P < 0.001, partial η2 = 0.001 and F(1, 125 459) = 349.704, P < 0.001, partial η2 = 0.013, respectively.

Male prescribers are more likely to prescribe BZDs, and male patients are more likely to receive BZDs. Further studies are required to characterize factors that influence this gender-by-gender interaction.

To explore the relationships between dose changes to antipsychotic and/or benzodiazepine medications and resident outcomes, including variations in neuropsychiatric symptoms, quality of life (QoL), and social withdrawal, within a multicomponent, interdisciplinary antipsychotic and benzodiazepine dose reduction program.

Prospective, observational, longitudinal study.

The Reducing Use of Sedatives (RedUSe) project involved 150 Australian Long-Term Care Facilities (LTCFs) incorporating auditing and benchmarking of prescribing, education, and multidisciplinary sedative reviews.

A convenience sample of LTCFs (n = 28) involved in RedUSe between January 2015 and March 2016.

Permanent residents (n = 206) of LTCFs involved in RedUSe taking an antipsychotic and/or benzodiazepine daily. Residents were excluded if they had a severe psychiatric condition where antipsychotic therapy should generally be maintained long-term (e.g., bipolar disorder, schizophrenia) or were considered end-stage palliative.

Neuropsychiatric symptoms (Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory (CMAI)), QoL (Assessment of Quality of Life-4D), and social withdrawal (Multidimensional Observation Scale for Elderly Subjects-withdrawal subscale) were measured at baseline and 4 months where nursing staff completed psychometric tests as proxy raters.

There was no evidence that psychometric measures were worsened following dose reductions. In fact, dose reduction was associated with small, albeit non-statistically significant, improvements in behavior, particularly less physically non-aggressive behavior with both drug groups (−0.36 points per 10% reduction in antipsychotic dose, −0.17 per 10% reduction in benzodiazepine dose) and verbally agitated behavior with benzodiazepine reduction (−0.16 per 10% dose reduction), as measured with the CMAI. Furthermore, antipsychotic reduction was associated with non-statistically significant improvements in QoL and social withdrawal.

Antipsychotic and benzodiazepine dose reduction in LTCFs was not associated with deterioration in neuropsychiatric symptoms, QoL, or social withdrawal. Trends toward improved agitation with antipsychotic and benzodiazepine dose reduction require further evaluation in larger, prospective, controlled studies.