The effect of selective serotonin reuptake inhibitors on fear learning:: a systematic review and meta-analysis

Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders such as panic disorder, generalized anxiety disorder and post-traumatic stress disorder. Fear learning plays an important role in the etiopathology of these disorders. However, it is unclear if and which fear learning processes are affected by SSRIs. This systematic review investigated the effect of six clinically effective SSRIs on the fear learning processes acquisition, expression and extinction. Since SSRIs have been shown to effectively treat anxiety-like disorders, the results of this systematic review could provide insight into which fear learning processes are important to include in future research regarding the development and treatment of anxiety-like disorders. A systematic search in the Medline and Embase databases yielded 128 articles that met the inclusion criteria. Of these articles 120 were eligible for the meta-analysis. Data regarding the study subjects, intervention, experimental design and size and direction of the effects were extracted. Meta-analysis was conducted in R, the R-package metafor [1] was used to estimate the overall effect size, using a random-effects model. Five categorical predefined moderators were coded to account for between-studies heterogeneity (type of SSRI, duration of treatment, disease induction, species, type of test). The effect of these moderators was analysed with a Bayesian penalized meta-regression (BRMA) which is a new method. This analysis was carried out with the pema R-package [2]. The meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian penalized meta-regression further suggested that chronic treatment with SSRIs is associated with stronger anxiolytics effects on cued fear expression than acute treatment. Other variables, including type of SSRI, species, disease induction and type of test, did not seem to moderate the effect of SSRIs This systematic review suggests that the clinical efficacy of SSRIs may be specifically related to their effects on fear expression and extinction, rather than fear acquisition. It could be that the effects of SSRIs on these fear processes are due to general inhibition of fear-related emotions. Therefore, it would be interesting to investigate how SSRIs affect other forms of anxiety, such as unconditioned fear responses. In addition, studies aimed at explaining the sources of the high levels of heterogeneity observed in our meta-analyses could help to optimise the experimental set-up to further investigate the mechanisms underlying fear learning. In order to gain more insight in how the effects of SSRIs on these processes contribute to the anxiolytic effects seen in the clinic, it would be valuable to conduct studies that use experimental designs that allow us to selectively evaluate the effects of SSRIs on fear extinction. This experimental data is interesting to obtain since various exposure therapies in patients are based on promoting extinction. Furthermore, we want to encourage fellow researchers to consider using BRMA when working with a dataset with small sample sizes containing high levels of multicollinearity to avoid overestimation of effects

Cannabidiol in anxiety research: a translational integration of preclinical and clinical studies

Introduction: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Guidelines to inform the study design of future human studies are however lacking. Aims: We aimed to determine the boundary conditions for anxiolytic effects of CBD in humans by integrating, both qualitatively and quantitatively, pharmacokinetic (PK) and pharmacodynamic (PD) (and subsidiary safety) data from preclinical and clinical studies. Methods: We conducted two systematic reviews in Pubmed and Embase up to August 2021, into PK and PD data of systemic CBD exposure in both humans and animals, which includes anxiolytic and potential side effects. Risk of bias was assessed for effects on anxiety outcomes (SYRCLE’s RoB tool [1] and Cochrane RoB 2.0 [2]), PK outcomes, and harm-related outcomes. A control group was an inclusion criterion in outcome studies across species. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool [3] for a translational integration of PK and PD data. Further, a meta-analysis, stratified by type of anxiety and using three-level random effects models, was conducted to investigate sources of heterogeneity of CBD effects on anxiety outcomes. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach [4] was used to rate the quality of the evidence. Results: We synthesized data from 87 articles with the IB-derisk tool. Most studies (70.3%) reported null effects of CBD on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiolytic effects of CBD seemed to be clustered in certain differential concentration ranges, which differed between species. Data from 61 articles were included in the meta-analysis. The overall pooled effects of CBD on anxiety differed significantly from zero, p≤.02. The effect was moderate to large for conditioned anxiety in animals, Hedge’s G=0.68, 95%CI[0.11, 1.26], moderate for unconditioned anxiety in animals, Hedge’s G=0.50, 95%CI[0.29, 0.70], and large for human experimental anxiety, Hedge’s G=0.79, 95%CI[0.28, 1.31]. In all cases, compared to placebo/vehicle, CBD exerted beneficial effects on anxiety outcomes. No severe adverse effects were reported. There was substantial heterogeneity between average effect sizes within studies, σ2w Conclusions: A straightforward recommendation for optimal dosing was not possible, because there was no consistent linear effect of CBD on anxiety reduction, and concentration-effect relations were variable across species. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations. The low quality meta-analytic evidence confirmed the often discussed potential of CBD for treating anxiety symptoms. The compound induced anxiolytic effects, regardless of the type of anxiety studied. Moderator analyses will be conducted to determine other sources of heterogeneity of CBD effects, such as type of anxiety test and anxiety outcome

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

RATIONALE: Repeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission. OBJECTIVE: The present study investigated molecular and functional alterations in GABA(A) receptor (GABA(A)R) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF. METHODS: CRF(1) receptor, GABA(A)R, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABA(A)R α subunits and mGluRs in the amygdala and hypothalamus. RESULTS: CRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF(1) receptor antagonists CP154,526 and DMP695, the GABA(A)R α(3)-selective agonist TP003 (0–3 mg/kg) and the mGluR(2/3) agonist LY379268 (0–10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABA(A)R agonist diazepam (0–4 mg/kg) and the α(1)-subunit-selective GABA(A)R agonist zolpidem (0–10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA(A)R α(5)-subunit preferential compound SH-053-2′F-R-CH(3) and mGluR(5) antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABA(A)R α(2) subunit and mGluR(3) mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α(1) and α(5) GABA(A)R subunits. CONCLUSIONS: We found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABA(A) and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission

Anxiolytic effects of endocannabinoid enhancing compounds:A systematic review and meta-analysis

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications.</p

The effect of SSRIs on fear learning: a systematic review and meta-analysis

RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. OBJECTIVE: We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. METHODS: We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. RESULTS: Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. CONCLUSIONS: This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs

Pharmacological modulation of conditioned fear in the fear-potentiated startle test: a systematic review and meta-analysis of animal studies

RATIONALE AND OBJECTIVES: Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear. METHODS: Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals. RESULTS: Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT 1A agonists, 5-HT 1A antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT 1A antagonists. No associations were found between drug effects and methodological characteristics, except for strain. CONCLUSIONS: The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review

Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool

BACKGROUND: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. AIM: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. METHODS: We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. RESULTS: We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. DISCUSSION: A straightforward dosing recommendation was not possible, given variable concentration-effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations

Anxiolytic effects of endocannabinoid enhancing compounds: A systematic review and meta-analysis

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia:A randomised controlled trial

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid-and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (beta = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (beta = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens. (c) 2022 Published by Elsevier B.V

5-HT1A receptor blockade reverses GABAA receptor α3 subunit-mediated anxiolytic effects on stress-induced hyperthermia

Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the anxiolytic actions of benzodiazepines could be present. The main aim of the present study was to investigate whether the anxiolytic effects of (non-)selective alpha subunit GABA(A) receptor agonists could be reversed with 5-HT1A receptor blockade using the stress-induced hyperthermia (SIH) paradigm. The 5-HT1A receptor antagonist WAY-100635 (0.1-1 mg/kg) reversed the SIH-reducing effects of the non-alpha-subunit selective GABA(A) receptor agonist diazepam (1-4 mg/kg) and the GABA(A) receptor alpha(3)-subunit selective agonist TP003 (1 mg/kg), whereas WAY-100635 alone was without effect on the SIH response or basal body temperature. At the same time, co-administration of WAY-100635 with diazepam or TP003 reduced basal body temperature. WAY-100635 did not affect the SIH response when combined with the preferential alpha(1)-subunit GABA(A) receptor agonist zolpidem (10 mg/kg), although zolpidem markedly reduced basal body temperature. The present study suggests an interaction between GABA(A) receptor alpha-subunits and 5-HT1A receptor activation in the SIH response. Specifically, our data indicate that benzodiazepines affect serotonergic signaling via GABA(A) receptor alpha(3)-subunits. Further understanding of the interactions between the GABA(A) and serotonin system in reaction to stress may be valuable in the search for novel anxiolytic drugs