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Cited by 237Anxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesNeuroscience and Neuropharmacology ResearchTreatment of Major Depression

Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders

Open access
Sartori, Simone B., Singewald, Nicolas·2019·Pharmacology & Therapeutics
DOI 10.1016/j.pharmthera.2019.107402
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Abstract

Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need for improved drug treatments. In this review an overview of drugs being studied in different phases of clinical trials for their potential in the treatment of fear-, anxiety- and trauma-related disorders is presented. One strategy followed in drug development is refining and improving compounds interacting with existing anxiolytic drug targets, such as serotonergic and prototypical GABAergic benzodiazepines. A more innovative approach involves the search for compounds with novel mechanisms of anxiolytic action using the growing knowledge base concerning the relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anxiety. The target systems evaluated in clinical trials include glutamate, endocannabinoid and neuropeptide systems, as well as ion channels and targets derived from phytochemicals. Examples of promising novel candidates currently in clinical development for generalised anxiety disorder, social anxiety disorder, panic disorder, obsessive compulsive disorder or post-traumatic stress disorder include ketamine, riluzole, xenon with one common pharmacological action of modulation of glutamatergic neurotransmission, as well as the neurosteroid aloradine. Finally, compounds such as D-cycloserine, MDMA, L-DOPA and cannabinoids have shown efficacy in enhancing fear-extinction learning in humans. They are thus investigated in clinical trials as an augmentative strategy for speeding up and enhancing the long-term effectiveness of exposure-based psychotherapy, which could render chronic anxiolytic drug treatment dispensable for many patients. These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of relative stagnation.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys novel pharmacological targets in clinical development for anxiety and anxiety-related disorders, covering refinements of existing serotonergic and GABAergic targets as well as compounds acting on glutamate, endocannabinoid, neuropeptide, ion channel, and phytochemical targets. It also reviews drugs used to augment exposure-based psychotherapy via fear-extinction enhancement, concluding that renewed interest and optimism have returned to a field stagnant since the approvals of pregabalin and duloxetine.

Key findings

  • Current first-line pharmacotherapy (SSRIs, SNRIs) yields meta-analytic response rates of 40–75% (mean 55%), with delayed onset (2–3 weeks or more) and substantial non-response, relapse, and tolerability problems; no new drug has been approved for any anxiety or related disorder since pregabalin (2006) and duloxetine (2007).
  • As of the review, 12 compounds have entered Phase 3, 25 are in Phase 2, and 8 are in Phase 1 for anxiety and trauma-related disorders, with most drugs evaluated for PTSD.
  • Promising novel candidates modulating glutamatergic neurotransmission include ketamine, riluzole/troriluzole, and xenon; a single intravenous ketamine dose reduced core PTSD symptom severity at 24 h to the same extent as the active comparator midazolam, and xenon inhalation in an open-label study of 80 PD patients reduced panic attacks and general anxiety for up to 6 months.
  • Extinction-enhancing adjuncts to exposure-based therapy include D-cycloserine (most studied, but meta-analyses show only small if any clinical effects), MDMA (six Phase 2 trials showed clinically relevant PTSD symptom reductions lasting ~3.5 years), L-DOPA, and cannabinoids; the neurosteroid aloradine (PH94B) reduced performance and social interaction anxiety within 15 min of intranasal application in SAD patients.

Methods

  • Narrative review; the authors conducted a comprehensive search of clinicaltrials.gov for ongoing trials (active, not yet recruiting, recruiting, enrolling by invitation, recently suspended as of September 2018, updated April 2019) involving pharmacotherapy for GAD, SAD, specific phobias, PD, PTSD, and OCD, complemented by open internet searches for press releases and announcements, with identified compounds then used as PubMed search terms.
  • The review synthesizes preclinical and clinical studies and approved/ongoing trials across four development avenues: refining existing targets, novel mechanisms of action, phytochemicals, and pharmacological augmentation of psychotherapy.
  • No primary data collection or meta-analysis was performed; findings are presented in narrative form with summary tables (Tables 2 and 3) of compounds, mechanisms, sponsors, phases, and trial identifiers.

Limitations

  • The paper states that the neurobiology underlying anxiety and the exact mechanisms of therapeutic treatments remain incompletely understood, and that the study of epigenetic drug targets for anxiety remains in its infancy with unclear superiority over existing treatments.
  • The authors note that most phytochemical evidence comes from animal models, with few clinical trials and limited sample sizes, and that structure-activity relationships, metabolism, absorption, and mechanisms are unclear for most phytochemicals.
  • The text makes evident (not framed as author-stated limitations) that many cited trials are ongoing with data not yet available, that several key findings rest on open-label, pilot, or small studies (e.g., the 80-patient xenon study, the 21-patient BHV-0223 SAD study), and that the review's clinicaltrials.gov search was current only to April 2019.

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Registry

Crossref · 10.1016/j.pharmthera.2019.107402

Cites

458 of 458 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Findingnone given

    Most drugs in development for anxiety and related disorders are evaluated for the indication PTSD.

    “Interestingly, most drugs are evaluated for the indication PTSD”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Approximately 20 pharmaceutical companies and several academic consortia are involved in current trials for anxiety-related disorders.

    “Approximately 20 pharmaceutical companies as well as several academic consortia (Table 2) are involved in these trials at present”
    Quote in the paperNot a substantial claim
  • Premisecitation

    BDZs demonstrate efficacy for the treatment of GAD.

    “In contrast, BDZs demonstrate efficacy for the treatment of GAD (Gomez, Barthel, & Hofmann, 2018) and are still and even increasingly prescribed (Agarwal & Landon, 2019;Bachhuber, Hennessy, Cunningham, & Starrels, 2016).”
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    • cites Gomez, Barthel, & Hofmann, 2018 source

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  • Premisecitation

    SSRIs are proposed to have a better benefit/risk ratio than any other form of current pharmacotherapy.

    “Selective serotonin (5-HT) reuptake inhibitors (SSRIs), including for example (es)citalopram, sertraline, fluoxetine are currently first-line drug treatment options for most anxiety disorders as they are proposed to have a better benefit/risk ratio than any other form of current pharmacotherapy (Bandelow, Michaelis, & Wedekind, 2017).”
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    • cites Bandelow, Michaelis, & Wedekind, 2017 source

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  • Interpretationreasoning

    Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability.

    “Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need for improved drug treatments.”
    • Also stated in: § 2. Overview and historical account of current medication options for anxiety and related disorders · hedged
      “Such problems suggest that current therapies are insufficient and they have rekindled the interest to develop drugs with novel mechanisms of action to improve this situation, particularly for non-responding patients.”
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  • May combine two claims. 103
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 21

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    Findingnone given

    Currently, 12 compounds have entered Phase 3, 25 compounds are in Phase 2, and eight compounds are in Phase 1 for treatment of different forms of anxiety and trauma-related disorders.

    “Currently, 12 compounds have entered Phase 3 of clinical development, 25 compounds are in Phase 2 and eight compounds are in Phase 1 for the treatment of different forms of anxiety and trauma-related disorders, as summarised in Table 3.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingreasoning

    There has recently been a revival of the potential medicinal use of psychedelics, including LSD and psilocybin, as potential adjuncts to psychotherapy in anxiety treatment, based mainly on a low number of pilot clinical trials.

    “there has recently been a kind of revival of the potential medicinal use of psychedelics, including LSD and psilocybin, as potential adjuncts to psychotherapy in anxiety treatment.”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    There is an urgent need for the development of novel approaches in the treatment of anxiety and related disorders.

    “Taken together, there is still an urgent need for the development of novel approaches in the treatment of anxiety and related disorders (Griebel & Holmes, 2013).”
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    • cites Griebel & Holmes, 2013

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    • Rests on an assumption: The onset of therapeutic action of antidepressants is delayed for 2-3 weeks or more.

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    Premisecitation

    University-led drug discovery centres targeting neurological and psychiatric indications have increased considerably in numbers in recent years.

    “This low overall success rate of compounds in clinical development is costly and has led to a 50% decline in CNS drug discovery and development programs by major pharmaceutical companies from 2009 to 2014, while university led drug discovery centres targeting neurological and psychiatric indications have increased considerably in numbers in the last years (Nutt & Attridge, 2014;Yokley, Hartman, &”
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    • cites Yokley, Hartman, & Slusher, 2017

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    Premisecitation

    Between 50 and 60% of all failures of CNS drugs are the result of poor efficacy/efficiency.

    “Between 50 and 60% of all failures of CNS drugs are the result of poor efficacy/efficiency, while poor safety accounts for 20-30% of failures (McArthur, 2017).”
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    • cites McArthur, 2017 source

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    Poor safety accounts for 20-30% of failures of CNS drugs.

    “Between 50 and 60% of all failures of CNS drugs are the result of poor efficacy/efficiency, while poor safety accounts for 20-30% of failures (McArthur, 2017).”
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    Premisecitation

    Full clinical remission is often not achieved, and a significant number of patients do not respond to treatment or relapse after treatment cessation even after an initial positive response.

    “However, full clinical remission is often not achieved, a significant number of patients does not respond to treatment or they relapse after treatment cessation even after an initial positive response (Batelaan et al., 2017).”
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    Clinical development and approval of CNS drugs takes longer than any other drug class.

    “In general, b10% of promising CNS drug candidates identified in preclinics and taken to humans make it through the clinical development to the market and the clinical development and approval of CNS drugs takes longer than any other drug class (Kaitin, 2014(Kaitin, , 2018)).”
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    Premisecitation

    Enhanced amygdala responsivity is often associated with hyperactivity in a network that mediates anticipation of negative outcomes and hypoactivity in inhibitory systems involving ventromedial PFC.

    “Enhanced amygdala responsivity is often associated with hyperactivity in a network that mediates the anticipation of negative outcomes and consists of the anterior cingulate cortex, insula, dorsolateral PFC and the medial orbitofrontal cortex, and hypoactivity in inhibitory systems, for example involving the ventromedial PFC, which is implicated in top-down inhibition of amygdala output [Fig.3;”
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    Interpretationreasoning

    Current therapies are insufficient, which has rekindled interest to develop drugs with novel mechanisms of action.

    “Such problems suggest that current therapies are insufficient and they have rekindled the interest to develop drugs with novel mechanisms of action to improve this situation, particularly for non-responding patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fear and anxiety are distinct but have clear overlaps and co-occurrence.

    “Hence, although fear and anxiety are distinct (Perusini & Fanselow, 2015;Parsafar & Davis, 2018), there are clear overlaps, as well as co-occurrence, as anxiety often follows a fearful experience and in turn modulates the fear responses to a threat.”
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    • cites Parsafar & Davis, 2018

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of relative stagnation.

    “These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of relative stagnation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Following SSRI treatment, connectivity is reduced between dmPFC/dorsal ACC and amygdala or between amygdala and BNST.

    “findings of a reduced dmPFC/dorsal ACC-amygdala or amygdala-BNST connectivity following treatment with SSRIs (Grillon, Robinson, Cornwell, & Ernst, 2019;Robinson et al., 2019)”
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    Premisereasoning

    A more innovative approach involves search for compounds with novel mechanisms of anxiolytic action using growing knowledge base concerning relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anxiety.

    “A more innovative approach involves the search for compounds with novel mechanisms of anxiolytic action using the growing knowledge base concerning the relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anxiety.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    One strategy in drug development is refining and improving compounds interacting with existing anxiolytic drug targets, such as serotonergic and prototypical GABAergic benzodiazepines.

    “One strategy followed in drug development is refining and improving compounds interacting with existing anxiolytic drug targets, such as serotonergic and prototypical GABAergic benzodiazepines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Histone-deacetylase inhibitors may be useful in anxiety disorders by promoting relevant gene expression and targeting some common comorbidities of anxiety disorders.

    “histone-deacetylase inhibitors may be useful in anxiety disorders, by promoting relevant gene expression (Sah et al., 2019;Tran, Schulkin, Ligon, & Greenwood-Van Meerveld, 2015;Whittle & Singewald, 2014) and targeting also some common comorbidities of anxiety disorders (Moloney, Stilling, Dinan, & Cryan, 2015).”
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    • cites Sah et al., 2019 source

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    • cites Tran, Schulkin, Ligon, & Greenwood-Van Meerveld, 2015

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    • cites Whittle & Singewald, 2014 source

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    Premisecitation

    Disturbances in the composition of the microbiome have been linked to anxiety, and treatments aimed at normalising these disturbances using specific probiotics have been proposed.

    “Disturbances in the composition of the microbiome have been linked to anxiety (Lach et al., 2018;Leclercq et al., 2016) and treatments aimed at normalising these disturbances using specific probiotics have been proposed (Yang, Wei, Ju, & Chen, 2019).”
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    Interpretationreasoning

    At present the study of epigenetic drug targets for anxiety remains in its infancy, and it is not clear yet whether these agents actually offer superior outcomes to existing treatments.

    “At present the study of epigenetic drug targets for anxiety remains in its infancy, and it is not clear yet whether these agents actually offer superior outcomes to existing treatments.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SSRIs in particular are recommended as first-line treatment for various different anxiety disorders.

    “SSRIs in particular are recommended as first-line treatment for various different anxiety disorders (Table 1).”
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    Premisecitation

    F13714 acts as a full agonist at presynaptic 5-HT1A receptors only and exerts anxiolytic and fear-reducing effects in animals, but has not been tested in humans so far.

    “F13714 is a substance that acts as a full agonist at presynaptic 5-HT 1A receptors only and exerts anxiolytic and fearreducing effects in animals (Depoortere, Bardin, Varney, & Newman-Tancredi, 2019;Zhao et al., 2019), but has not been tested in humans so far.”
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    • cites Zhao et al., 2019 source

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    • Rests on an assumption: Preclinical findings in animal models of anxiety predict anxiolytic efficacy in humans.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Stimulation of 5-HT2B and blockade of 5-HT2A, 5-HT3, and probably 5-HT5A receptors are important for inducing anxiolytic effects.

    “It has been suggested that stimulation of 5-HT 2B and the blockade of 5-HT 2A , 5-HT 3 , and probably 5-HT 5A receptors are important for inducing anxiolytic effects.”
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    Premisereasoning

    Buspirone is approved for the treatment of GAD and is an example of a partial agonist strategy.

    “Buspirone, approved for the treatment of GAD (Table 1, Fig. 1) is an example of such a strategy.”
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    Premisecitation

    Vilazodone treatment demonstrated greater improvement in anxiety measures than placebo in a randomised controlled study for adult separation anxiety and in generalised SAD.

    “vilazodone treatment demonstrated greater improvement in anxiety measures than placebo treatment in a randomised controlled study for adult separation anxiety (Schneier et al., 2017) and in generalised SAD (Careri, Draine, Hanover, & Liebowitz, 2015).”
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    Premisenone given

    A Phase 1b trial completed in 2018 reported that after treatment with AVN-101 for several weeks, the occurrence of adverse events was low and that it was well tolerated in a wide range of doses.

    “A Phase 1b trial, completed in 2018, reported that after treatment with AVN-101 for several weeks, the occurrence of adverse events was low and that it was well tolerated in a wide range of doses.”
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    Premisecitation

    Brexpiprazole is an antagonist at 5-HT2A, 5-HT2B and 5-HT7 receptors, a partial agonist at 5-HT1A, dopamine D2 and D3 receptors, and has antagonistic properties at α1-adrenoceptor, α2-adrenoceptor and histaminergic H1 receptor.

    “The atypical antipsychotic brexpiprazole is an antagonist at the 5-HT 2A , 5-HT 2B and 5-HT 7 receptors, a partial agonist at the 5-HT 1A as well as dopamine D 2 and D 3 receptors and has antagonistic properties at the α 1 -adrenoceptor, the α 2 -adrenreoceptor and the histaminergic H 1 receptor (Maeda et al., 2014).”
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    Premisecitation

    There is little evidence of sexual dysfunction and of treatment-emergent suicidal ideation with vilazodone.

    “Although there is little evidence of sexual dysfunction (Shi, Wang, Xu, & Lu, 2016) and of treatment-emergent suicidal ideation (Thase et al., 2017)”
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    Premisecitation

    A recent meta-analysis provides some support for the potential of vortioxetine for the treatment of anxiety, whereby it seems to be more efficient in lowering relapse rate and improving quality of life in adults integrated into the working world or in education than in non-engaged subjects.

    “a recent meta-analysis provides some support for the potential of vortioxetine for the treatment of anxiety (Yee, Ng, & Seng, 2018), whereby it seems to be more efficient in lowering relapse rate and improving quality of life in adults integrated into the working world or in education than in non-engaged subjects (Christensen, Loft, Florea, & McIntyre, 2017).”
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    Premisenone given

    FKW00GA has been shown to be safe and well tolerated and there is some evidence of efficacy in patients with GAD as assessed in several Phase 2 clinical trials.

    “So far, FKW00GA has been shown to be safe and well tolerated and there is some evidence of efficacy in patients with GAD as assessed in several Phase 2 clinical trials.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and an inhibitor of the 5-HT transporter, with a good tolerability and long-term safety profile and no evidence of sexual dysfunction as a side effect.

    “The antidepressant vortioxetine, developed by Lundbeck and Takeda and approved in 2013, is a 5-HT 3 , 5-HT 7 and 5-HT 1D receptor antagonist, a 5-HT 1B receptor partial agonist, a 5-HT 1A receptor agonist and an inhibitor of the 5-HT transporter (Bang-Andersen et al., 2011) with a good tolerability and long-term safety profile and no evidence of sexual dysfunction as a side effect.”
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    Premisecitation

    Previous studies showed that the immediate release formulation of gepirone improved anxiety ratings as compared with placebo with similar efficacy to the comparator diazepam.

    “This evidence is supported by previous studies showing that the immediate release formulation of gepirone was able to improve anxiety ratings as compared with placebo with similar efficacy to the comparator diazepam.”
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    Premisenone given

    Gepirone is a full 5-HT1A receptor agonist at raphe 5-HT1A autoreceptors and a partial agonist at postsynaptic 5-HT1A receptors.

    “The azapirone gepirone is a full 5-HT 1A receptor agonist at raphe 5-HT 1A autoreceptors and a partial agonist at postsynaptic 5-HT 1A receptors.”
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    Premisecitation

    Travivo is the extended-release formulation of gepirone reducing fluctuations in plasma drug concentrations and the incidence of adverse events associated with high peak plasma concentrations.

    “Travivo®, by Fabre-Kramer Pharmaceuticals, is the extended-release (ER) formulation of gepirone reducing fluctuations in plasma drug concentrations and the incidence of adverse events that were associated with high peak plasma concentrations (Robinson, Sitsen, & Gibertini, 2003).”
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    Premisecitation

    Cyclobenzaprine is proposed to improve sleep quality via blockade of 5-HT2A and H1 receptors, and to reduce trauma-related nightmares and sleep disturbance via blockade of α1-adrenoceptors.

    “Cyclobenzaprine is proposed to improve sleep quality via its blockade of 5-HT 2A and H 1 receptors (Krystal, Richelson, & Roth, 2013;Monti, 2011), and to reduce trauma-related nightmares and sleep disturbance via blockade of α1-adrenoceptors (Hendrickson & Raskind, 2016).”
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    Premisenone given

    FKW00GA is a 5-HT1A receptor partial agonist that also exerts 5-HT2A receptor antagonistic properties.

    “Another 5-HT 1A receptor partial agonist developed by Fabre-Kramer Pharmaceuticals is FKW00GA that also exerts 5-HT 2A receptor antagonistic properties.”
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    Premisecitation

    In a retrospective analysis, Tonmya exerted clinically significant effects only in the subgroup of PTSD patients in whom the trauma had been experienced within nine years prior to study participation, but no longer than that.

    “in a retrospective analysis it was revealed that Tonmya® exerted clinically significant effects only in that subgroup of PTSD patients in whom the trauma had been experienced within nine years prior to study participation, but no longer than that (Sullivan et al., 2018).”
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    Interpretationcitation

    Agomelatine has been shown to positively affect sleep-related measures including REM and slow wave sleep and the quality of sleep, so it is likely to be particularly useful for anxiety patient populations with sleep-related symptoms including PTSD and OCD.

    “Since agomelatine has been shown to positively affect sleep-related measures including REM and slow wave sleep and the quality of sleep (Buoli et al., 2017;Guardiola-Lemaitre et al., 2014;Levitan et al., 2015), it is likely to be particularly useful for anxiety patient populations with sleep-related symptoms including also PTSD and OCD (De Berardis et al., 2015).”
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    • cites Guardiola-Lemaitre et al., 2014 source

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    • cites Levitan et al., 2015 source

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    • Rests on an assumption: Findings and treatments for one anxiety disorder generalize to other anxiety disorders.

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    Premisecitation

    Agomelatine is an agonist at melatonin MT1 and MT2 receptors and an antagonist at 5-HT2C and 5-HT2B receptors with very low binding affinity to most other monoaminergic, GABAergic and glutamatergic receptors as well as to potassium and calcium channels.

    “Agomelatine has a unique mechanism of action (Levitan, Papelbaum, & Nardi, 2015) as it is an agonist at the G-protein coupled melatonin MT 1 and MT 2 receptors and an antagonist at the 5-HT 2C and 5-HT 2B receptors with very low binding affinity to most other monoaminergic, GABAergic and glutamatergic receptors as well as to potassium and calcium channels (Millan et al., 2003).”
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    Premisecitation

    BDZs exhibit rapid anxiolytic effects, but also have sedative, amnestic, anticonvulsant, muscle relaxant and addictive properties.

    “BDZs, which have been in clinical use for decades, not only exhibit rapid anxiolytic effects, but also have sedative, amnestic, anticonvulsant, muscle relaxant and addictive properties (Coric et al., 2005;Engin et al., 2018).”
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    Premisecitation

    Vortioxetine was shown to decrease the number of panic attacks and to moderately improve the quality of life of patients with PD in an open-label trial with flexible doses.

    “vortioxetine was shown to decrease the number of panic attacks and to moderately improve the quality of life of patients with PD in an open-label trial with flexible doses (Shah & Northcutt, 2018).”
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    Premisecitation

    Agomelatine has been approved for the treatment of major depressive disorder in Europe since 2009, and was shown to have anxiolytic properties.

    “agomelatine, developed by Servier, has been approved for the treatment of major depressive disorder in Europe since 2009, and was shown to have anxiolytic properties (Stein et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stein et al., 2014 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    These results suggest that vortioxetine could be beneficial for some groups of anxiety patients, but this needs to be further evaluated in long-term placebo-controlled studies and/or in postmarket surveys of patients with depression.

    “These results suggest that vortioxetine could be beneficial for some groups of anxiety patients, but this needs to be further evaluated in long-term placebo-controlled studies and/or in postmarket surveys of patients with depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The key neuronal circuits and brain areas mediating the anxiolytic effects of BDZs are still not entirely clear, although the limbic system, and the amygdala in particular, has been revealed as a central component.

    “The key neuronal circuits and brain areas mediating the anxiolytic effects of BDZs are still not entirely clear, although the limbic system, and the amygdala in particular, has been revealed as a central component (Engin et al., 2018;Griessner et al., 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Engin et al., 2018 source

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    • cites Griessner et al., 2018

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  • May combine two claims.

    Premisecitation

    Etifoxine exerts anxiolytic effects without sedation and ataxia via a direct PAM action at β2 and β3 subunits of the GABA-A receptor, preferentially potentiating α2β3γ2S and α3β3γ2S containing GABA-A receptors.

    “Interestingly, etifoxine exerts its anxiolytic effects without sedation and ataxia via two mechanisms of action at the GABA-A receptor: a direct action as a PAM binding to the β 2 and β 3 subunits of the GABA-A receptor preferentially potentiating α2β3γ2S and α3β3γ2S containing GABA-A receptors, and indirectly by stimulating the biosynthesis of neurosteroids including 17-hydroxypregnenolone that”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mattei et al., 2019 source

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    • cites Nuss, Ferreri, & Bourin, 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Etifoxine is marketed in approximately 40 countries including France (approved in 1979) for the treatment of anxiety disorders.

    “Although it is not approved by the FDA or EMA, it is marketed in approximately 40 countries including France (approved in 1979) for the treatment of anxiety disorders (Poisbeau et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poisbeau et al., 2018 source

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  • May combine two claims.

    Premisecitation

    BDZs act as positive allosteric modulators on compatible GABA-A receptors and thus increase GABA-induced chloride conductance and inhibitory postsynaptic potentials.

    “They act as positive allosteric modulators (PAMs) on compatible GABA-A receptors and thus increase GABA-induced chloride conductance and inhibitory postsynaptic potentials (Olsen & Sieghart, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Olsen & Sieghart, 2009

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  • May combine two claims.

    Premisecitation

    Preclinical research for subtype-selective BDZ ligands is still ongoing in parallel with the identification of novel interesting subunit-specific target sites at the GABA-A receptor such as the α6 subunit.

    “The preclinical research for such ligands is still ongoing (Prevot et al., 2019) in parallel with the identification of novel interesting subunit-specific target sites at the GABA-A receptor such as the α 6 subunit (Gonda et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Prevot et al., 2019

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    • cites Gonda et al., 2019 source

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    • Rests on an assumption: Preclinical findings in animal models of anxiety predict anxiolytic efficacy in humans.

  • May combine two claims.

    Premisecitation

    In healthy humans, only TPA023 with α1 antagonistic properties, but not MRK-409 with weak α1 partial agonistic effects, causes sedation-free anxiolysis, as well as in patients with GAD as shown in Phase 2 trials.

    “In healthy humans, only TPA023 with α1 antagonistic properties, but not MRK-409 with weak α1 partial agonistic effects, causes sedation-free anxiolysis (de Haas et al., 2007), as well as in patients with GAD as shown in Phase 2 trials (Atack, 2009).”
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    • cites de Haas et al., 2007 source

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    • cites Atack, 2009 source

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  • May combine two claims.

    Premisecitation

    Aloradine lacks affinity for steroid hormone receptors but binds with high affinity to nasal chemosensory receptors in humans, a group of G-protein coupled receptors that mediate detection of pheromone signals.

    “Aloradine lacks affinity for the steroid hormone receptors, but binds with high affinity to the nasal chemosensory receptors in humans, a group of G-protein coupled receptors that mediate the detection of pheromone signals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liebowitz et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glutamate is the principal excitatory neurotransmitter in the brain, exerting its functions via ionotropic NMDA, AMPA and kainate receptors, as well as mGluR1-8.

    “Glutamate is the principal excitatory neurotransmitter in the brain, and it exerts its various biological functions via the fast-acting ionotropic N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPA) and kainate receptors, as well as the mGluR1-8 (Reiner & Levitz, 2018).”
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    • cites Reiner & Levitz, 2018

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  • May combine two claims.

    Premisecitation

    Etifoxine exerts anxiolytic effects without sedation and ataxia indirectly by stimulating the biosynthesis of neurosteroids including 17-hydroxypregnenolone that potentiate GABA-A receptor activity.

    “and indirectly by stimulating the biosynthesis of neurosteroids including 17-hydroxypregnenolone that potentiate GABA-A receptor activity (Mattei et al., 2019;Nuss, Ferreri, & Bourin, 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mattei et al., 2019 source

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    • cites Nuss, Ferreri, & Bourin, 2019

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  • May combine two claims.

    Premisecitation

    Both BDNF and mTOR complex appear to be key effectors for rapidly enhancing synaptic connectivity and increasing dendritic spines and are proposed to underlie the persistent antidepressant effects of ketamine.

    “Both BDNF and mTOR complex appear to be the key effectors for rapidly enhancing synaptic connectivity and increasing dendritic spines (Castren & Hen, 2013;Fortress, Smith, & Pang, 2018) and are proposed to underlie the persistent antidepressant effects of ketamine.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Castren & Hen, 2013 source

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    • cites Fortress, Smith, & Pang, 2018

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  • May combine two claims.

    Premisecitation

    Ketamine was shown to reduce anxiety symptoms in adults with treatment-refractory GAD and with SAD, with reported increased social engagement on subsequent days.

    “Ketamine was also shown to reduce anxiety symptoms in adults with treatment-refractory GAD (Glue et al., 2017) and with SAD, with reported increased social engagement on subsequent days (Taylor et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Glue et al., 2017 source

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    • cites Taylor et al., 2018 source

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  • May combine two claims.

    Premisecitation

    Ketamine causes increased stimulation of postsynaptic 5-HT1A receptors in the mPFC, activating the phosphoinositide-3 kinase/Akt/mTOR complex pathway.

    “Forth, there is recent evidence that ketamine also causes increased stimulation of postsynaptic 5-HT1A receptors in the mPFC activating the phosphoinositide-3 kinase/Akt/mTOR complex pathway further downstream (Fukumoto, Iijima, Funakoshi, & Chaki, 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fukumoto, Iijima, Funakoshi, & Chaki, 2018

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  • May combine two claims.

    Premisecitation

    Ketamine elicits euphoric and dissociative effects and may increase the incidence of cardiovascular effects, hepatotoxicity and ulcerative cystitis.

    “its safety has to be carefully evaluated when given at higher doses over a longer period of time as it elicits euphoric and dissociative effects and may increase the incidence of cardiovascular effects, hepatotoxicity and ulcerative cystitis (Cohen et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cohen et al., 2018

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  • May combine two claims.

    Premisecitation

    The NMDA receptor antagonist AZD6765, or lanicemine, exerts rapid but short-lived antidepressant effects in clinical trials without evidence of eliciting psychotomimetic effects.

    “Similar to ketamine, the NMDA receptor antagonist AZD6765, or lanicemine (AstraZeneca), a blocking molecule that is trapped inside the NMDA channel pore, exerts rapid, but short-lived, antidepressant effects in clinical trials without evidence of eliciting psychotomimetic effects (Zarate Jr. et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zarate Jr. et al., 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    S-ketamine (esketamine) has been approved for the treatment of treatment-resistant depression by the FDA in the form of a nasal spray.

    “Although ketamine treatment was generally well tolerated in these clinical trials and S-ketamine (esketamine) has just been approved for the treatment of treatment-resistant depression by the FDA in form of a nasal spray (FDA, 2019; The Scientist, 2019), its safety has to be carefully evaluated when given at higher doses over a longer period of time as it elicits euphoric and dissociative effects”
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    • cites FDA, 2019

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    • cites The Scientist, 2019

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  • May combine two claims.

    Premisecitation

    Xenon is a multi-target agent reducing excitatory neurotransmission by inhibition of the NMDA receptor, AMPA, nicotinic acetylcholine and 5-HT3 receptors and HCN channels, and causing neuronal hyperpolarization by activating potassium channels.

    “Pharmacologically, it is a multi-target agent reducing excitatory neurotransmission by inhibition of the NMDA receptor (by competing with the co-agonist glycine at aromatic residues of the glycine binding site), AMPA-, nicotinic acetylcholine, 5-HT 3 receptors and HCN (hyperpolarization-activated cyclic nucleotide-gated) channels and causing neuronal hyperpolarization by activating potassium”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhou, Liu, & Chen, 2012

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  • May combine two claims.

    Premisecitation

    Treatment with xenon decreases pro-inflammatory cytokine levels, including TNFα and IL1β, and upregulates growth factors such as BDNF.

    “Furthermore, treatment with xenon has been shown to decrease pro-inflammatory cytokine levels, including TNFα and IL1β, and to upregulate growth factors such as BDNF [for details and references, see (Dobrovolsky, Ichim, Ma, Kesari, & Bogin, 2017)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dobrovolsky, Ichim, Ma, Kesari, & Bogin, 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1 is densely expressed in brain areas relevant to anxiety and is the main eCB receptor to which AEA and 2-AG bind, mediating many behavioural and brain functions of eCB.

    “CB1 is densely expressed in brain areas relevant to anxiety and is the main eCB receptor to which AEA and 2-AG bind, mediating the many behavioural and brain functions of eCB (Patel et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Patel et al., 2017 source

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  • May combine two claims.

    Premisecitation

    In an open-label study involving 80 patients with diagnosed PD, sub-chronic inhalation of sub-anaesthetic concentrations of a xenon-oxygen mixture immediately and progressively reduced the occurrence of panic attacks as well as anxiety in general, and this reduction lasted up to 6 months after treatment.

    “In a recently published open-label study involving 80 patients with diagnosed PD, the sub-chronic inhalation of sub-anaesthetic concentrations of a xenon-oxygen mixture immediately and progressively reduced the occurrence of panic attacks as well as of anxiety in general, and this reduction lasted up to 6 months after treatment (Dobrovolsky et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dobrovolsky et al., 2017 source

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  • May combine two claims.

    Premisecitation

    CBD acts as a negative allosteric modulator at the CB1 receptor and as a partial agonist at the 5HT1A receptor, which seem important for its anxiolytic and anti-panic effects.

    “It acts as negative allosteric modulator at the CB 1 receptor -explaining the lack of CB1-associated psychotropic effects -and as a partial agonist at the 5HT1A receptor which seem to be important for its anxiolytic and anti-panic effects.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Crippa, Guimaraes, Campos, & Zuardi, 2018

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    • cites Soares & Campos, 2017

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  • May combine two claims.

    Premisecitation

    Enhanced eCB signalling, for example induced by blocking FAAH, reduces stress and anxiety responses and promotes fear-extinction learning.

    “Enhanced eCB signallingfor example, induced by blocking the serine hydrolase enzyme FAAHreduces stress and anxiety responses and promotes fear-extinction learning (Gunduz-Cinar, Hill, McEwen, & Holmes, 2013;Lisboa et al., 2019;Mayo et al., 2019;Patel et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gunduz-Cinar, Hill, McEwen, & Holmes, 2013

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    • cites Lisboa et al., 2019 source

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    • cites Mayo et al., 2019

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  • May combine two claims.

    Premisecitation

    Cannabis use itself can increase the risk for the onset of anxiety disorders, with greater symptom severity and with poorer treatment outcome.

    “However, cannabis use itself can increase the risk for the onset of anxiety disorders, with greater symptom severity and with poorer treatment outcome [ (Grunberg, Cordova, Bidwell, & Ito, 2015;Mammen et al., 2018;Zvolensky et al., 2006), but see (Feingold, Rehm, Factor, Redler, & Lev-Ran, 2018)].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Grunberg, Cordova, Bidwell, & Ito, 2015

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    • cites Mammen et al., 2018 source

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    • cites Zvolensky et al., 2006 source

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  • May combine two claims.

    Premisecitation

    Low doses of THC are anxiolytic and high doses of THC are arousing and anxiogenic, and CBD is able to block the anxiogenic effects of THC.

    “This is an important question as low doses of THC are anxiolytic and high doses of THC are arousing and anxiogenic, and CBD is able to block the anxiogenic effects of THC (Kamal, Kamal, & Lantela, 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kamal, Kamal, & Lantela, 2018

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  • May combine two claims.

    Premisecitation

    CBD attenuates anxiety measures and autonomic arousal as well as activation of the amygdala and the anterior cingulate cortex in response to fearful faces in healthy volunteers.

    “CBD, which has anticonvulsant, antipsychotic and muscle-relaxant properties, but lacks the psychoactive and 'high-inducing' effects of THC, attenuates anxiety measures and autonomic arousal as well as the activation of the amygdala and the anterior cingulate cortex in response to fearful faces in healthy volunteers (Rabinak & Phan, 2014).”
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    • cites Rabinak & Phan, 2014

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  • May combine two claims.

    Premisecitation

    In treatment-naïve patients with generalised SAD, a single dose of CBD significantly reduces anxiety and associated anticipatory alert, as well as discomfort provoked during a public-speaking test.

    “In treatment-naïve patients with generalised SAD a single dose of CBD was found to significantly reduce anxiety and associated anticipatory alert, as well as discomfort provoked during a public-speaking test (Bergamaschi et al., 2011;Crippa et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bergamaschi et al., 2011 source

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    • cites Crippa et al., 2011 source

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  • May combine two claims.

    Premisecitation

    A destabilising polymorphism in the FAAH gene causes increased AEA levels and is associated with lower indices of trait anxiety as well as enhanced cortico-amygdala connectivity and reduced amygdala activation in response to threat stimuli.

    “Moreover, a destabilising polymorphism in the FAAH gene causes increased AEA levels and is associated with lower indices of trait anxiety as well as with enhanced cortico-amygdala connectivity and reduced amygdala activation in response to threat stimuli (Patel et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Patel et al., 2017 source

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  • May combine two claims.

    Premisecitation

    Plasma vasopressin levels are elevated in patients with PTSD and with OCD.

    “Furthermore, plasma vasopressin levels are elevated in patients with PTSD (de Kloet, Vermetten, Geuze, Wiegant, & Westenberg, 2008) and with OCD (Altemus, Cizza, & Gold, 1992).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites de Kloet, Vermetten, Geuze, Wiegant, & Westenberg, 2008

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    • cites Altemus, Cizza, & Gold, 1992

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  • May combine two claims.

    Premisecitation

    Vasopressin's central actions are mediated by binding to V1A and V1B receptors distributed in many anxiety- and fear-related brain areas including the lateral septum, cortex and hippocampus, with V1A receptors being predominant.

    “Its central actions are mediated by binding to the two G-protein coupled V 1A and V 1B receptors which are distributed in many anxiety-and fear-related brain areas including in the lateral septum, cortex and hippocampus, with V 1A receptors being the predominant receptor (Landgraf, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Landgraf, 2006 source

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  • May combine two claims.

    Premisecitation

    Genetic and epigenetic variations in the OXT receptor gene are associated with alterations in socio-emotionality and, in part, with increased stress responses.

    “Furthermore, genetic and epigenetic variations in the OXT receptor gene have been associated with alterations in socio-emotionality and, in part, with increased stress responses (Naja & Aoun, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Naja & Aoun, 2017

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  • May combine two claims.

    Premisecitation

    SRX246 attenuated amygdala activation in response to angry faces and vasopressin administration, indicating a role of amygdalar V1A receptors in the processing of aversive emotional information.

    “and attenuated amygdala activation in response to angry faces (Fig. 3) and vasopressin administration indicating a role of amygdalar V 1A receptors in the processing of aversive emotional information (Lee et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lee et al., 2013 source

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  • May combine two claims.

    Premisecitation

    OXT treatment decreases amygdala activity in response to negative/fearful emotions and increases activity of cortical and subcortical regions, often in a sex-specific way.

    “As a result of these actions OXT treatment decreases amygdala activity in response to negative/ fearful emotions (Fig. 3) and increases the activity of cortical and subcortical regions, often in a sex-specific way (Gao et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gao et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NPY is the most abundant neuropeptide in the brain and acts via at least five G-protein coupled receptors (Y1, Y2, Y4-6).

    “NPY is the most abundant neuropeptide in the brain, acting via at least five different G-protein coupled receptors (Y 1 , Y 2 , Y 4-6 ) (Reichmann & Holzer, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Reichmann & Holzer, 2016

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  • May combine two claims.

    Premisecitation

    In animal studies, NPY mediates anxiolysis through mechanisms including inhibiting amygdalar activation, increasing calcineurin-induced synaptic remodelling in the basolateral amygdala via the Y1 receptor, counteracting the anxiogenic effect of CRH, reducing noradrenergic activity in the locus coeruleus, and inhibiting excitatory neurotransmission in the dorsal periaqueductal grey.

    “From animal studies it is known that NPY mediates anxiolysis e.g. by inhibiting amygdalar activation and increasing calcineurin-induced synaptic remodelling in the basolateral amygdala (via the Y 1 receptor), counteracting the anxiogenic effect of CRH, reducing noradrenergic activity in the locus coeruleus and inhibiting excitatory neurotransmission in the dorsal periaqueductal grey (Kask et al.,”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kask et al., 2002 source

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    • cites Reichmann & Holzer, 2016

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  • May combine two claims.

    Premisecitation

    Elaborate preclinical studies show that overactivation of CRHR1 by CRH drives the stress system and anxiety-related behaviours, triggering development of CRHR1 antagonists.

    “Elaborate preclinical studies showing that the overactivation of CRHR 1 by CRH drives the stress system and anxiety-related behaviours, have triggered the development of a number of non-peptidergic, orally available and brain-penetrating CRHR1 antagonists (Holsboer, 2001;Zorrilla & Koob, 2010).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Holsboer, 2001 source

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    • cites Zorrilla & Koob, 2010

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    Premisecitation

    Monotherapy with CRHR1 receptor antagonists including verucerfont, R121919 and pexacerfont does not exhibit greater efficacy than placebo for the treatment of PTSD, GAD, SAD and major depressive disorder, despite good tolerability.

    “However, since monotherapy with CRHR 1 receptor antagonists including verucerfont (GSK-561679, NBI-77860), R121919 (NBI-30775) and pexacerfont (BMS-562086) does not exhibit greater efficacy than placebo for the treatment of PTSD (Dunlop et al., 2017), GAD, SAD and major depressive disorder, despite good tolerability of these drugs in all of these clinical trials (Griebel & Holsboer, 2012),”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dunlop et al., 2017 source

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    • cites Griebel & Holsboer, 2012

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    Premisecitation

    Activation of the orexin system is involved in the expression and consolidation of fear while it counteracts fear extinction.

    “Furthermore, activation of the orexin system has been shown to be involved in the expression and consolidation of fear while it counteracts fear extinction (Flores et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Flores et al., 2015 source

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    Premisecitation

    NPS is a more recently characterized neuropeptide that exerts anxiolytic and arousal/activity promoting effects and has been shown to enhance extinction learning.

    “Finally, NPS is a more recently characterized neuropeptide that exerts anxiolytic and arousal/activity promoting effects, and has been shown to enhance extinction learning-[for recent review, see (Grund & Neumann, 2019)].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grund & Neumann, 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    After the latest disappointing clinical trials, verucerfont has disappeared from the product pipeline of Neurocrine Biosciences for PTSD, but remains a treatment for congenital adrenal hyperplasia.

    “After the latest disappointing clinical trials, verucerfont has disappeared from the product pipeline of Neurocrine Biosciences for PTSD, but remains a treatment for congenital adrenal hyperplasia (https://www.neurocrine.com/pipeline/ pipeline-overview/).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites https://www.neurocrine.com/pipeline/ pipeline-overview/

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  • May combine two claims.

    Premisecitation

    Riluzole is a voltage-sensitive sodium channel blocker with high affinity for inactivated channels, resulting in inhibition of high-frequency neuronal firing.

    “It is a voltagesensitive sodium channel blocker with high affinity for inactivated channels resulting in the inhibition of high-frequency neuronal firing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bellingham, 2011 source

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  • May combine two claims.

    Premisecitation

    As a proposed main mechanism, riluzole reduces glutamatergic neurotransmission by blocking NMDA receptors, increasing synaptic AMPA receptor trafficking and the clearance of glutamate via glutamate transporters.

    “As a proposed main mechanism, riluzole reduces glutamatergic neurotransmission by blocking NMDA receptors, increasing synaptic AMPA receptor trafficking and the clearance of glutamate via glutamate transporters.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bellingham, 2011 source

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  • May combine two claims.

    Premisecitation

    A polymorphism in the NPS receptor gene resulting in an amino acid exchange of asparagine to isoleucine (A/T) at position 107 and a more functional variant is associated with PD and distorted cortico-limbic activity during emotion processing in healthy adults and PD patients, as well as with increased anxiety-sensitivity upon gene-environment interactions.

    “The potential of the NPS system as a novel anxiolytic target is supported by studies in humans showing that a polymorphism in the NPS receptor gene, resulting in an amino acid exchange of asparagine to isoleucine (A/T) at position 107 and a more functional variant, is associated with PD and distorted cortico-limbic activity during emotion processing in healthy adults and PD patients, as well as”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grund & Neumann, 2019

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  • May combine two claims.

    Premisecitation

    Riluzole improves anxiety symptoms in patients with diagnosed major depressive disorder when given alone or in combination with standard antidepressant treatment, although the newest study was not able to reproduce this effect.

    “Furthermore, it has been shown to improve anxiety symptoms in patients with diagnosed major depressive disorder when given alone or in combination with standard antidepressant treatment (Sanacora, Kendell, Fenton, Coric, & Krystal, 2004), although the newest study was not able to reproduce this effect (Mathew, Gueorguieva, Brandt, Fava, & Sanacora, 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sanacora, Kendell, Fenton, Coric, & Krystal, 2004

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    • cites Mathew, Gueorguieva, Brandt, Fava, & Sanacora, 2017

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  • May combine two claims.

    Premisecitation

    Of the kava constituents, kavain and dihydrokavain have the strongest anxiolytic potential, thought to be mediated via positive allosteric modulation of BDZ-sensitive and -insensitive forms of GABA-A receptors.

    “Of these, kavain and dihydrokavain have the strongest anxiolytic potential, thought to be mediated via the positive allosteric modulation of BDZ-sensitive and -insensitive forms of GABA-A receptors (Chua et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chua et al., 2016 source

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  • May combine two claims.

    Premisecitation

    In rodents, a single dose of riluzole produces clear anxiolytic effects in a dose-dependent manner without evidence of oversedation, amnesia or coordinative problems as seen with BDZs.

    “In rodents, a single dose of riluzole produces clear anxiolytic effects in a dose-dependent manner (Sugiyama et al., 2012) without evidence of oversedation, amnesia or coordinative problems as seen with BDZs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sugiyama et al., 2012 source

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  • May combine two claims.

    Premisecitation

    Kava does not elicit acute anxiolysis comparable to a BDZ, but reduces anxiety measures within a week of treatment.

    “Kava does not elicit acute anxiolysis comparable to a BDZ, but reduces anxiety measures within a week of treatment (Gastpar & Klimm, 2003;Volz & Kieser, 1997).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gastpar & Klimm, 2003

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    • cites Volz & Kieser, 1997

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  • May combine two claims.

    Premisecitation

    While several classes of phytochemicals are already considered in cases of mild anxiety or as supplements to conventional anxiolytic therapies, the anxiolytic effects of phytochemicals have been demonstrated predominantly in animal models, and structure-activity relationships, metabolism, absorption and neuropharmacological mechanisms are not clear in most cases.

    “While several classes of phytochemicals are already considered in cases of mild anxiety or as supplements to conventional anxiolytic therapies, the anxiolytic effects of phytochemicals have been demonstrated predominantly in studies involving animal models (Fedotova et al., 2017), and the structure-activity relationships, metabolism, absorption and neuropharmacological mechanisms are not clear in”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fedotova et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent meta-analysis revealed that the current evidence is promising but still insufficient to support claims of superior effectiveness of kava over placebo in GAD.

    “Nevertheless, a recent meta-analysis revealed that the current evidence is promising, but still insufficient to support claims of superior effectiveness of kava over placebo in GAD (Ooi, Henderson, & Pak, 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ooi, Henderson, & Pak, 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A systematic review supports the use of kava for the short-term treatment (up to eight weeks) of anxiety, but points out that it is not a replacement for prolonged anti-anxiety drug use.

    “So far, a systematic review supports the use of kava for the short-term treatment (up to eight weeks) of anxiety, but points out that it is not a replacement for prolonged anti-anxiety drug use (Smith & Leiras, 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smith & Leiras, 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combining psychotherapy with existing anxiety medication treatment does not seem to provide consistently superior benefits across anxiety disorders, but may be useful for those patient groups that do not adequately respond to CBT alone.

    “This approach, however, does not seem to provide consistently superior benefits across anxiety disorders, but may be useful for those patient groups that do not adequately respond to CBT alone (Etkin et al., 2019;Tolin, 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Etkin et al., 2019 source

      Not checked in the free run.

    • cites Tolin, 2017 source

      Not checked in the free run.

    • Rests on an assumption: Psychotherapeutic programmes are often insufficiently available, time-consuming and require extensive training of the therapist.

  • May combine two claims.

    Premisecitation

    A standardised extract containing 0.374 mg of Galphimine-B per dose demonstrated similar efficacy in reducing anxiety, but better tolerability after four and 10 weeks of treatment as compared with the active comparators lorazepam and alprazolam.

    “It was reported that the standardised extract containing 0.374 mg of Galphimine-B per dose demonstrated similar efficacy in reducing anxiety, but better tolerability after four and 10 weeks of treatment as compared with the active comparators lorazepam and alprazolam (Herrera-Arellano et al., 2007;Romero-Cerecero et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Herrera-Arellano et al., 2007 source

      Not checked in the free run.

    • cites Romero-Cerecero et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chamomile was safe and efficacious in reducing anxiety symptoms in moderate GAD cases, but did not affect the rate of relapse.

    “It was found that chamomile was safe and efficacious in reducing anxiety symptoms in moderate GAD cases, but did not affect the rate of relapse.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Amsterdam et al., 2009 source

      Not checked in the free run.

    • cites Mao et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While DCS is not anxiolytic per se, it has been shown to facilitate fear extinction in rodents, although fear recovery was still seen under certain conditions following cycloserine-promoted extinction.

    “While DCS is not anxiolytic per se, it has been shown to facilitate fear extinction in rodents although fear recovery was still seen under certain conditions following cycloserine-promoted extinction (Richardson, Ledgerwood, & Cranney, 2004;Walker, Ressler, Lu, & Davis, 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Richardson, Ledgerwood, & Cranney, 2004

      Not checked in the free run.

    • cites Walker, Ressler, Lu, & Davis, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CBT is not efficacious or acceptable for all patients, as demonstrated by considerable rates of partial or non-response (mean rate 35-54% in meta-analyses) as well as of non-adherence.

    “Furthermore, CBT is not efficacious or acceptable for all patients, as demonstrated by considerable rates of partial or non-response (the mean rate is 35-54% in meta-analyses) as well as of non-adherence (Loerinc et al., 2015;Taylor et al., 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Loerinc et al., 2015 source

      Not checked in the free run.

    • cites Taylor et al., 2012 source

      Not checked in the free run.

    • Rests on an assumption: Psychotherapeutic programmes are often insufficiently available, time-consuming and require extensive training of the therapist.

  • May combine two claims.

    Premisecitation

    Mounting preclinical data demonstrate that activation of the eCB system using FAAH and MAG-L inhibitors or CB1 receptor agonists enhances fear extinction while its pharmacological or genetic inactivation impairs fear extinction.

    “Mounting preclinical data demonstrate that activation of the eCB system using FAAH and MAG-L inhibitors or CB 1 receptor agonists enhances fear extinction while its pharmacological or genetic inactivation impairs fear extinction (Patel et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Patel et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Boosting dopamine signalling with systemic administration of L-DOPA accelerates fear extinction and reduces fear relapse in humans, in particular in conditions when low fear is displayed at the end of the extinction session.

    “Indeed, boosting dopamine signalling with systemic administration of the dopamine bioprecursor L-3,4dihydroxyphenylalanine (L-DOPA) accelerates fear extinction and reduces fear relapse in humans (Gerlicher, Tuscher, & Kalisch, 2018;Haaker et al., 2013), in particular in conditions when low fear is displayed at the end of the extinction session (Gerlicher, Tuscher, & Kalisch, 2019).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gerlicher, Tuscher, & Kalisch, 2018

      Not checked in the free run.

    • cites Haaker et al., 2013

      Not checked in the free run.

    • cites Gerlicher, Tuscher, & Kalisch, 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both LSD and psilocybin are agonists at 5-HT1A, 5-HT2A and 5-HT2C receptors with varying affinities, whereby full or partial agonism at the 5-HT2A receptor is likely to be the necessary site of action for eliciting an altered state of consciousness including prosocial and pro-cognitive effects.

    “Both drugs are agonists at 5-HT 1A , 5-HT 2A and 5-HT 2C receptors with varying affinities, whereby the full or partial agonism at the 5-HT 2A receptor is likely to be the necessary site of action for eliciting an altered state consciousness including prosocial and pro-cognitive effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liechti, 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Beneficial effects of combining propranolol with trauma reactivation have been reported in a recent small randomised controlled trial and three earlier pilot studies; however, negative outcomes have also been reported.

    “Beneficial effects of combining propranolol with trauma reactivation have been reported in a recent small randomised controlled trial (Brunet et al., 2018) as well as in three earlier pilot studies (Brunet et al., 2008;Pitman et al., 2002;Vaiva et al., 2003); however, negative outcomes have also been reported (Hoge et al., 2012;Wood et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Brunet et al., 2018 source

      Not checked in the free run.

    • cites Brunet et al., 2008 source

      Not checked in the free run.

    • cites Pitman et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A single dose of either LSD or psilocybin in a controlled clinical setting can considerably improve quality of life of patients with relatively few side effects and a low prevalence of abuse.

    “the use of a single dose of either LSD or psilocybin in a controlled clinical setting can considerably improve the quality of life of patients in parallel with relatively few side effects and a low prevalence of abuse”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Johnson, Griffiths, Hendricks, & Henningfield, 2018 source

      Not checked in the free run.

    • cites Johnson, Hendricks, Barrett, & Griffiths, 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Modest to high doses of psilocybin rapidly reduce clinical signs of anxiety and depression in cancer patients and in patients with treatment-resistant depression receiving psychotherapeutic support for up to six months.

    “Likewise, modest to high doses of psilocybin have been shown to rapidly reduce clinical signs of anxiety and depression in cancer patients (Griffiths et al., 2016;Ross et al., 2016) and in patients with treatment-resistant depression (Carhart-Harris et al., 2016) receiving psychotherapeutic support for up to six months.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Griffiths et al., 2016 source

      Not checked in the free run.

    • cites Ross et al., 2016 source

      Not checked in the free run.

    • cites Carhart-Harris et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Propranolol is the most widely studied compound in regard to both the potential blocking of memory consolidation following trauma and the interference with reconsolidation mechanisms.

    “Propranolol is the most widely studied compound in regard to both the potential blocking of memory consolidation following trauma (Amos, Stein, & Ipser, 2014) and the interference with reconsolidation mechanisms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Amos, Stein, & Ipser, 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, pharmacological strategies for interfering with fear reconsolidation appear to be viable, but data are insufficient and variable, and thus do not support their clinical application at present.

    “Overall, pharmacological strategies for interfering with fear reconsolidation appear to be viable, but data are insufficient and variable, and thus do not support their clinical application at present.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The mechanisms of the acute anxiolytic effects of LSD, psilocybin and MDMA are not clear but are thought to involve common changes in functional connectivity of key substrates of the anxiety/fear neurocircuitries and attenuated reactivity of the amygdala.

    “It should be noted that the mechanism(s) of the acute anxiolytic effects of LSD, psilocybin and MDMA are not clear, but are thought to involve common changes in the functional connectivity of key substrates of the anxiety/fear neurocircuitries (Carhart-Harris & Nutt, 2017) and attenuated reactivity of the amygdala (Grimm, Kraehenmann, Preller, Seifritz, & Vollenweider, 2018;Kraehenmann et al., 201”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Carhart-Harris & Nutt, 2017

      Not checked in the free run.

    • cites Grimm, Kraehenmann, Preller, Seifritz, & Vollenweider, 2018

      Not checked in the free run.

    • cites Kraehenmann et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Ketamine, riluzole and xenon all modulate glutamatergic neurotransmission.

    “Such promising novel candidates include ketamine, riluzole and xenon, all modulating glutamatergic neurotransmission.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Ketamine and xenon inhibit NMDA receptors, while riluzole and its prodrug troriluzole increase clearance of glutamate and decrease glutamate release.

    “While ketamine and xenon inhibit NMDA receptors, riluzole and its prodrug troriluzole increase the clearance of glutamate and decrease glutamate release.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    DCS is the most studied among extinction-enhancing drugs and has shown promising outcomes in some clinical studies and specific anxiety disorders, but negative results in others.

    “Among those drugs, DCS is the most studied and is an example of successful research from bench to bedside, with promising outcomes in some clinical studies and specific anxiety disorders, but also negative results in others.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Conclusions from DCS studies have helped refine DCS-assisted EBT and are guiding development of other candidates to facilitate fear-inhibitory learning, such as MDMA and L-DOPA.

    “Conclusions derived from these studies have retrospectively helped to refine DCS-assisted EBT and are guiding the development of other candidates to facilitate fear-inhibitory learning, such as MDMA and L-DOPA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Many new treatments have not yet been sufficiently clinically investigated for long-term safety, and there are concerns about risk of dependence with psychedelics, ketamine, MDMA, medicinal cannabis/marijuana and synthetic cannabinoids.

    “Many of these new treatments have not been yet sufficiently clinically investigated in terms of their long-term safety, and there are concerns about the risk of dependence with the above-mentioned psychedelics, but also with the use of ketamine, MDMA, medicinal cannabis/marijuana and synthetic cannabinoids.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Drug-induced relief in anxiety-related symptoms can be immediate (acute) or delayed requiring repeated treatment.

    “Drug-induced relief in anxiety-related symptoms can be immediate (acute) or delayed requiring repeated treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Polypharmacy, combining several target-specific drugs, is widely used in clinical/outpatient settings and carries risk of more and/or more severe side effects due to drug-drug interactions.

    “polypharmacy, that is widely used in the clinical/outpatient setting with the risk of more and/or more severe side effects due to drug-drug interactions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Multi-target drugs address several biological targets and may either treat two aspects of the disease or produce additive and even synergistic effects.

    “multi-target drugs address several biological targets and may either treat two aspects of the disease (e.g.propranolol reduces somatic symptoms and interferes with fear re-consolidation in PTSD patients, see Section 8) or produce additive and even synergistic effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Polymorphisms in the 5-HT transporter, as well as in the 5-HT1A, 5-HT2A and 5-HT3 receptors, have been reported in different anxiety disorders and likely influence efficacy of 5-HT-based pharmacotherapy.

    “polymorphisms in the 5-HT transporter, as well as in the 5-HT 1A , 5-HT 2A and 5-HT 3 receptors, have been reported in different anxiety disorders, likely influencing the efficacy of 5-HT-based pharmacotherapy (Helton & Lohoff, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Helton & Lohoff, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The shift in drug discovery to multi-target approaches is increasingly being promoted in other CNS research areas, such as neurodegenerative disorders.

    “The shift in drug discovery to multi-target approaches is also increasingly being promoted in other CNS research areas, such as neurodegenerative disorders (Anighoro, Bajorath, & Rastelli, 2014;Ramsay, Popovic-Nikolic, Nikolic, Uliassi, & Bolognesi, 2018;Zheng, Fridkin, & Youdim, 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Anighoro, Bajorath, & Rastelli, 2014

      Not checked in the free run.

    • cites Ramsay, Popovic-Nikolic, Nikolic, Uliassi, & Bolognesi, 2018

      Not checked in the free run.

    • cites Zheng, Fridkin, & Youdim, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anxiety patients display changes in processing of information in relevant neuronal pathways and networks and show sensitivity to existing anxiolytic treatments.

    “anxiety patients display changes in processing of information in relevant neuronal pathways and networks which will be further characterized using novel methods (see e.g.(Yang et al., 2019) and show sensitivity to existing anxiolytic treatments.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yang et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anxiety disorders are polygenetic and associated with disturbances in multiple complex neuronal systems.

    “anxiety disorders are polygenetic and associated with disturbances in multiple complex neuronal systems (Bandelow et al., 2016;Millan, 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bandelow et al., 2016

      Not checked in the free run.

    • cites Millan, 2003

      Not checked in the free run.

115 of 115

  • The paper relies on this without support.

    The onset of therapeutic action of antidepressants is delayed for 2-3 weeks or more.

    “The onset of therapeutic action is delayed for 2-3 weeks or more, therefore antidepressants cannot be used as an acute anxiolytic intervention.”

  • The paper relies on this without support.

    Duloxetine and pregabalin were approved by FDA and/or EMA for GAD in 2006/07.

    “In 2006/07, the two latest anxiolytic drugs, duloxetine and pregabalin, were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for the treatment of GAD (Fig. 1).”

  • The paper relies on this without support.

    Anxiety symptoms are typically core features of all anxiety-related disorders and they have in part overlapping neurobiological mechanisms.

    “Considering that anxiety symptoms are typically core features of all of these disorders and they have in part overlapping neurobiological mechanisms, the drug development for anxiety disorders, PTSD and OCD is discussed jointly in this review and the used term anxiety and related disorders includes all of these disorders.”

  • The paper relies on this without support.

    Anxiety disorders are multifactorial in cause, involving an interaction between multiple genetic and environmental factors.

    “Family and twin studies have indicated that anxiety disorders are multifactorial in cause, involving an interaction between multiple genetic and environmental factors.”

  • The paper relies on this without support.

    Current approaches such as antidepressants or CBT produce plastic changes after chronic treatment only.

    “Current approaches such as antidepressants or CBT produce plastic changes after chronic treatment only.”

  • The paper relies on this without support.

    Levels of inborn anxiety-related behaviour and sensitivity to anxiolytics can differ greatly between mouse strains, but this fact is scarcely taken into consideration in preclinical studies exploring the anxiolytic properties of novel drugs.

    “Moreover, although levels of inborn anxiety-related behaviour and sensitivity to anxiolytics can differ greatly between mouse strains, this fact is scarcely taken into consideration in preclinical studies exploring the anxiolytic properties of novel drugs.”

  • The paper relies on this without support.

    Some brain areas such as BNST, amygdala, and PFC are partitioned into subregions that can mediate distinct and sometimes even opposite functions.

    “Some of the brain areas such as the BNST, amygdala, and PFC are partitioned into subregions that can mediate distinct and sometimes even opposite functions (e.g.anxiogenic vs. anxiolytic).”

  • The paper relies on this without support.

    Preclinical findings in animal models of anxiety predict anxiolytic efficacy in humans.

    “preclinical evidence of anxiolytic and antidepressant properties has stimulated further investigation for its use in GAD and major depression as well as for schizophrenia and multiple sclerosis (Ivachtchenko, Lavrovsky, & Okun, 2016).”

  • The paper relies on this without support.

    Findings and treatments for one anxiety disorder generalize to other anxiety disorders.

    “it is likely to be particularly useful for anxiety patient populations with sleep-related symptoms including also PTSD and OCD (De Berardis et al., 2015).”

  • The paper relies on this without support.

    TSPO promotes endogenous neurosteroidogenesis by supplying cholesterol to the cytochrome P450 enzyme for conversion into pregnenolone.

    “Ligands targeting the translocator protein (TSPO), which promotes the endogenous neurosteroidogenesis by supplying cholesterol to the cytochrome P450 enzyme for conversion into pregnenolone, have received particular interest.”

  • The paper relies on this without support.

    Preclinical anxiolytic-like effects in animals predict clinical anxiolytic efficacy in humans.

    “There is strong preclinical evidence that drugs reducing glutamatergic neurotransmission cause fast antidepressant and anxiolytic effects in animals and humans (Williams & Sanacora, 2015).”

  • The paper relies on this without support.

    Mimicking or enhancing endogenous anxiety-reducing neuropeptide systems will produce clinical anxiolysis with fewer side effects than traditional anxiety medications.

    “Specifically, neuropeptides such as neuropeptide S (NPS), neuropeptide Y (NPY), oxytocin (OXT) and others can act as natural anxiety-reducing molecules, and therefore mimicking their effect or enhancing their endogenous action would potentially produce anxiolysis with fewer side effects than traditional anxiety medications.”

  • The paper relies on this without support.

    Aloradine has so far shown a side-effect profile similar to placebo.

    “Given that aloradine, so far, has shown a side-effect profile similar to placebo, the follow-up multi-centre Phase 3 trial launched by VistaGen in 2019 will be of considerable interest.”

  • The paper relies on this without support.

    In animal studies, substance P modulates anxiety-related behaviour via its three neurokinin receptors.

    “In animal studies, substance P modulates anxiety-related behaviour via its three neurokinin receptors.”

  • The paper relies on this without support.

    Psychotherapeutic programmes are often insufficiently available, time-consuming and require extensive training of the therapist.

    “The disadvantage of psychotherapeutic programmes is that apart from the fact that they are often insufficiently available, they are time-consuming and require extensive training of the therapist.”

  • The paper relies on this without support.

    Safety concerns around long-term consumption of kava remain.

    “Although the ban by some European countries at the beginning of the 21st century on kava products for human consumption due to cases of hepatotoxicity has subsequently been lifted, e.g. in Germany, safety concerns around long-term consumption of kava remain.”

  • The paper relies on this without support.

    After pregabalin and duloxetine were last approved for GAD in 2006 and 2007, no other drug was successful in completing clinical development for anxiety and related disorders.

    “After pregabalin and duloxetine were last approved for the treatment of GAD in 2006 and 2007, respectively, no other drug was successful in completing clinical development for the treatment of anxiety and related disorders.”

  • The paper relies on this without support.

    Anxiety and related disorders are the most prevalent mental disorders.

    “the most prevalent mental disorders”

  • The paper relies on this without support.

    Current first-line treatments are ineffective for a considerable proportion of patients.

    “The finding that current first line treatments proved ineffective for a considerable proportion of patients indicates the need to change treatment strategies”

  • The paper relies on this without support.

    Heterogeneity within anxiety disorders and inaccurate subgroup stratification tools have hampered development of novel anxiolytic drugs with improved treatment outcome.

    “Problems associated with the heterogeneity within a given anxiety disorder as classified presently, together with inaccurate subgroup stratification tools have likely hampered the development of novel anxiolytic drugs with improved treatment outcome.”
20 of 20

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • As pharmacology-based and psychotherapy-based interventions are independently capable of modulating circuit-level neural activity, pharmacologically-enhanced psychotherapy would seem an obvious opportunity to target specific circuits more effectively and potentially reduce the need for chronic pharmacological therapy.

    “As pharmacology-based and psychotherapy-based interventions are independently capable of modulating circuit-level neural activity, pharmacologically-enhanced psychotherapy would seem an obvious opportunity to target specific circuits more effectively and potentially reduce the need for chronic pharmacological therapy [58].”

    From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [58]

  • Promising results have been obtained by enhancing psychotherapy with MDMA, oxytocin, L-DOPA, and other compounds.

    “Promising results have been obtained by enhancing psychotherapy with methylenedioxymethamphetamine (MDMA; phase three clinical trial NCT03537014 is currently assessing MDMA-assisted psychotherapy for PTSD), oxytocin [59], L-DOPA [60], and other compounds (for review, see [58]).”

    From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [58]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • JNJ-42165279 is credited with efficacy despite unavailable trial results

    Major

    The conclusion includes JNJ-42165279 among FAAH inhibitors for which clinical trials show promising anxiety reduction, but the drug's section says results from its anxiety-disorder trial were not yet available.

  • Aloradine's GABA-A mechanism is asserted and described as uncertain

    Minor

    The conclusion calls GABA-A receptor targeting aloradine's mechanism, whereas its dedicated section says whether aloradine targets that receptor is unclear.

  • Gepirone ER has conflicting development phases for GAD

    Minor

    Table 2 assigns gepirone ER to Phase 3 for GAD, while Table 3 puts it in the Phase II column for GAD.

  • Brexpiprazole's PTSD development phase differs between tables

    Minor

    Table 2 lists the PTSD study of brexpiprazole as Phase 2, while Table 3 places brexpiprazole in the Phase III column for PTSD.

  • Nabilone's OCD trial is assigned two phases

    Minor

    The text calls the ongoing nabilone trial for OCD Phase 1, but Table 3 places nabilone in its Phase II column for OCD.

5 of 5

Cites

1 retracted

Flagged first, then by citations

2 of the 460 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Anonymous, 2018, Drug and device news, Pharmacy Therapeutics, 43, 74
  2. Pittler, 2003, Kava extract for treating anxiety, Cochrane Database of Systematic Reviews, CD003383
  3. Sullivan, 2018, Time since trauma in PTSD: Phase 3 multi-center, double-blind, placebo-controlled trial of TNX-102 SL, a sublingual formualtion of cyclopbenzaprine, in military-RElated PTSD (study TNX-CY-P301), Innoations in Clincial Neuroscience, 15, S10

Cited by

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Related

Authors
Sartori, S. B., & Singewald, N.
Affiliations
Universität Innsbruck (AT)
Corresponding author
Singewald, Nicolas
ORCID
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2019-12
Volume
204
Pages
107402
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/j.pharmthera.2019.107402
OpenAlex
W2970453706
Semantic Scholar
4797d7c796f1e05cba4c8ad314f35e67a58995c0
Cited by
236
References
460
Citations by year
2026: 10 · 2025: 29 · 2024: 65 · 2023: 41 · 2022: 33 · 2021: 38 · 2020: 18 · 2019: 2
FWCI
3.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacology & Therapeutics (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Austrian Science Fund (DK W-1206, SFB F4410, I2433-B26)
Topics
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
anxiety disorders, anxiolytic drug development, therapeutic target, fear extinction, glutamatergic neurotransmission, ketamine, riluzole, xenon, neurosteroids, D-cycloserine, MDMA, L-DOPA, cannabinoids, endocannabinoid system, neuropeptides, ion channels, phytochemicals, benzodiazepines, serotonergic system, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder
MeSH terms
Animals, Anxiety Disorders, Humans, Anti-Anxiety Agents, Molecular Targeted Therapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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