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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Griebel & Holmes, 2013

In the paper

“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, &”

What the sources say

• Not checked yetcites Nutt & Attridge, 2014
• Not checked yetcites Yokley, Hartman, & Slusher, 2017

In the paper

“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).”

What the sources say

• Not checked yetcites McArthur, 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites McArthur, 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Batelaan et al., 2017 source

In the paper

“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)).”

What the sources say

• Not checked yetcites Kaitin, 2014
• Not checked yetcites Kaitin, 2018

In the paper

“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;”

What the sources say

• Not checked yetcites Schmidt, Khalid, Loukas, & Tubbs, 2018
• Not checked yetcites Tovote et al., 2015 source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites Perusini & Fanselow, 2015
• Not checked yetcites Parsafar & Davis, 2018

In the paper

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

In the paper

“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)”

What the sources say

• Not checked yetcites Grillon, Robinson, Cornwell, & Ernst, 2019
• Not checked yetcites Robinson et al., 2019 source

In the paper

“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.”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Sah et al., 2019 source
• Not checked yetcites Tran, Schulkin, Ligon, & Greenwood-Van Meerveld, 2015
• Not checked yetcites Whittle & Singewald, 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Lach et al., 2018 source
• Not checked yetcites Leclercq et al., 2016 source
• Not checked yetcites Yang, Wei, Ju, & Chen, 2019

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Table 1

In the paper

“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.”

What the sources say

• Not checked yetcites Depoortere, Bardin, Varney, & Newman-Tancredi, 2019
• Not checked yetcites Zhao et al., 2019 source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Table 1
• Not checked yetcites Fig. 1

In the paper

“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).”

What the sources say

• Not checked yetcites Schneier et al., 2017 source
• Not checked yetcites Careri, Draine, Hanover, & Liebowitz, 2015

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Maeda et al., 2014 source

In the paper

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

What the sources say

• Not checked yetcites Shi, Wang, Xu, & Lu, 2016
• Not checked yetcites Thase et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Yee, Ng, & Seng, 2018
• Not checked yetcites Christensen, Loft, Florea, & McIntyre, 2017

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites Bang-Andersen et al., 2011 source

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Robinson, Sitsen, & Gibertini, 2003

In the paper

“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).”

What the sources say

• Not checked yetcites Krystal, Richelson, & Roth, 2013
• Not checked yetcites Monti, 2011 source
• Not checked yetcites Hendrickson & Raskind, 2016

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Sullivan et al., 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Buoli et al., 2017 source
• Not checked yetcites Guardiola-Lemaitre et al., 2014 source
• Not checked yetcites Levitan et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Levitan, Papelbaum, & Nardi, 2015
• Not checked yetcites Millan et al., 2003

In the paper

“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).”

What the sources say

• Not checked yetcites Coric et al., 2005 source
• Not checked yetcites Engin et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Shah & Northcutt, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Stein et al., 2014 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Engin et al., 2018 source
• Not checked yetcites Griessner et al., 2018

In the paper

“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”

What the sources say

• Not checked yetcites Mattei et al., 2019 source
• Not checked yetcites Nuss, Ferreri, & Bourin, 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Poisbeau et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Olsen & Sieghart, 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Prevot et al., 2019
• Not checked yetcites Gonda et al., 2019 source

In the paper

“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).”

What the sources say

• Not checked yetcites de Haas et al., 2007 source
• Not checked yetcites Atack, 2009 source

In the paper

“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.”

What the sources say

• Not checked yetcites Liebowitz et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Reiner & Levitz, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Mattei et al., 2019 source
• Not checked yetcites Nuss, Ferreri, & Bourin, 2019

In the paper

“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.”

What the sources say

• Not checked yetcites Castren & Hen, 2013 source
• Not checked yetcites Fortress, Smith, & Pang, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Glue et al., 2017 source
• Not checked yetcites Taylor et al., 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Fukumoto, Iijima, Funakoshi, & Chaki, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Cohen et al., 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Zarate Jr. et al., 2013 source

In the paper

“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”

What the sources say

• Not checked yetcites FDA, 2019
• Not checked yetcites The Scientist, 2019

In the paper

“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”

What the sources say

• Not checked yetcites Zhou, Liu, & Chen, 2012

In the paper

“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)].”

What the sources say

• Not checked yetcites Dobrovolsky, Ichim, Ma, Kesari, & Bogin, 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Patel et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Dobrovolsky et al., 2017 source

In the paper

“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.”

What the sources say

• Not checked yetcites Crippa, Guimaraes, Campos, & Zuardi, 2018
• Not checked yetcites Soares & Campos, 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Gunduz-Cinar, Hill, McEwen, & Holmes, 2013
• Not checked yetcites Lisboa et al., 2019 source
• Not checked yetcites Mayo et al., 2019

In the paper

“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)].”

What the sources say

• Not checked yetcites Grunberg, Cordova, Bidwell, & Ito, 2015
• Not checked yetcites Mammen et al., 2018 source
• Not checked yetcites Zvolensky et al., 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Kamal, Kamal, & Lantela, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Rabinak & Phan, 2014

In the paper

“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).”

What the sources say

• Not checked yetcites Bergamaschi et al., 2011 source
• Not checked yetcites Crippa et al., 2011 source

In the paper

“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).”

What the sources say

• Not checked yetcites Patel et al., 2017 source

In the paper

“Furthermore, plasma vasopressin levels are elevated in patients with PTSD (de Kloet, Vermetten, Geuze, Wiegant, & Westenberg, 2008) and with OCD (Altemus, Cizza, & Gold, 1992).”

What the sources say

• Not checked yetcites de Kloet, Vermetten, Geuze, Wiegant, & Westenberg, 2008
• Not checked yetcites Altemus, Cizza, & Gold, 1992

In the paper

“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).”

What the sources say

• Not checked yetcites Landgraf, 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Naja & Aoun, 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Lee et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Gao et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Reichmann & Holzer, 2016

In the paper

“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.,”

What the sources say

• Not checked yetcites Kask et al., 2002 source
• Not checked yetcites Reichmann & Holzer, 2016

In the paper

“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).”

What the sources say

• Not checked yetcites Holsboer, 2001 source
• Not checked yetcites Zorrilla & Koob, 2010

In the paper

“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),”

What the sources say

• Not checked yetcites Dunlop et al., 2017 source
• Not checked yetcites Griebel & Holsboer, 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Flores et al., 2015 source

In the paper

“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)].”

What the sources say

• Not checked yetcites Grund & Neumann, 2019

In the paper

“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/).”

What the sources say

• Not checked yetcites https://www.neurocrine.com/pipeline/ pipeline-overview/

In the paper

“It is a voltagesensitive sodium channel blocker with high affinity for inactivated channels resulting in the inhibition of high-frequency neuronal firing.”

What the sources say

• Not checked yetcites Bellingham, 2011 source

In the paper

“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.”

What the sources say

• Not checked yetcites Bellingham, 2011 source

In the paper

“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”

What the sources say

• Not checked yetcites Grund & Neumann, 2019

In the paper

“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).”

What the sources say

• Not checked yetcites Sanacora, Kendell, Fenton, Coric, & Krystal, 2004
• Not checked yetcites Mathew, Gueorguieva, Brandt, Fava, & Sanacora, 2017

In the paper

“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).”

What the sources say

• Not checked yetcites Chua et al., 2016 source

In the paper

“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.”

What the sources say

• Not checked yetcites Sugiyama et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Gastpar & Klimm, 2003
• Not checked yetcites Volz & Kieser, 1997

In the paper

“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”

What the sources say

• Not checked yetcites Fedotova et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Ooi, Henderson, & Pak, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Smith & Leiras, 2018

In the paper

“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).”

What the sources say

• Not checked yetcites Etkin et al., 2019 source
• Not checked yetcites Tolin, 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Herrera-Arellano et al., 2007 source
• Not checked yetcites Romero-Cerecero et al., 2019 source

In the paper

“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.”

What the sources say

• Not checked yetcites Amsterdam et al., 2009 source
• Not checked yetcites Mao et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Richardson, Ledgerwood, & Cranney, 2004
• Not checked yetcites Walker, Ressler, Lu, & Davis, 2002

In the paper

“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).”

What the sources say

• Not checked yetcites Loerinc et al., 2015 source
• Not checked yetcites Taylor et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Patel et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Gerlicher, Tuscher, & Kalisch, 2018
• Not checked yetcites Haaker et al., 2013
• Not checked yetcites Gerlicher, Tuscher, & Kalisch, 2019

In the paper

“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.”

What the sources say

• Not checked yetcites Liechti, 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Brunet et al., 2018 source
• Not checked yetcites Brunet et al., 2008 source
• Not checked yetcites Pitman et al., 2002 source

In the paper

“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”

What the sources say

• Not checked yetcites Johnson, Griffiths, Hendricks, & Henningfield, 2018 source
• Not checked yetcites Johnson, Hendricks, Barrett, & Griffiths, 2019 source

In the paper

“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.”

What the sources say

• Not checked yetcites Griffiths et al., 2016 source
• Not checked yetcites Ross et al., 2016 source
• Not checked yetcites Carhart-Harris et al., 2016 source

In the paper

“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.”

What the sources say

• Not checked yetcites Amos, Stein, & Ipser, 2014

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites Carhart-Harris & Nutt, 2017
• Not checked yetcites Grimm, Kraehenmann, Preller, Seifritz, & Vollenweider, 2018
• Not checked yetcites Kraehenmann et al., 2015 source

In the paper

“Such promising novel candidates include ketamine, riluzole and xenon, all modulating glutamatergic neurotransmission.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Helton & Lohoff, 2015

In the paper

“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).”

What the sources say

• Not checked yetcites Anighoro, Bajorath, & Rastelli, 2014
• Not checked yetcites Ramsay, Popovic-Nikolic, Nikolic, Uliassi, & Bolognesi, 2018
• Not checked yetcites Zheng, Fridkin, & Youdim, 2014

In the paper

“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.”

What the sources say

• Not checked yetcites Yang et al., 2019

In the paper

“anxiety disorders are polygenetic and associated with disturbances in multiple complex neuronal systems (Bandelow et al., 2016;Millan, 2003).”

What the sources say

• Not checked yetcites Bandelow et al., 2016
• Not checked yetcites Millan, 2003