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Depress Anxiety. Author manuscript; available in PMC 2021 August 01.
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Published in final edited form as:

Depress Anxiety. 2020 August ; 37(8): 747–759. doi:10.1002/da.23038.

Novel Pharmacological Treatments for Generalized Anxiety

Disorder: Pediatric Considerations
A. Irem Sonmez, MD1, Ammar Almorsy, MBBCh1, Laura B. Ramsey, PhD2, Jeffrey R.
Strawn, MD3, Paul E. Croarkin, DO, MSCS1,*
1Department of Psychiatry and Psychology Mayo Clinic, Rochester, Minnesota, USA;
2Divisionof Research in Patient Services and Clinical Pharmacology, Cincinnati Children’s
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Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati, Ohio, USA;
3Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati,
Ohio, USA;

Abstract
Pediatric anxiety disorders such as generalized anxiety disorder (GAD) are common, impairing,
and often undertreated. Moreover, many youth do not respond to standard, evidence-based
psychosocial or psychopharmacologic treatment. An increased understanding of the gamma-
aminobutyric acid (GABA) and glutamate neurotransmitter systems has created opportunities for
novel intervention development for pediatric GAD. This review examines potential candidates for
pediatric GAD: eszopiclone, riluzole, Eglumegad (LY354740), pimavanserin, agomelatine. The
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pharmacology, preclinical data, clinical trial findings and known side effects of these compounds
are reviewed, particularly with regard to their potential therapeutic relevance to pediatric GAD.
Notwithstanding numerous challenges, some of these agents represent potential candidate drugs
for pediatric GAD. Further treatment development studies of agomelatine, eszopiclone,
pimavanserin and riluzole for pediatric GAD also have the prospect of informing the
understanding of GABAergic and glutamatergic function across development.

Keywords
Agomelatine; Anxiety; Drug Development; Eglumegad (LY354740); Eszopiclone; Generalized
Anxiety Disorder; Pediatric; Pimavanserin; Riluzole
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Introduction
Pediatric anxiety disorders affect up to 20% of youth and contribute to social impairment,
poor academic performance, and family stress (Essau et al., 2000). Anxiety disorders

*
Reprints: Paul E. Croarkin, DO, MSCS, Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN
55905, croarkin.paul@mayo.edu, Telephone: (507) 293-2557, Fax: (507) 293-3933.
Data Sharing:
Data Sharing is not applicable to this article as no new data were created or analyzed in this study.
Conflicts of Interest
The authors report no financial or other relationship relevant to the subject of this article.
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increase the risk of developing depressive disorders (Pine, 1999), substance use disorders,
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and suicidality (Asselmann et al., 2018; Husky et al., 2012). Generalized anxiety disorder
(GAD) is one of the more common anxiety disorders in childhood and is characterized by
diffuse, difficult-to-control anxiety that typically emerges during adolescence (Beesdo-Baum
& Knappe, 2012).

Putative variations in the serotonin transporter gene (5-HTT) may predispose children and
adolescents to developing GAD (Tsuang et al., 2004). However, the neurochemical basis of
GAD in children and adolescents is likely more wide-ranging and complex with
contributions from serotonin, norepinephrine, glutamate, and GABA systems. This
complexity creates clinical challenges in precision medicine approaches to tailoring
treatment in youth with GAD but also presents immense research opportunities for
developing new pharmacological treatments. Neurodevelopmental considerations are
important in considering the pathophysiology of anxiety as the glutamatergic and
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GABAergic neurotransmitter systems also undergo substantial changes, potentially

facilitating more heterogeneity in the clinical picture, pathophysiology, and pharmacological
response in childhood GAD (Pine, 1999).

Current, evidence-based pharmacologic treatments for GAD as main diagnosis in children

and adolescents are limited to selective serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) (Dobson et al., 2019). Duloxetine is the only
antidepressant approved by the FDA for pediatric GAD (Jeffrey R Strawn et al., 2015).

Despite the promise of novel therapeutics, there are significant challenges to developing
more effective treatments. These challenges relate not only to the fluctuating course of
anxiety disorders but to developmental factors and inherent limitations of clinical trials
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design. In youth, anxiety symptoms—like depressive symptoms—tend to fluctuate over time

(Costello et al., 2005). Thus, a group of anxious youth may have symptoms and variance of
symptom measures as well as the autocorrelation of symptoms that are determined by non-
treatment. From a clinical trial design standpoint, even with current statistical approaches,
some degree of stationarity is necessary to detect treatment-related improvement. Treatments
are also largely borrowed by those that have demonstrated efficacy in adults with anxiety
disorders (J. R. Strawn et al., 2018).This approach assumes that the pathophysiology and by
extension the neuropharmacology of these disorders is the same in pediatric and adult
populations. However, differences in neurocircuitry have been observed in anxious adults
relative to anxious youth. Measures of anxiety symptoms that have been used in pediatric
(and adult studies) are encumbered by issues related to unidimensionality and over
representation of some symptoms (e.g., somatic symptoms) relative to psychic symptoms or
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functional impairment (e.g., relationship dysfunction and avoidant behavior). Importantly,

problems introduced by the unidimensionality of these measures are amplified in the
pediatric population that often has greater co-morbidity (Kendall et al., 2010).

This review examined potential investigational pharmacologic treatments for pediatric GAD
with the objective of informing related, clinical research, and drug development. Embase
and Medline from 2008 to 2019 were searched with the assistance of a research librarian
using keywords listed for this review. Studies and manuscripts that were published in

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English were included. The reference list was finalized in March 2019 through review of
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initial literature search and discussion among all authors. The reference list of each
manuscript was reviewed for additional potential references. Additional manuscripts were
reviewed and included by PEC and JS as deemed necessary for a comprehensive manuscript.

(1) Rationale for GABA and glutamate neurotransmitter systems for pediatric GAD
In pre-clinical models, stress enhances excitatory neurotransmission, mediated by elements
of the glutamatergic neurotransmission system and chronic stress increases vulnerability to
developing anxiety disorders (Simon & Gorman, 2006). Glutamatergic tone in the anterior
cingulate cortex correlates with the severity of anxiety symptoms in adolescents with GAD
(Jeffrey R Strawn et al., 2014). Thus, glutamate-modulating agents may have a role in
treating severe anxiety disorders. Acute administration of N-Methyl-D-Aspartic acid
(NMDA) receptor antagonists has anxiolytic effects in preclinical and clinical models (Javitt,
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2004; Plaznik et al., 1994). Conventional antidepressants and NMDA antagonists decrease
glutamatergic neurotransmission without histologic changes in the neuron which may be
associated with remission from depression or anxiety disorders via restoration of a basal rate
of neurogenesis (Duman, 2002; Jacobs et al., 2000; Manji et al., 2003; Santarelli et al.,
2003). Notably, prior work suggests that glutamatergic and GABAergic balances may
regulate the expression of BDNF (Marmigère et al., 2003).

(2) Promising Drugs

Eszopiclone—Eszopiclone, a γ-aminobutyric acid (GABAA) receptor agonist, is rapidly
absorbed after oral administration and extensively metabolized by CYP3A4 and CYP2E1.
N-desmethylzopiclone, the pharmacologically active primary metabolite, is distributed in
brain and among other tissues and then eliminated via urine and saliva. In pediatric studies
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of eszopiclone, body weight significantly affects clearance and volume of distribution

(Maier et al., 2011; Sunovian Pharmaceuticals Inc., 2012). With a 7.5 mg dose, the time to
peak concentration (TMAX) is 1 hour and the t½ is 6 hours. As eszopiclone is weakly protein
bound, drug interactions related to protein binding are not concerning. CYP3A4 and
CYP2E1 play a role in the metabolism of eszopiclone. Eszopiclone does not inhibit CYP
1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4 (Sunovion Pharmaceuticals Inc., 2014).

In pre-clinical rodent models of insomnia, eszopiclone decreases acetylcholine release in

sleep promoting regions of pontine reticular formation (Hambrecht-Wiedbusch et al., 2010)
and in the amygdala suggesting its potential in regulation of fear and anxiety as well as
learning, memory, sleep and autonomic control (Hambrecht-Wiedbusch et al., 2014). In
terms of anxiety, low dose eszopiclone (1–10 mg/kg) had promising effects controlling
anxiety and anxiety related insomnia on rats (Huang et al., 2010). Eszopiclone may also
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facilitate neurogenesis. Co-administration of eszopiclone with fluoxetine significantly

increased survival of marked newborn cells in the adult rat dorsal hippocampus (Su et al.,
2009). In another trial twice daily eszopiclone treatment strongly enhanced the survival of
proliferating cells in hippocampal dentate gyrus cells in rats (Methippara et al., 2010). This
effect may be due to responsiveness of adult born hippocampal cells GABAergic stimulation
(Nakamichi et al., 2009). Neurogenesis involves proliferation of neural progenitors, survival

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of newly proliferating cells, and differentiation to neural phenotypes, all of which may be
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involved in the pathophysiology and treatment of anxiety (Revest et al., 2009).

Eszopiclone is currently indicated for insomnia in adults and 6 randomized controlled trials
supporting this indication (Sunovion Pharmaceuticals Inc., 2014). In one of these trials add-
on eszopiclone to escitalopram resulted in greater improvement in HAM-A scores at each
week, even when the insomnia item was removed, and also enhanced the possibility of
response and remission in a 10 week long insomnia trial. Despite discontinuation of
eszopiclone, treatment differences in anxiety measures were maintained (Pollack et al.,
2008).

In a more recent trial comparing cognitive behavioral therapy (CBT) and eszopiclone
combined therapy versus eszopiclone alone in adults with sleep disorder (N=29), greater
improvement in self-reported anxiety (self-rating anxiety scale, SAS) was observed in the
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combined group (Zhang et al., 2018). Another study of perimenopausal women with
impaired daytime functioning due to insomnia as well as some depressive and/or anxiety
symptoms demonstrated improvement in insomnia as well as depression and anxiety
symptoms in eszopiclone group compared to placebo (Joffe et al., 2010).

There are no pediatric trials of eszopiclone in GAD. One study of youth with attention
deficit hyperactivity disorder (ADHD) and insomnia (age 6–17 years, N=486) failed to
detect differences in efficacy for insomnia and safety between eszopiclone and placebo
(Sangal et al., 2014).

In general, eszopiclone is well tolerated (Joffe et al., 2010; Pollack et al., 2008; Zhang et al.,
2018). Most frequently reported adverse event was metallic taste (Joffe et al., 2010; Pollack
et al., 2008); other adverse events were reported as somnolence, headache, dry mouth,
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dizziness, jitteriness and heart palpitations (Greenblatt & Zammit, 2012). There may be an
impairment of driving in the initial waking hours(Greenblatt & Zammit, 2012). Among
youth with ADHD, the most frequent adverse events were headache, dysgeusia and
dizziness (Sangal et al., 2014).

In terms of safety concerns for pediatric GAD studies, eszopiclone is a schedule IV

controlled substance. However eszopiclone may still be a promising candidate for study and
development in pediatric GAD, particularly given concerns about tolerability limitations
associated with benzodiazepines in pediatric GAD and other anxiety disorders (Dobson et
al., 2019).

Riluzole—The exact mechanism of action of riluozole is unknown. Theories postulate that

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riluzole inhibits glutamate release considering its role in amyotrophic lateral sclerosis
(ALS). But there might be other processes involved. Riluzole inhibits glutamic acid release
in cultured neurons, from brain slices, and from corticostriatal neurons in vivo (Doble, 1996)
and decreases release of glutamate from synaptic terminals throughout the CNS (Prakriya &
Mennerick, 2000). Riluzole also blocks some of the postsynaptic effects of glutamic acid by
noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors(Doble, 1996),
increases glutamate reuptake (Frizzo et al., 2004), include inhibition of voltage-dependent

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sodium channels in CNS neurons (Urbani & Belluzzi, 2000), enhances of hippocampal
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alpha-amino-3-hydrosy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit

(GluR1 and GluR2) expression (Du et al., 2007). Riluzole stimulates growth factor
synthesis, including BDNF (Katoh-Semba et al., 2002; Mizuta et al., 2001); promotes
neurogenesis, neurite branching, and neurite outgrowth (Shortland et al., 2006).

Riluzole is well-absorbed and its bioavailability is approximately 60%. Riluzole is highly

protein-bound (90%) and has a t½ 12 hours. Metabolism is mostly hepatic and consists of
hydroxylation mainly and glucuronidation. CYP1A2 is the principal isoenzyme responsible
for N-hydroxylation. Primary excretion pathways are urine (90%) and feces (5%)(ITF
Pharma Inc., 2018; Sanofi-Aventis U.S. LLC., 2008).

In preclinical models of anxiety (elevated plus maze, light/dark and open field tests), the
anxiolytic effects of riluzole are comparable to diazepam (Sugiyama et al., 2012). Riluzole
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infusion into the basolateral amygdala in rats improved recognition memory and resulted in
anxiolytic effect in the elevated plus-maze test and decreased freezing time in contextual
fear conditioning test with foot shocks (Sugiyama et al., 2017; Sugiyama et al., 2018).
Riluzole attenuated anxiety-like behaviors in mice that were pre-treated with veratrine, a
sodium channel activator and anxiety inducer, in the open field test (Ohashi et al., 2015).

Other preclinical studies are available in various models including traumatic brain injury,
spinal cord injury, Huntington’s disease, ischemia and ALS showing neuroprotective effects
of riluzole(Wahl & Stutzmann, 1999). In another trial, riluzole stimulated human platelets to
release BDNF, which is a contributor molecule in brain development, neuronal plasticity and
neuronal survival (Turck & Frizzo, 2015).

One open-label study suggested that riluzole (100 mg/day) in adults with GAD may reduce
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anxiety and is associated with increased hippocampal N-acetylaspartate increase (as a

marker of neuronal integrity) (Mathew et al., 2005). Eighteen GAD patients (seven of the
participants with comorbid panic disorder) received riluzole monotherapy and 8 patients
(44%) remitted based on HAM-A score. Most of comorbid panic disorder patients (5 out of
7) completed the trial and all had significant improvement in PDSS (Abdallah et al., 2013;
Mathew et al., 2008).

Riluzole’s side effect profile was favorable and preliminary results regarding riluzole for the
treatment of severe mood, anxiety and impulsive disorders were encouraging (Zarate &
Manji, 2008). In trials of adults with GAD, the most common adverse events during the trial
were insomnia/sleep disturbance, nausea, abdominal discomfort, sedation, and dry mouth.
No serious adverse events were noted. One patient who completed the trial required a dose
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reduction of riluzole due to sedation. Transient increase in alanine aminotransferase ranging

from 1.1 to 1.8 times the upper limit of normal was observed; for some patients, it
normalized within 2 weeks while receiving riluzole and remained normal at endpoint; and
for the remaining patients, aminotransferase values normalized after discontinuation of
riluzole. No patient exhibited symptoms of hepatic toxicity (Mathew et al., 2005; Mathew et
al., 2008).

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The safety of riluzole in pediatric patients has been examined in two OCD trials. Six
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treatment resistant OCD patients received riluzole for 12 weeks in an open label trial. All
subjects reached a target dose of 100 mg daily without limitation of adverse events aside
from one patient who experienced drowsiness. Increases in lactate dehydrogenase and liver
transaminases were observed with riluzole and both resolved on their own despite continued
riluzole treatment (Grant et al., 2007). An RCT with 60 pediatric OCD patients (mean age
14 years) did not demonstrate a significant difference between riluzole and placebo with
respect to adverse events(Grant et al., 2014). One serious adverse event (pancreatitis) was
recorded in the riluzole group which resolved. Five other patients with asymptomatic
elevations of transaminases were recorded. There were no differences in primary and
secondary outcome measures among the riluzole and placebo groups. This patient sample
was treatment refractory and taking a variety of other medications concurrently (Grant et al.,
2014).
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In considering safety, riluzole may be promising agent to study in pediatric GAD. The safety
data from the prior pediatric OCD clinical trial are promising. Although efficacy was not
demonstrated for OCD, this sample was highly treatment refractory and taking variable
concomitant medications (Grant et al., 2014). Further study as monotherapy in pediatric
GAD may be worth considering.

Eglumegad (LY354740)—Eglumegad (LY354740) is a selective agonist of Group II

mGluRs (Schoepp et al., 2003). The mGlu2/3 belongs to Group II mGluRs that are located
mainly presynaptically. Their major role is to inhibit neurotransmitter release (Nicoletti et
al., 2011). They have an established role in synaptic plasticity regulation and in drug
addiction (Lindsley et al., 2016).
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The clinical use of Eglumegad (LY354740) is limited by its poor gastrointestinal absorption
and poor bioavailability (3–5%) (Rorick-Kehn et al., 2006). To improve Eglumegad
(LY354740) absorption and further assess the therapeutic effects of mGlu2/3 agonists, a
pharmacologically inactive peptidyl prodrug (L-alanine) form of the active compound
Eglumegad (LY354740), named LY544344, was developed. LY544344 is an Eglumegad
(LY354740) prodrug that increases Eglumegad (LY354740) bioavailability. In rodents, oral
administration of LY544344 improves its bioavailability by 10-fold compared to Eglumegad
(LY354740) and produces comparable behavioral effects observed with parenteral
administration of Eglumegad (LY354740) (Rorick-Kehn et al., 2006). Pharmacokinetic data
are currently available for Eglumegad (LY354740) in animals (Johnson et al., 2002). In rats
and dogs, oral Eglumegad (LY354740) has a linear pharmacokinetic profile from 30 to 1000
mg/kg. The bioavailability is 10% and 45 % respectively. The primary elimination route was
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urine in both animals. Metabolism of Eglumegad (LY354740) was evaluated in vitro using
rat and dog liver microsomes and rat liver slices. Neither rats nor dogs metabolized
Eglumegad (LY354740). In summary, Eglumegad (LY354740) is poorly absorbed in rats,
moderately absorbed in dogs and rapidly excreted as unchanged drug in the urine (Johnson
et al., 2002; Pilc, 2003).

Rat models of anxiety have supported a mechanistic role for an imbalance between
glutamatergic and GABAergic tone in panic attacks(Johnson & Shekhar, 2012). Group II

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metabotropic glutamate (mGlu) receptors are located in areas that are thought to be
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implicated in panic networks such as dorsomedial hypothalamic regions and dorsal

periaqueductal gray areas (Johnson et al., 2013). Eglumegad (LY354740) has anxiolytic
activity in many rodent stress and anxiety models, including fear-potentiated startle, elevated
plus maze, lactate-induced panic, and stress-induced hyperthermia (Helton et al., 1998;
Kłodzińska et al., 1999; Shekhar & Keim, 2000; Spooren et al., 2002). Eglumegad
(LY354740) had similar efficacy to benzodiazepines in animal models, but had no evidence
for central nervous system (CNS) depression of motor function, learning, and memory
(Helton et al., 1998; Tizzano et al., 2002). Pretreatment with Eglumegad (LY354740)
inhibits panic-like response without producing sedation in rats (Shekhar & Keim, 2000).
Neuroprotective characteristics of mGlu2/3 receptor agonists were also shown in animal
models of cerebral ischemia(Bond et al., 2000; Bond et al., 1999) and mGlu2/3 knock out
mice(Corti et al., 2007).
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A double-blind trial in patients with panic disorder revealed no statistically significant

differences between Eglumegad (LY354740) and placebo in reducing Panic Disorder
Severity Scale (PDSS) scores and the clinical global impression (CGI) (Bergink &
Westenberg, 2005). However, in infusion studies with cholecystokinin tetrapeptide (CCK-4)
—a reliable panicogen—suggested benefit for the pro-drug LY544344 (which has higher
bioavailability than Eglumegad [LY354740])(Kellner et al., 2005).

One double-blind trial for adults with GAD (N=738)(Michelson et al., 2005) that
randomized patients to Eglumegad (LY354740) (100 or 200 mg BID), placebo, or lorazepam
(4–5 mg daily) demonstrated that Eglumegad (LY354740) had greater efficacy compared to
placebo and comparable reductions to lorazepam over 5 weeks. The tolerability profile of
Eglumegad (LY354740) was superior to lorazepam (Michelson et al., 2005). Reported side
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effects can be found in Table 1. A subsequent study of LY544344 in adults with GAD
(Dunayevich et al., 2008) randomized patients to LY544344 (8 or 16 mg BID) or placebo;
however, secondary to a preclinical concern for treatment-emergent seizures (dog at 60
mg/kg, and in rat and mouse studies at doses 70 mg/kg) the study was terminated and active
patients were discontinued after only 29 patients (26.1%) completed the double-blind
treatment phase and entered the single-blind placebo, drug discontinuation assessment
phase. Primary efficacy analysis showed a positive treatment effect for patients in the
LY544344 treatment groups relative to placebo treatment (p=0.027). Patients who received
LY544344 16 mg b.i.d., but not 8 mg b.i.d., had greater mean improvement from baseline on
the HAM-A total score than those who received placebo (Dunayevich et al., 2008).

There are no trials of LY544344 in pediatric patients. Further study in children and
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adolescents could prove challenging as the adult clinical trial was halted for preclinical
concerns related to seizure risk.

(3) Other Potential Drugs

Agomelatine—Agomelatine, a selective melatonergic MT1 and MT2 receptor agonist may
have hypnotic effects (Fornaro et al., 2010). Agomelatine is also an antagonist at
serotonergic 5-hydroxytryptamine 2C (5-HT2C) receptors that are implicated in underlying
neurobiology of anxiety related behaviors(De Berardis et al., 2013). Additionally, the

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anxiolytic activity of agomelatine may be related to its modulation of GABAergic pathways

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and 5-HT2C antagonism (De Berardis et al., 2013; Fornaro et al., 2010; Loiseau et al., 2006).

It is rapidly absorbed (>75%) after oral administration, although, extensive first-pass

metabolism lowers its absolute bioavailability to <5% (Zupancic & Guilleminault, 2006).
Thus, intranasal and transdermal formulations that have been developed may circumvent its
extensive first-pass metabolism (Fatouh et al., 2017; Said et al., 2017). Agomelatine is
mainly metabolized by hepatic CYP450 CYP1A2 and CYP2C9 to its main metabolites, 3-
hydroxy-agomelatine and 7-desmethyl-agomelatine. Agomelatine is primarily eliminated by
urinary excretion of metabolites and has a mean half-life (t½) of approximately 2 h.

Preclinical studies demonstrated anxiolytic effects of agomelatine under basal conditions

and in fear conditioning models (Guardiola‐Lemaitre et al., 2014). Agomelatine has
demonstrated anxiolytic effects in a wide variety of preclinical models of anxiety including
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prenatal restraint stress (Morley-Fletcher et al., 2011), hypercortisolemic mice (Rainer et al.,
2012), social defeat (Tuma et al., 2005), and social isolation rearing [SIR] model (Regenass
et al., 2018). Additionally, agomelatine increased hippocampal brain-derived neurotrophic
factor (BDNF) levels in another rat model (Lu et al., 2018; Marmigère et al., 2003). Chronic
(3 weeks) agomelatine administration increased cell proliferation and neurogenesis in the
ventral dentate gyrus, a region implicated in fear-related behaviors. Chronic agomelatine
treatment facilitated neuronal survival throughout the dentate gyrus, although this effect
appears to be restricted to developing neurons (Banasr et al., 2006). Another trial with light
stress-exposed rat brains revealed that agomelatine stimulated neurogenesis and prevented
apoptosis (Yucel et al., 2016). Agomelatine appeared to protect the rat brain from cerebral
ischemia and reperfusion injury by suppressing apoptosis (Chumboatong et al., 2017). Also,
chronic agomelatine treatment prevented transcription of the interleukin–1β and
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metabotropic glutamatergic receptor (mGluR) genes (Rossetti et al., 2018).

In three randomized, placebo-controlled, clinical trials, agomelatine was superior to placebo

in adults with GAD (Stein et al., 2017; Stein et al., 2014; Stein et al., 2008) and, in another
RCT, was more tolerable, but equally effective, compared to escitalopram in adults with
GAD (Stein et al., 2018). High and low-dose (10 and 25 mg/day) agomelatine groups
outperformed the placebo group, although only the high dose group showed a robust
difference in remission rate compared to placebo (40.2 versus 12.5%) (Stein et al., 2017).
When escitalopram and agomelatine compared over the course of 12 weeks, both
significantly decreased Hamilton Anxiety Rating Scale (HAM-A) scores, however non-
inferiority of agomelatine versus escitalopram was not established (Stein et al., 2018).
Agomelatine (25–50 mg/kg) has been reported to be clinically effective and well tolerated in
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adults with GAD (Buoli et al., 2017; Stein et al., 2018) but is not approved by the FDA. At
present there are no studies of agomelatine in pediatric patients.

In regards to safety, agomelatine, escitalopram, and placebo have similar tolerability in

adults with GAD (Stein et al., 2017; Stein et al., 2014; Stein et al., 2008; Stein et al., 2018).
The most frequently reported adverse events included dizziness, nausea, headache,
nasopharyngitis, diarrhea and somnolence. Adverse events leading to discontinuation were
less frequent in the agomelatine-treated patients compared to those who received placebo

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and escitalopram. The most recent agomelatine study (Stein et al., 2018) reported that
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agomelatine had superior tolerability compared to escitalopram with respect to headache,

nausea, insomnia, dizziness, anxiety, hyperhidrosis, and diarrhea. There were no differences
between agomelatine and escitalopram in terms of other adverse events. No suicidal
behavior was reported during the study.

Rare cases of severe and life-threatening liver injury have been reported (Friedrich et al.,
2016; Štuhec, 2013). Agomelatine is contraindicated in patients with impaired liver function
(Freiesleben & Furczyk, 2015) and pre-treatment transaminases should be evaluated with
subsequent hepatic profiles being obtained after 3, 6, 12, and 24 weeks(European Medicines
Agency, 2016). If an elevation of transaminases is detected, these exams should be repeated
within 48 h and agomelatine should be discontinued if it increases more than three times the
higher limit of normal value (European Medicines Agency, 2016).
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There are safety concerns to consider for future study in children and adolescents. Liver
toxicity is a challenge to consider in further development of agomelatine for pediatric GAD.
Agomelatine-induced hepatotoxicity appears to be rare and unpredictable (Gahr et al.,
2013). Analysis of 9,234 patients who were treated with agomelatine showed that serum
transaminases increased three fold higher than the upper normal limit in 1.3 and 2.5 % of
patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for
placebo. The incidence of abnormal transaminases was low and dose dependent. No patient-
specific factors were identified regarding potential risk factors and withdrawal of
agomelatine led to rapid recovery (Perlemuter et al., 2016).

Pimavanserin—Pimavanserin, is a potent selective serotonin 5-HT2A inverse agonist with

a combination of inverse agonist and antagonist activity to a lesser extent for 5-HT2C and
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sigma-1 receptors (σ1R) (ACADIA Pharmaceuticals Inc, 2016). Pimavanserin has no

affinity for the dopaminergic, adrenergic, histaminergic, or muscarinic receptors which
separates it from other antipsychotic drugs (Vanover et al., 2006).

The mean t½ for pimavanserin and its active metabolite (N-desmethylated metabolite) are
approximately 60 hours and 200 hours, respectively. Pimavanserin demonstrates dose-
proportional pharmacokinetics and is predominantly metabolized by CYP3A4 and CYP3A5
and to a lesser extent by CYP2J2, CYP2D6, and various other CYP and FMO enzymes.
CYP3A4 is responsible for the formation of its major active metabolite and in vitro data
suggest that pimavanserin does not irreversibly inhibit major hepatic and intestinal human
CYP enzymes. Elimination is both via urine and feces (ACADIA Pharmaceuticals Inc,
2016).
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In rodents, activation of 5-HT2C receptors in the basolateral amygdala complex induces

anxiogenic behaviors (Campbell & Merchant, 2003; Hackler et al., 2007)and 5-HT2C
receptor antagonists have shown to have anxiolytic properties (Aloyo et al., 2009). The 5-
HT2C and 5-HT2A receptors have been implicated in the etiology and treatment of various
psychiatric disorders. Activation of 5-HT2C receptors, with agonists results in feelings of
anxiety and panic in humans (Gatch, 2003). Pimavanserin’s activity on 5-HT2A and 5-HT2C
receptors may suggest its potential on anxiety and fear conditions. Serotonin 2A receptors

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 Sonmez et al. Page 10

are concentrated in the limbic system and are important for mediating fear. There is evidence
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showing that the processing of emotionally loaded information is modulated by the 5HT2A
receptor and that the expression of these receptors related to anxiety traits (Frokjaer et al.,
2008). Individuals with higher serotonin activity tend to have more fearful personalities, and
interestingly, animals with a deficiency of 5-HT2A receptors lack normal fear reactions
(Moresco et al., 2002).

Pimavanserin has not yet been studied in clinical trials for GAD. In adults, pimavanserin and
other 5-HT2A receptor inverse agonists attenuated insomnia in few trials through increases in
slow wave sleep (Ancoli-Israel et al., 2011; Monti, 2010; Rosenberg et al., 2008; Teegarden
et al., 2008). There are no pediatric trials of pimavanserin in pediatric patients with GAD, or
any other disorder.

Overall, clinical trials for pimavanserin in Parkinson’s demonstrated an acceptable safety

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profile (Bozymski et al., 2017). Prescription information reported most frequent side effects
in Parkinson patients in the pimavanserin arms in Parkinson’s disease trials and in healthy
volunteers as drowsiness, nausea, peripheral edema, confusion, hallucinations, constipation,
and gait disturbance (Vanover et al., 2007). Pimavanserin may prolong QT intervals and
concomitant administration of medications that prolong the QT interval should be avoided
(ACADIA Pharmaceuticals Inc, 2016).

The primary safety concern for development of pimavanserin is the knowledge gaps related
to its safety profile in children and adolescents. Initial and ongoing studies would need to
examine this in a systematic fashion (ACADIA Pharmaceuticals Inc, 2016). A secondary
challenge is the cost of pimavanserin—approximately $3,000/month.
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Conclusion
Many children and adolescents with GAD do not respond completely to standard
interventions such as CBT, SSRIs, and SNRIs (Bushnell et al., 2019). There is an urgent
need to expand pharmacologic treatment options for pediatric GAD. Moreover, GABAergic
and glutamatergic dysfunction are implicated in the pathophysiology of GAD in children,
adolescents and adults, yet in youth, relatively few treatment studies have targeted these
systems (Figure 1). These neurotransmitter systems undergo substantial shifts in childhood
and adolescence (Benarroch, 2012; Chugani et al., 2001). This trajectory is poorly
understood in GAD but could present strategic opportunities for pharmacological
intervention, thereby sparing the need for lifelong treatment. In this regard, agomelatine,
eszopiclone, and riluzole are promising agents to consider in for clinical development in
pediatric GAD. Given that an adult clinical trial of Eglumegad (LY354740) was
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discontinued in adults due to safety concerns it is unlikely that this drug will have promise
for clinical development in children (Dunayevich et al., 2008).

Previous anxiolytic drug discovery has largely focused on single targets (highly selective
agents acting on specific molecular targets). However, the notion of better and safety drugs
for GAD has not been realized. Multimodal drug candidates in development, like

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 Sonmez et al. Page 11

agomelatine, with the intention of re-equilibrating perturbed circuits, may potentially lead to
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more effective treatments (Figure 2).

Each of these candidates has unique strengths and barriers to consider for future study.
Broadly, eszopiclone and riluzole may have the most promise in the short-term for
development in pediatric GAD as there are existing safety data in children. Preclinical work
with eszopiclone and riluzole also are encouraging. Eszopiclone and riluzole also have a
favorable cost profile compared to other agents. Agomelatine may be another promising
agent to consider for pediatric GAD with respect to prior preclinical work and adult clinical
trials. Unfortunately at present there are substantial barriers to developing LY354740 and
pimavanserin for pediatric GAD related to safety, preclinical seizure evidence and cost.
Further preclinical studies of agomelatine, eszopiclone, pimavanserin and riluzole in the
context of neurodevelopment are critical to advance mechanistic understanding of anxiety in
children and adolescents and to facilitate drug discovery.
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Acknowledgments:
Preparation of this manuscript was supported by the National Institutes of Health under awards R01 MH113700
(PEC) and R01 HD098757 (JRS). The content of this publication is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institutes of Health. The supporters had no role in the
literature review, interpretation, or publication. We thank Anosha Zanjani for her expertise and assistance with the
creation of Figure 1. We thank Danielle Gerberi for her help with literature search.

Financial Disclosures

Dr. Croarkin receives research support from the National Institutes of Health (NIH). Dr. Croarkin has received
research grant support from Pfizer, Inc.; equipment support from Neuronetics, Inc.; and received supplies and
genotyping services from Assurex Health, Inc. for investigator-initiated studies. He is the primary investigator for a
multicenter study funded by Neuronetics, Inc. and a site primary investigator for a study funded by NeoSync, Inc.
Dr. Croarkin serves as a paid consultant for Procter & Gamble Company and Myriad Neuroscience. Dr. Ramsey has
Author Manuscript

received research support from the National Institutes of Health (NICHD) and BTG, International Ltd. Dr. Strawn
has received research support from the National Institutes of Health (NIMH/NIEHS), Patient-Centered Outcomes
Research (PCORI) , Allergan, Otzuka,and Neuronetics. He has received material support from Myriad Genetics and
receives royalties from the publication of two texts (Springer). Dr. Strawn serves as an author for UpToDate. He is
an Associate Editor for Current Psychiatry.,He has received honoraria from CMEology and Neuroscience
Educational Institute. The other authors have no disclosures or potential conflicts of interest to declare.

Abbreviations
ACh acetylcholine

ADHD attention deficit hyperactivity disorder

AMPA alpha-amino-3-hydrosy-5-methyl-4-isoxazolepropionic acid

ALS amyotrophic lateral sclerosis

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BDNF brain-derived neurotrophic factor

CBT cognitive behavioral therapy

CCK-4 cholecystokinin tetrapeptide

CNS central nervous system

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 Sonmez et al. Page 12

CYP cytochrome P450

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EPS extrapyramidal symptoms

h hours

HAM-A Hamilton anxiety rating scale

HDRS-17 Hamilton depression rating scale

5-HT 5-hydroxytryptamine (serotonin) receptor

5-HTT serotonin transporter gene

5-HT2C 5-hydroxytryptamine c receptor

GABA gamma-aminobutyric acid

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GAD generalized anxiety disorder

mGluR metabotropic glutamatergic receptor

M1 and M2 melatonin receptors

NMDA N-Methyl-D-aspartic acid

OCD obsessive compulsive disorder

σ1R sigma-1 receptors

SIR social isolation rearing

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SNRIs serotonin norepinephrine reuptake inhibitors

SSRIs selective serotonin reuptake inhibitors

t½, half-life

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Figure 1.
GABAergic and Glutamatergic Modulators. Agomelatine modulates (GABAergic receptors
and pathways broadly. Eglumegad (LY354740) is a selective agonist of presynaptic Group II
MGluRs, Eszopiclone is GABA A receptor agonist. Riluzole inhibits glutamate release and
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blocks the postsynaptic effects by noncompetitive antagonism of N-methyl-D-aspartate

(NMDA) receptors. Further, riluzole increases glutamate uptake and enhances hippocampal
alpha-amion-3–3hydrosy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit
(GluR1 and GluR2) expression.

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Figure 2.
Pharmacodynamic Targets of Novel Agents for Anxiety. Pharmacodynamic targets of novel
agents for anxiety. Agomelatine is a selective melatonin 1 and 2 receptor agonist.
Pimavanserin is a selective serotonin 5-HT2A inverse agonist. Pimavanserin also has inverse
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agonist and antagonist activity for 5-HT2C and sigma-1 receptors. Riluzole inhibits voltage-
dependent sodium channels.

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Summary of the mechanism of action, pharmacokinetics, and pharmacodynamics of the potential drugs for GAD
Mechanism of action
MT1 and MT2 receptor agonist.
Agomelatine
5-HT2C receptor antagonist.
Eglumegad Selective mGlu2/3 agonist.
Unknown, likely interactions
with GABA-receptor complexes
Eszopiclone binding domains near or linked
allosterically to benzodiazepine
receptors.
5-HT2A antagonist/inverse
agonist. Some affinity for 5-
Pimavanserin
HT2C and sigma-1 receptors
(σ1R).
Exact mechanism is unknown.
Likely glutamate inhibitor and
Riluzole
noncompetitive NMDA receptor
blocker.
Note: NMDA N-Methyl-D-aspartic acid, 5-HT 5-hydroxytryptamine (serotonin) receptor, MT melatonergic receptor, CYP cytochrome p enzyme, UGT-HP4 UDP-glucuronosyltransferase enzyme.
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Table 1.
Bioavailability Half-life Metabolism Excretion
Sonmez et al.
Metabolized by hepatic CYP450, CYP1A2,
Rapidly absorbed after oral administration Eliminated by urinary
and CYP2C9 to 3-hydroxy-agomelatine
(>75%), but absolute bioavailability after 2.3 hours. excretion of its
(inactive), and 7-desmethyl-agomelatine
first-pass metabolism is (<5%). metabolites.
(inactive).
Oral bioavailability in humans is only 3–
5% due to limited gastrointestinal No human studies Primarily eliminated via
No human studies for metabolism.
absorption. The oral bioavailability of the for half-life. renal excretion.
drug was ~ 10% in rats and 45% in dogs.
Extensively metabolized by CYP3A4 Eliminated via excretion in
isoforms and CYP2E1 into its active urine (up to 75% as
Rapidly absorbed after oral administration. ~6 hours.
metabolite, N-desmethylzopiclone, which is metabolite), and saliva
then distributed in brain and other tissues. (<10% as parent drug).
Pimavanserin has dose-proportional
Pimavanserin: ~57
pharmaco-kinetics after single oral doses Feces (<2% as parent
hours. N- Primarily metabolized via CYP3A4 and
from 17 to 255 mg (0.5–7.5 times the drug); urine (<1% as
desmethylated CYP3A5 to form the active N-
dosage recommendation). The parent drug; <1% as
metabolite: ~200 desmethylated metabolite.
bioavailability of pimavanserin oral tablets metabolites).
hours.
and oral solution is identical.
Almost 88% of the drug is metabolized by
either oxidation (via CYP1A2) or Feces (5%); urine (90%,
Approximately 60% by oral administration. ~12 hours.
glucoronidation (via UGT-HP4). Some 2% as unchanged).
metabolites are pharmacologically active.
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