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Add-on clinical effects of selective antagonist of
5HT6 receptors AVN-211 (CD-008-0173) in patients
with schizophrenia stabilized on antipsychotic
1 Laboratory of Psychopharmacology, National Center of Mental Health, Russian Academy of Medical Science, Moscow, Russia
3 Avineuro Pharmaceuticals Inc., San Diego, California, USA
4 Chemical Diversity Research Institute, Khimki, Moscov Region, Russia
The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients
Objective. To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive
effects to stable antipsychotic treatment.
Methods. A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia
patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic
medication was performed. Seventeen patients from the study drug group and 25 patients from the
placebo group completed the trial. Treatment effects were measured using clinical rating scales and
Results. With no differences at baseline, there was a significant difference between the groups in Positive
and Negative Syndrome Scale (PANSS) positive subscale score (p 5 0.058) in favor of patients in the
treatment group at the endpoint. The PANSS positive subscore (p 5 0.0068) and Clinical Global
Impression–Severity (CGI-S) (p 5 0.048) score significantly changed only in the treatment group. Only in
the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score
registered. The indices of attention tests at endpoint did not show differences between the groups, with the
exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale
(WAIS), which showed difference between the groups (p 5 0.02) and was significantly larger in the
treatment group. Only inside the study drug group, significant changes in selectivity and continuous
attention were observed regarding total correct responses (p 5 0.0038) and reaction time (p 5 0.058) in the
Continuous Attention Task (CAT) test.
Conclusion. Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive
(attention) effects to antipsychotic medication.
Received 11 April 2013; Accepted 1 May 2013
Key words: 5HT6 receptor antagonist, add-on, clinical effects, schizophrenia.
antipsychotic treatment on cognitive dysfunction in
schizophrenia, but only in the attention domain.
It is a well-established fact that the existing anti-
Data on the effect produced on other domains are
psychotic treatment is more effective against acute
contradictory.According to Kane,the level of
psychotic and disorganized symptoms than other
diverse residual psychopathology, including both resi-
dual positive, negative, and cognitive disorders, is a
studies have demonstrated a direct positive effect of
critical factor in determining the long-term therapeutic
*Address for correspondence: Margarita Morozova, National Center
Over the last several years, researchers have repeatedly
of Mental Health, Russian Academy of Medical Science, Kashirskoye
tried to find a way to expand the profile of therapeutic
action of antipsychotics through pharmacological agents
complimentary to treatment targets other than the
binding is 88%. The compound weakly interacts with
dopaminergic system.Hypotheses about the role
of the serotonin system in the development of various
The compound was tested for anti-amnestic, anxio-
mental disorderscontinue to be relevant. Of recent
lytic, and antipsychotic effects in various in vivo
special interest is one of the serotonergic system
models: the passive avoidance test, the Morris water
structures—the type 6 serotonergic receptors (5-HT6),
maze test, the elevated plus maze test, and prepulse
which are localized primarily in the central nervous
system (CNS), particularly in the limbic
5-HT6 receptor antagonists have been shown to
modulate multiple neurotransmitter systems, the gluta-
Male adult BALB/c mice (24–25 g) were used in the
matergic and cholinergic in particular, and therefore to
experiments. A passive avoidance cage (Ugo Basile,
Italy Comerio VA) was used. On the first day, mice
It is generally assumed that 5-HT6 receptors may
were treated intraperitoneally with pro-amnesic agent
be involved in the pathogenesis of psychosis, cognitive
scopolamine (0.3 mg/kg) 30 min before training. Inde-
functioning, learning, convulsive disorders, sleep dis-
pendent groups of mice were treated additionally with
orders, and appetite control.Many antipsychotics and
one of the reference drugs (tacrine, 10 mg/kg, 30 min
antidepressants have a high affinity to 5-HT6 receptors.
before training or memantine, 5 mg/kg, 60 min before
The positive results of the phase II study of the effects
training) or with AVN-211, which was administered
of the 5-HT6 receptor antagonist SGS 518 on cognitive
5 min before training. The control animals were injected
dysfunction in 20 patients with schizophrenia were
with physiological solution. According to the results of
publisheIn the study of LuAE8054 adding of the
the test performed, AVN-211 (CD-008-0173) was more
study drug to donepezil showed better efficacy of the
effective than Memantine or Tacrine. The most pro-
combined treatment vs donepezil alone in patients with
nounced effect of AVN-211 (CD-008-0173) was observed
in 0.05 mg/kg (i/p) and 0.2 mg/kg (p/o) doses.
Our attempts to treat schizophrenic patients in the
period of transition from acute psychosis to remission
with non-selective 5-HT6 receptor antagonist dimebo
as an add-on to risperidone treatment revealed that
Male adult BALB/c mice (24–25 g) were used in the
dimebon has a positive impact on negative symptoms
experiments. On every day of testing, mice were treated
and some aspects of cognitive functioning.
intraperitoneally with (a) scopolamine (1.5 mg/kg) or
The data mentioned above underpin our objective in
(b) scopolamine (1.5 mg/kg) combined with tacrine
the present study to evaluate the effects of a highly
(3 mg/kg), donepezil (3 mg/kg), or AVN-211 (0.05, 0.2,
selective 5-HT6 receptor antagonist on residual symp-
or 1 mg/kg). Scopolamine was administered 30 min
toms and attention in patients with schizophrenia.
before training, tacrine and donepezil were adminis-
tered 60 min before training, and AVN-211 was
administered 5 min before training. The control group
animals were injected with physiological solution.
The study, entitled ‘‘Double Blind Placebo-Controlled
The Morris water maze test AVN-211 (CD-008-0173)
Pilot Phase IIa Study of Efficacy and Safety of Orally
(0.05 and 0.2 mg/kg p.o) revealed a pronounced anti-
Administered AVN-211 (CD-008-0173) in Stable Patients
amnestic effect comparable to that of acetylcholinesterase
with Schizophrenia Receiving Stable Antipsychotic
inhibitor donepezil (trade name Aricept).
Treatment,’ was conducted in 2010 in outpatient male
subjects diagnosed with schizophrenia under Diagnostic
and Statistical Manual of Mental Disorders, 4th Edition
(DSM-IV) criteria. All patients provided signed a written
Male BALB/c mice weighing approximately 25 g were
informed consent form. Clinical study approval was
used in the experiment. Mice were treated with either
obtained from the Ministry of Health of the Russian
placebo, buspirone (5 mg/kg, i.p. 30 min before the
training), lorazepam (0.05 mg/kg, i.p. 60 min before the
AVN-211 (CD-008-0173) is a small molecule,
training), fenobam (5 mg/kg, 60 min before the training),
3-sulfonyl-pyrazolo[1,5-a]pyrimidine (number of inter-
rufinamide (15 mg/kg, 60 min before the training), or
national publication WO 2009/093206 A2), MW 5 333.44,
AVN-211 (0.05, 0.2, or 1 mg/kg, i.p. 5 min before the
serotonin receptor antagonist with specifically high
training). Buspirone and lorazepam were administered
activity in respect to 5-HT6 and 5-HT2b (Ki 5 2.1 nM
at the maximum dose; sedative side-effects were not
and Ki 5 125 nM, respectively) AVN 211 (CD-008-0173).
seen at this dose, ie, there was no decrease in general
Bioavailability of the compound is 24%, and protein
Selective antagonist of 5HT6 receptors in schizophrenia
Buspirone, lorazepam, fenobam, rufinamide, and
stable antipsychotic treatment (basic therapy). The basic
AVN-211 (CD-008-0173) (0.05 and 0.2 mg/kg) pro-
therapy included mostly risperidone, quetiapine, halo-
duced a clear anxiolytic effect in the elevated plus
peridol, or zuclopenthixol; in a few cases, the patients’
maze test. They significantly increased the number of
current therapy included paliperidone, olanzapine,
visits to the open arms of the maze, time spent in the
sulpiride, flupentixol, chlorpromazine, trifluoperazine,
open arms, and decreased the number of defecations.
perphenazine, levomepromazine, or chlorprothixene.
AVN-211 (CD-008-0173), lorazepam, buspirone, feno-
Key inclusion criteria included willingness to give
bam, and rufinamide did not affect locomotor activity,
written informed consent, age between 18 and 60, male
thus their anxiolytic activity does not produce a sedative
sex, initial diagnosis of schizophrenia according to
effect. The most prominent anxiolytic effect was observed
DSM-IV, Positive and Negative Syndrome Scale
in the case of AVN-211 (CD-008-0173) injected i.p. in
(PANSS) remission criteria (fewer than 80 points
the doses of 0.01–0.2 mg/kg, lorazepam injected i.p. at
overall, 3 or fewer points in 2, 3, 4, and 6 positive
the dose of 0.05 mg/kg, and fenobam injected i.p. in the
subscale symptoms), stable antipsychotic treatment
(constant therapy with one antipsychotic drug without
changing the dose during the last 2 months or more),
and pronounced disorders of selective attention. The
study included patients with attention test results that
AVN-211 (CD-008-0173) was also tested for antipsychotic
were lower than the lower limit of normal level of
effect in the acoustic startle reflex. Naive male SHK,
performance. Six patients were excluded after the
weighing 24–30 g, were used. All experiments were
screening due to failure to fulfill this requirement.
conducted in the light phase of a dark/light cycle.
Positive and Negative Syndrome cale (PANSS),
Apomorphine and haloperidol were obtained from
Clinical Global Impression–Severity (CGI-S),Clinical
Sigma Chemicals (St. Louis, MO, USA). Haloperidol
Global Impression–Improvement (CGI-I),Negative
was administered 60 min prior to the testing (volume of
injection was 10 mL/kg). Apomorphine was adminis-
Depression Rating Scale (CDRS)were used as tools to
tered s.c. 20 min before the testing (volume of injection
study the possible influence of AVN-211 (CD-008-0173).
was 1 mL/kg.). AVN-211 was administered i.p. 5 min
A battery of 5 attention tests was chosen for the
before the testing (volume of injection was 10 mL/kg).
evaluation of attention and its properties (switching,
The results demonstrated about 53% prepulse inhibi-
volume, concentration, productivity, stability, resis-
tion in the placebo group. The propsychotic agent
tance, fatigue, selectivity, and errors of attention).
apomorphine reduced this variable, which showed a
Other considerations our choice of tests were the
deterioration of the ability for filtration of sensory
duration of testing (16–23 min) and the possibility of
signals. Haloperidol (1 mg/kg) and AVN-211 (CD-008-
obtaining quantitative results for statistical evaluation.
0173) (0.05 and 0.2 mg/kg) prevented the disruptive
Clinical assessment and psychological testing were
effect of apomorphine on the startle prepulse inhibition.
performed by qualified and certified clinicians and
AVN-211 (CD-008-0173) was studied in Phase I and
clinical psychologists, respectively, whose inter-rater
Phase Ib in 2–8 mg doses. Both studies demonstrated
reliability was previously established. One patient dealt
that AVN-211 (CD-008-0173) was well tolerated, and
with the same clinician and the same psychologist
had a long half-life exceeding 24 hrs. Steady-state
plasma concentration was achieved on day 3 of q.d.
The mean age of participants at baseline was
administration and equaled 13–18 ng/mL. AVN-211
36.16 ± 10.4 years (see In the group receiving
(CD-008-0173) metabolism leads to the formation of
the study drug, the mean age was 34.93 ± 9.98 years
2 metabolites: M1, which is a reversible metabolite and
(with a range of 23–52 years), while in the placebo
can serve as an AVN-211 (CD-008-0173) plasma depot,
group the mean age was 37.1 ± 1.8 years (with a range
and M2 metabolite, which is 3 orders of magnitude less
of 19–59 years). The mean age of onset of the disease
was 20.2 ± 8.84 years. In the AVN-211 (CD-008-0173)
Twenty-one patients were randomized into the
group, this was 21 ± 10.36, while in the placebo group
study drug group, and 26 were randomized in the
the mean age of onset was 19.62 ± 7.56. Statistically
control group. Randomization was performed with the
significant differences were observed in neither the
help of randomization tables by the specially assigned
independent person, who did not participate in other
After the patients signed the informed consent form,
study procedures. It was a double-blind, placebo-
they were subjected to the screening procedures and
then randomized into either the AVN-211 (CD-008-0173)
AVN-211 (CD-008-0173) (4 mg) or placebo were
group or the placebo group. Patients received 4 mg of
administered orally q.d. as comedication to the patients’
AVN-211 (CD-008-0173) or placebo q.d. in the morning
Table 1. Tests used in the study and evaluated parameters
Total time in sec (shifting)Total errorStability attentionFatigabilityLearning to be attentive
Total false responsesReaction time, msec (correct responses)
during a period of 28 days, in addition to their stable
2 due to emerging side effects. In the placebo group,
antipsychotic monotherapy. The patients had their final
only 1 patient decided to drop out. The mean PANSS
visit to the hospital 7 days after the completion of drug
score at the beginning of the study in the study drug
group was 62.53 ± 9.05, and in the placebo group was
64.08 ± 7.80; this proves that this was a stable patient
population. The indices of clinical assessment are
At the beginning of the trial, there was no difference
The only difference between the groups at endpoint
between the groups either in terms of clinical or
was registered on the PANSS positive subscale score
cognitive test indices. Seventeen patients from the
(p 5 0.058, effect size d 5 0.57). Intragroup analysis
study drug group (80.95%) and 25 patients from the
showed that, in the study drug group, there was a
placebo group (96.15%) completed the study. Four
difference between the baseline and the endpoint both
patients from the study drug group prematurely
in the positive and the negative subscale PANSS scores
discontinued the trial. The reasons for discontinuation
and in CGI-S score, though in the placebo group the
were as follows: 2 patients due to patient decision and
difference was observed only in the negative subscale
Selective antagonist of 5HT6 receptors in schizophrenia
Table 3. Results of attention measurements
PANSS score The CDRS scores significantly
in Subtest VIII of WAIS. The magnitude of standard
changed only in the placebo group, though positive
score changes was 31.27% ± 26.77% in the AVN-211
(CD-008-0173) group and 12.72% ± 17.24% in the
Analysis of the individual PANSS scores at endpoint
revealed a difference in the delusion score in favor of
We found that there was no difference between
the study drug group (p 5 0.02). The changes in
the groups depending on the type of primary pharma-
the delusion score from baseline to endpoint in this
cotherapy (typical or atypical antipsychotics) with respect
group reached the level of tendency (p 5 0.062), and
to clinical symptoms (though there was a difference in
in the placebo group no changes were observed
the results of cognitive tests). By the end of the study, this
(p 5 0.78). Intragroup analysis showed a difference in
difference remained for most cognitive tasks in the
the set of symptoms that demonstrated changes in
placebo group, but not in the experimental group.
severity. In the study drug group, significant changes
There was no difference in the total PANSS score
were observed with regard to grandiosity (p 5 0.03),
between patients who took typical antipsychotics and
blunted affect (p 5 0.04), difficulty in abstract thinking
those who took atypical ones, either at the beginning
(p 5 0.0039), stereotyped thinking (p 5 0.01). In the
or at the end of the study, nor was there a difference
placebo group, significant changes were observed
between the AVN-211 (CD-008-0173) group and the
with regard to suspiciousness (p 5 0.03), emotional
placebo group, or within study groups.
withdrawal (p 5 0.007), anxiety (p 5 0.03), and poor
At the beginning of the study those patients
who were given atypical therapy (in both groups)
Passive/apathetic social withdrawal significantly
demonstrated better results in Digit Symbol Coding
decreased in both groups (study drug group:
(p 5 0.01), total time (p 5 0.01185) and ‘‘learning to be
p 5 0.027; placebo group: p 5 0.0027).
attentive’’ (0.03469) in Schulte tables, correct responses’
The cognitive indices that showed significant
mean reaction time (p 5 0.00409) and the number of
correct responses (p 5 0.00806) in Continues Attention
It is notable that the Digit Symbol Coding scores in the
Task (CAT), attention productivity in the Bourdohn
placebo group worsened, while no change was observed
test (p 5 0.01287) in the beginning of the study. At the
in the AVN-211 (CD-008-0173) group. Selectivity of
end of the study, these differences were intact in the
attention and continuous attention improved in the
placebo group but were leveled in the AVN-211 (CD-
AVN-211 (CD-008-0173) group (effect size d 5 0.21), and
008-0173) group in Digit Symbol Coding, total time and
showed no change in the placebo group.
‘ learning to be attentive’ in the Schulte tables, and
In analyzing the magnitude of changes in both
attention productivity in the Bourdohn test. Differences
groups (differences of cognitive parameter between
in the number of correct responses in CAT disappeared
baseline and endpoint visits), we find that the
in both study groups. The number of incorrect responses
experimental group showed better results (p 5 0.02)
in CAT did not differ at the beginning of the study, but
the patients in the placebo group who took typical
even in spite of the relatively small number of patients,
antipsychotics gave a significantly greater number of
we registered significant intragroup changes in respect
to selectivity and maintenance of attention. We consider
The patients who underwent typical antipsychotic
the difference between the groups in the scale of
therapy with the add-on of AVN-211 (CD-008-0173)
improvement in the results of the Subtest VIII of WAIS
revealed more evident positive changes than those
(‘‘Missing details’’) to be important. We think that this
receiving combination of typical antipsychotics and
test is one of the most relevant in the case of the typical
placebo in the following parameters: PANSS positive
for schizophrenia disorder regarding selectivity of
subscale (p 5 0.004), PANSS negative subscale (p 5 0.03),
attention, considering the context of the task.
and Subtest VIII of WAIS score (p 5 0.03). There was no
In the context of the current discussion on the
difference in the changes of clinical or cognitive para-
similarity or difference in effects of typical and atypical
meters between the study groups for patients receiving
antipsychotics, of special interest is the difference in
atypical antipsychotics as primary pharmacotherapy.
the results of attention tests depending on the form of
basic treatment. At baseline, the patients receiving the
typical antipsychotic treatment performed worse than
the patients receiving atypical antipsychotic treatment.
The 5-HT6 receptor appears to be a prospective
Adding the 5HT6R inhibitor graded the difference,
pharmacological target for treatment of different CNS
possibly due to the optimization of the efficacy of
diseases. More and more experimental and clinical
studies have examined the effects of 5HT6 agonists
and antagonists in neurodegenerative diseases, depres-
The data that we presented here can be regarded as
The main goal of the present study was to reveal the
additional proof in favor of the hypothesis that 5-HT6
additional clinical effects of the selective 5HT6 AVN-211
receptors play a role in the pathogenesis of psychotic
(CD-008-0173) in patients with schizophrenia who were
disorders and elements of cognitive dysfunction.
stabilized on the antipsychotic medication. The results
We suggest that the dysfunction of 5-HT6 receptors
showed that AVN-211 (CD-008-0173) improved a signi-
plays a role in the pathogenesis of both psychopatho-
ficant aspect of functioning of this group of schizophrenia
logical manifestation and some aspects of cognitive
patients regarding residual psychotic symptoms. The
dysfunction in schizophrenia. Though we did not get
most important changes were decrease in the severity of
robust data on the effects of the compound AVN-211
the residual delusions accompanied by a decrease in
(CD-008-173) with strong 5HT6 antagonist activity, new
overall severity of the disease (no changes in CGI-S score
trials in more selective groups of patients, for example,
in the placebo group and significant changes in the study
patients with acute psychotic symptoms and patients
drug group). Similar data were obtained in the study
with residual delusions, are advisable. A wider range of
which showed that the combined treatment of clozapine
dosages would be important to test as well.
and aripiprazole had advantages over the monotherapy
In relation to cognitive dysfunction, this study aimed
to assess the impact of the study drug (AVN-211)
The present study is a pilot one and has many
attention in schizophrenia patients. This aspect of
limitations. We examined a clinically mixed group of
cognitive dysfunction was chosen for two reasons:
patients, since they were chosen according to the
First, attention was considered to be the only cognitive
criterion of stability of condition but not the criterion
target for antipsychotic treatment, and second, atten-
of predominance of residual positive or negative
tion is the most basic cognitive function. Some authors
symptoms. The randomization system was organized
consider that one of the aspects of attention, vigilance,
in such a way that more patients were in the placebo
should be tested before all other more complicated
group than in the treatment group, so the treatment
group appeared to be small. The basic treatment varied
Our attempt to homogenize the group by the level of
depending on the patient. Also, we examined only one
attention dysfunction and gender was not fully
aspect of cognitive dysfunction, that of attention.
successful, as the individual variability of indices
regarding the cognitive tests was still very large.
Therefore, it was clear that we needed many more
patients to obtain reliable evidence that our pharmaco-
The authors do not have an affiliation with or financial
logical agent really has an effect on patients’ cognition.
interest in any organization that might pose a conflict
More significant seem to be the results of CAT, where,
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DARTFORD, GRAVESHAM & SWANLEY MIND EQUALITY & DIVERSITY POLICY Introduction This Policy combines the aspirations and detail of previous DGS Mind Documents entitled “Equal Opportunities Policy”, “Equal Opportunities Guidelines” and “Anti-Discrimination Policy” which are now superseded. Statement of Intent 1. Dartford, Gravesham & Swanley Mind is committe
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