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.
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