NBI-1070770 for Depression
Recruiting in Palo Alto (17 mi)
+12 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Neurocrine Biosciences
Must be taking: Antidepressants
Disqualifiers: Pregnancy, Unstable conditions, Neurological, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?To evaluate the efficacy, safety, and tolerability of NBI-1070770 compared to placebo on improving symptoms of depression in participants with major depressive disorder (MDD).
Will I have to stop taking my current medications?
No, you will not have to stop taking your current antidepressant medications. Participants must continue with their current antidepressant medication(s) during the trial.
What makes the drug NBI-1070770 unique for treating depression?
NBI-1070770 may be unique because it potentially involves GABA modulation, which is different from traditional antidepressants that often target monoamine systems. This approach could offer new treatment options for depression, especially for those who do not respond to standard therapies.
12345Eligibility Criteria
This trial is for adults with recurrent or persistent Major Depressive Disorder (MDD) who've been on their current antidepressants for at least 8 weeks. They must be willing to continue these meds and follow all study rules.Inclusion Criteria
I've been on my current antidepressants for 8 weeks or more and can keep taking them.
Participants must be willing and able to comply with all study procedures and restrictions
My condition is recurrent or persistent major depression.
Exclusion Criteria
Participant has an alcohol or substance use disorder
Participant is pregnant or breastfeeding or plan to become pregnant during the study
I have a chronic disease or medical condition that is not stable.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive NBI-1070770 or placebo to assess efficacy, safety, and tolerability in improving symptoms of depression
8 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests NBI-1070770 against a placebo to see if it's better at improving depression symptoms in MDD patients. It measures how safe and tolerable the drug is compared to not receiving the active medication.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: NBI-1070770: Medium DoseExperimental Treatment1 Intervention
Participants will receive medium-dose NBI-1070770.
Group II: NBI-1070770: Low DoseExperimental Treatment1 Intervention
Participants will receive low-dose NBI-1070770.
Group III: NBI-1070770: High DoseExperimental Treatment1 Intervention
Participants will receive high-dose NBI-1070770.
Group IV: PlaceboPlacebo Group1 Intervention
Participants will receive matching placebo.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Neurocrine Clinical SiteDecatur, GA
Neurocrine Clinical SiteDayton, OH
Neurocrine Clinical SiteHouston, TX
Neurocrine Clinical SiteRichardson, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Neurocrine BiosciencesLead Sponsor
References
GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. [2019]Increasing evidence suggests that abnormalities in amino neurotransmission are associated with the neurobiology of depression. Preclinical studies demonstrate that GABA modulating agents are active in commonly used rodent behavioral models of antidepressant activity, and that chronic administration of antidepressant drugs induces marked changes in GABAergic function. In humans, depressed patients have lower plasma, CSF and brain GABA concentrations than non-depressed comparison subjects. The recent discovery that several anticonvulsant and GABA-mimetic agents possess mood stabilizing and antidepressant properties has further increased interest in these findings. This review outlines the existing literature investigating the possible involvement of GABA in the neurobiology of depression and briefly highlights how this information may afford new targets for antidepressant drug development.
Mutation screen of the glutamate decarboxylase-67 gene and haplotype association to unipolar depression. [2020]Abnormally low concentrations of brain gamma-aminobutyric acid (GABA) have been reported in unipolar depression. Almost all of the brain GABA is synthesized by glutamate decarboxylase (GAD) enzymes (GAD67 and GAD65). These enzymes, therefore, play a central role in brain GABA homeostasis. We screened all the 17 exons of the GAD67 gene for mutations using single strand conformation polymorphism (SSCP) or denaturing high pressure liquid chromatography (dHPLC) in a sample of 43 individuals diagnosed with major unipolar depression or other disorders with putative GABAergic dysfunction. We identified eight novel variants (five synonymous base substitutions, two insertion/deletions and one tandem repeat). Three relatively common (minor allele frequency >20%) single nucleotide polymorphisms (SNPs), located in the 5' non-coding region (exon 0), intron 8, and the 3' non-coding region (exon 16) of the gene, were genotyped in 103 European-American (EA) subjects with depression and 125 EA psychiatrically screened controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated using the 3LOCUS program. Significant LD was observed between the intron 8 SNP and the exon 16 SNP and between the exon 0 SNP and the exon 16 SNP. Three common GAD67 haplotypes were observed in this population, which accounted for >90% of the possible GAD67 three-locus haplotypes. Comparison of SNP and haplotype frequencies between individuals with depression and controls revealed no differences. These results demonstrate a significant within-gene LD for GAD67 in the EA population and begin to establish a haplotype map for this gene. Furthermore, these results suggest that common genetic variation within the GAD67 gene does not play a major role in the predisposition to unipolar depression.
NMDA Antagonists for Treatment-Resistant Depression. [2019]Fifteen to thirty percent of patients with major depressive disorder do not respond to antidepressants that target the monoaminergic systems. NMDA antagonists are currently being actively investigated as a treatment for these patients. Ketamine is the most widely studied of the compounds. A brief infusion of a low dose of this agent produces rapid improvement in depressive symptoms that lasts for several days. The improvement occurs after the agent has produced its well characterized psychotomimetic and cognitive side effects. Multiple infusions of the agent (e.g., 2-3× per week for several weeks) provide relief from depressive symptoms, but the symptoms reoccur once the treatment has been stopped. A 96-h infusion of a higher dose using add-on clonidine to mitigate the psychotomimetic effects appears to also provide relief and resulted in about 40% of the subjects still having a good response 8 weeks after the infusion. As this was a pilot study, additional work is needed to confirm and extend this finding. Nitrous oxide also has had positive results. Of the other investigational agents, CERC-301 and rapastinel remain in clinical development. When careful monitoring of neuropsychiatric symptoms has been conducted, these agents all produce similar side effects in the same dose range, indicating that NMDA receptor blockade produces both the wanted and unwanted effects. Research is still needed to determine the appropriate dose, schedule, and ways to mitigate against unwanted side effects of NMDA receptor blockade. These hurdles need to be overcome before ketamine and similar agents can be prescribed routinely to patients.
A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder. [2021]NSI-189 is a novel neurogenic compound independent of monoamine reuptake pathways. This trial evaluated oral NSI-189 as monotherapy in major depressive disorder. To improve signal detection, the sequential-parallel comparison design (SPCD) was chosen. Two hundred and twenty subjects were randomized to NSI-189 40 mg daily, 80 mg daily, or placebo for 12 weeks. The primary outcome measure was the Montogmery Asberg Depression Rating Scale (MADRS). Secondary subject-rated measures included the Symptoms of Depression Questionnaire (SDQ), the Cognitive and Physical Functioning Scale (CPFQ), the patient-rated version of the Quick Inventory of Depressive Symptomatology Scale (QIDS-SR), and subtests from the CogScreen and Cogstate cognitive tests. MADRS score reduction versus placebo did not reach significance for either dose (40 mg pooled mean difference -1.8, p = 0.22, 80 mg pooled mean difference -1.4, p = 0.34, respectively). However, the 40 mg dose showed greater overall reduction in SDQ (pooled mean difference -8.2; Cohen's d for Stages 1 and 2 = -0.11 and -0.64, p = 0.04), and CPFQ scores (pooled mean difference -1.9; Cohen's d for Stages 1 and 2 = -0.28 and -0.47, p = 0.03) versus placebo, as well as QIDS-SR scores in Stage 2 of SPCD (-2.5; Cohen's d Stages 1 and 2 = -0.03 and -0.68, p = 0.04). The 40 mg dose also showed advantages on some objective cognitive measures of the CogScreen (absolute Cohen's d ranged between 0.12 and 1.12 in favor of NSI-189, p values between 0.002 and 0.048 for those with overall significance), but not the Cogstate test. Both doses were well tolerated. These findings replicate those of phase 1b study, and warrant further exploration of the antidepressant and pro-cognitive effects of NSI-189.
Molecular pathways of major depressive disorder converge on the synapse. [2023]Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high complexity of numerous interrelated pathways as the underpinnings of depression. Major systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, the opioid system, myelination, and the gut-brain axis, among others. This review aims at illustrating how these multiple signaling pathways and systems may interact to provide a more comprehensive view of MDD's neurobiology. In particular, considering the pattern of synaptic activity as the closest physical representation of mood, emotion, and conscience we can conceptualize, each pathway or molecular system will be scrutinized for links to synaptic neurotransmission. Models of the neurobiology of MDD will be discussed as well as future actions to improve the understanding of the disease and treatment options.