Cluster analysis of clinical data to identify subtypes within a study population following treatment with a new pentapeptide antidepressant

Feighner, John P.; Sverdlov, Lev; Nicolau, G.; Noble, John F.

doi:10.1017/s1461145700002017

Cited by 14 publications

(5 citation statements)

References 8 publications

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“…The first study clustered MDD subjects based on improvement after treatment (at 7-and 14-day follow-up) with netamiftide (a synthetic pentapeptide antidepressant) and subsequently measured platelet 5-hydroxytryptamine (5-HT) uptake levels [65]. This study found four subgroups with increasing levels of symptom improvement.…”

Section: Medication Responsementioning

confidence: 99%

Data-driven biological subtypes of depression: systematic review of biological approaches to depression subtyping

et al. 2019

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Research into major depressive disorder (MDD) is complicated by population heterogeneity, which has motivated the search for more homogeneous subtypes through data-driven computational methods to identify patterns in data. In addition, data on biological differences could play an important role in identifying clinically useful subtypes. This systematic review aimed to summarize evidence for biological subtypes of MDD from data-driven studies. We undertook a systematic literature search of PubMed, PsycINFO, and Embase (December 2018). We included studies that identified (1) data-driven subtypes of MDD based on biological variables, or (2) data-driven subtypes based on clinical features (e.g., symptom patterns) and validated these with biological variables post-hoc. Twenty-nine publications including 24 separate analyses in 20 unique samples were identified, including a total of ~4000 subjects. Five out of six biochemical studies indicated that there might be depression subtypes with and without disturbed neurotransmitter levels, and one indicated there might be an inflammatory subtype. Seven symptom-based studies identified subtypes, which were mainly determined by severity and by weight gain vs. loss. Two studies compared subtypes based on medication response. These symptom-based subtypes were associated with differences in biomarker profiles and functional connectivity, but results have not sufficiently been replicated. Four out of five neuroimaging studies found evidence for groups with structural and connectivity differences, but results were inconsistent. The single genetic study found a subtype with a distinct pattern of SNPs, but this subtype has not been replicated in an independent test sample. One study combining all aforementioned types of data discovered a subtypes with different levels of functional connectivity, childhood abuse, and treatment response, but the sample size was small. Although the reviewed work provides many leads for future research, the methodological differences across studies and lack of replication preclude definitive conclusions about the existence of clinically useful and generalizable biological subtypes.

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Section: Medication Responsementioning

confidence: 99%

Data-driven biological subtypes of depression: systematic review of biological approaches to depression subtyping

et al. 2019

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“…The lack of adverse events in these studies (data on file) allowed the administration of similar doses in the first two efficacy studies reported separately [2][3][4][5].…”

Section: Methodsmentioning

confidence: 99%

“…Nemifitide is the lead compound in a series of highly potent small-chain peptides synthesized at Innapharma [1]. In two previously conducted pilot phase 2 double-blind, placebo-controlled trials [2][3][4][5] nemifitide was administered subcutaneously for 5 or 10 days to patients diagnosed with major depression. The doses administered in these studies were similar: 18 mg/patient and 0.2 mg/kg, respectively.…”

Section: Introductionmentioning

confidence: 99%

Clinical pharmacokinetic studies with INN 00835 (Nemifitide), a novel pentapeptide antidepressant

Feighner

Nicolau

Abajian

et al. 2002

Biopharm & Drug Disp

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Nemifitide (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginylglycyl-L-tryptophanamide ditrifluoroacetate) is a novel antidepressant, currently in phase 2/3 clinical trials. The purpose of our phase 1 clinical trials (conducted over a three year period) was to provide safety and pharmacokinetic data to support its clinical development as an antidepressant drug. Single and multiple doses ranging from 18 to 320 mg were administered subcutaneously to healthy volunteers in five phase 1 studies. Plasma concentrations of unchanged parent drug were determined by a validated LC/MS/MS method in blood samples collected at timepoints between 10 min and 72 h after dosing. Nemifitide was rapidly absorbed (C(max) at 10 min) and eliminated (t(1/2) 15-30 min) in most subjects. Regression and power model analyses were used to evaluate the data. The results indicate that pharmacokinetic parameters: AUC(0-t), AUC (0-infinity) and C(max), were close to dose proportional in the dose range investigated. There was no evidence of systemic accumulation of drug following 5 daily doses. No serious adverse events or clinically significant systemic adverse events occurred at any of the doses investigated in the over 100 subjects dosed in these studies. Drug-related adverse events were limited to local and transient skin reactions (pain and/or erythema) at the injection site, especially at the high doses administered: 240 and 320 mg.

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“…INN 00835 (netamiftide) is a novel pentapeptide from a new platform of small chain putative peptide antidepressant agents [124][125][126][127]. Its mechanism of action is unclear, but it may involve serotonergic and dopaminergic pathways, as well as peptide receptors.…”

Section: Inn 00835mentioning

confidence: 99%

Monoamine and neuropeptide-related function: prospects for novel therapeutics of depression

Sporn¹,

Charney²

2002

Expert Review of Neurotherapeutics

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Treatment of depression has been dominated by monoamine hypotheses for nearly half a century. Although the ultimate downstream targets of manipulation of biogenic amine transport and metabolism are signal transduction cascades, neurotrophic factors and ultimately genomic fine-tuning, much of drug development has remained focused on strategies to facilitate a rapid initial augmentation of synaptic neurotransmitter levels. Both monoaminergic agents that are highly specific in their target receptor stimulation and agents that modify multiple monoamine systems will move through the stages of drug development in coming years. Furthermore, recent landmark successes and initial pilot data indicates that small molecule peptide receptor antagonists for substance P, corticotrophin releasing factor and eventually others will be of increasing importance, since they may more subtlety modulate neurotransmission and only act on already deranged neural circuits. Eventually treatment strategies may begin to target intracellular kinase and phosphatase activity and other signal systems responsible for transporter and receptor trafficking patterns, as well as via more direct pathways toward mobilization of neurotrophic factor activity. In the near future however, refinement of monoamine strategies to treat depression will continue to guide thinking and development of novel drugs for depression. This review focuses primarily on developments relevant for the evolution of monaminergic and neuropeptide-based drugs for depression.

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Cluster analysis of clinical data to identify subtypes within a study population following treatment with a new pentapeptide antidepressant

Cited by 14 publications

References 8 publications

Data-driven biological subtypes of depression: systematic review of biological approaches to depression subtyping

Data-driven biological subtypes of depression: systematic review of biological approaches to depression subtyping

Clinical pharmacokinetic studies with INN 00835 (Nemifitide), a novel pentapeptide antidepressant

Monoamine and neuropeptide-related function: prospects for novel therapeutics of depression

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