Spotlight on Pimavanserin Tartrate and Its Therapeutic Potential in the Treatment of Major Depressive Disorder: The Evidence to Date

Soogrim, Vicki; Ruberto, Valerie L.; Murrough, James; Jha, Manish K.

doi:10.2147/dddt.s240862

Cited by 8 publications

(5 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The agent seemed particular useful in tackling sexual dysfunction, reducing hypersomnia, and irritability in people with depression. However, a phase III trial did not demonstrate a significant effect 85 .…”

Section: Other Agents On the Horizonmentioning

confidence: 93%

Novel and emerging treatments for major depression

et al. 2023

View full text Add to dashboard Cite

Section: Other Agents On the Horizonmentioning

confidence: 93%

Novel and emerging treatments for major depression

et al. 2023

View full text Add to dashboard Cite

“…The effect of pimavanserin exposure on CGI-I scores was explored using 1545 CGI-I score measurements collected weekly from 167 patients for a maximum of 10 weeks following randomization to study therapy. The E-R efficacy model for CGI-I scores was a proportional odds model with three additive components on the logit scale: baseline CGI-I score, placebo time-course, and drug effect, as shown in Equation (6). The placebo time course was an inhibitory E max model, including parameters estimating E max and T 50 , as shown in Equation ( 7).…”

Section: Exposure-efficacy Relationshipmentioning

confidence: 99%

“…In the phase 2 CLARITY study (NCT03018340), pimavanserin demonstrated the potential to help reduce depressive symptoms and specific adverse events associated with concomitant antidepressant treatments (ie, impaired sexual function, anxiety, and sleep/wakefulness disturbances). 6 In addition, a post hoc analysis of CLARITY on the effect of pimavanserin on anxious depression demonstrated that, among patients with anxious MDD, adjunctive pimavanserin was associated with a significant improvement in depression as measured by the Hamilton Depression Rating Scale anxiety/somatization factor (HAMD-AS). 7 However, since the phase 3 CLARITY study (NCT03968159) did not meet its primary endpoint, pimavanserin is no longer being pursued for MDD.…”

mentioning

confidence: 99%

“…In addition, pimavanserin has been evaluated as monotherapy for dementia‐related psychosis and as a potential adjunctive treatment for Alzheimer's disease psychosis with its associated treatments (ie, antidepressants, acetylcholinesterase inhibitors, or memantine), adjunctive treatment for the negative symptoms of schizophrenia with antipsychotics, and adjunctive treatment for major depressive disorder (MDD) with antidepressants (ie, selective serotonin reuptake inhibitors). In the phase 2 CLARITY study (NCT03018340), pimavanserin demonstrated the potential to help reduce depressive symptoms and specific adverse events associated with concomitant antidepressant treatments (ie, impaired sexual function, anxiety, and sleep/wakefulness disturbances) 6 . In addition, a post hoc analysis of CLARITY on the effect of pimavanserin on anxious depression demonstrated that, among patients with anxious MDD, adjunctive pimavanserin was associated with a significant improvement in depression as measured by the Hamilton Depression Rating Scale anxiety/somatization factor (HAMD‐AS) 7 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Darwish

Dirks

Passarell

et al. 2023

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

In the 10-week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD-17) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure-response (E-R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population-pharmacokinetic empirical Bayesian estimates. E-R models were developed to describe exposure-efficacy (HAMD-17, SDS, and Clinical Global Impression-Improvement [CGI-I] scale) and exposure-safety relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD-17 scores), a sigmoid maximum-effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD-17 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (C max ) increased. At median pimavanserin C max (34-mg dose), the reduction from baseline in HAMD-17 scores was −11.1 and −13.5 at weeks 5 and 10, respectively. Relative to placebo, the model predicted comparable reductions in HAMD-17 scores at weeks 5 and 10. Similar improvements in favor of pimavanserin were detected with SDS, CGI-I, MGH-SFI, and KSS scores. No E-R relationship was found for AEs. E-R modeling predicted a relationship between higher pimavanserin exposure and improvement in HAMD-17 score and improvement across multiple secondary efficacy endpoints.

show abstract

“…Fourteen serotonin (5-HT) receptors are identified with 1 ionotropic receptor (5-HT 3 R) and 13 class A G protein-coupled receptors (GPCRs) designated as 5-HT 1‑7 R based on structural and pharmacological criteria. , Serotonin 5-HT 2 receptors (5-HT 2 Rs) are a pharmacologically important 5-HT receptor family that includes the three subtypes 5-HT 2A R, 5-HT 2B R, and 5-HT 2C R, which share approximately 80% sequence homology in the transmembrane (TM) ligand-binding regions. Among them, 5-HT 2C R and 5-HT 2A R have generated immense interest from pharmacologists and medicinal chemists in recent decades. − 5-HT 2A R and 5-HT 2C R are broadly distributed in the mammalian central nervous system (CNS) and mediate various brain functions including cognition, mood, learning, and memory. ,− …”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT_2C Receptor and Dual 5-HT_2C/5-HT_2A Receptor Modulators

et al. 2023

View full text Add to dashboard Cite

The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

show abstract

Spotlight on Pimavanserin Tartrate and Its Therapeutic Potential in the Treatment of Major Depressive Disorder: The Evidence to Date

Cited by 8 publications

References 46 publications

Novel and emerging treatments for major depression

Novel and emerging treatments for major depression

Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT_2C Receptor and Dual 5-HT_2C/5-HT_2A Receptor Modulators

Contact Info

Product

Resources

About

Spotlight on Pimavanserin Tartrate and Its Therapeutic Potential in the Treatment of Major Depressive Disorder: The Evidence to Date

Cited by 8 publications

References 46 publications

Novel and emerging treatments for major depression

Novel and emerging treatments for major depression

Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators

Contact Info

Product

Resources

About

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT_2C Receptor and Dual 5-HT_2C/5-HT_2A Receptor Modulators