Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies.

BACKGROUND: Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. OBJECTIVE: The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). METHODS: A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. RESULTS: Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. CONCLUSION: Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies. CLINICAL TRIAL REGISTRATION: TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Validation of the Waterless Empirical Taste Test (WETT®).

The sense of taste is rarely assessed quantitatively outside of a limited number of academic and industrial laboratories, despite its role in influencing nutrition, the flavor of foods and beverages, and protection against ingestion of spoiled and toxic foodstuffs. This dearth reflects, in part, practical limitations of most taste tests, most notably their reliance on liquid stimuli for stimulus presentation or rinsing. In this study, a novel portable taste test that requires neither liquid tastants nor liquid rinses is described and validated within a clinic population. This test, termed the Waterless Empirical Taste Test (WETT®), uses stimuli that are embedded in pads of monometer cellulose located on disposable plastic strips applied to the tongue's surface. The test-retest and split-half reliability coefficients of the WETT® were 0.92 and 0.88, respectively. These respective coefficients for sucrose, NaCl, citric acid, caffeine, and MSG were 0.82 and 0.80, 0.78 and 0.77, 0.56 and 0.73, and 0.84 and 0.84. The WETT® exhibited comparable, in some cases higher, sensitivity than two comparison taste tests, the Whole Mouth Taste Test and the Taste Quadrant Taste Test, to age, sex, etiology (head trauma vs. upper respiratory infections), and phenylthiocarbamide (PTC) taste ability. This study demonstrates that a taste test that does not require liquids can be as reliable and sensitive as more traditional liquid-based taste tests to clinical alterations in taste function.

Clinical validation of the olfactory detection threshold module of the Snap & Sniff® olfactory test system.

BACKGROUND: Quantitative olfactory testing is essential to determine the validity and nature of a patient's complaint, accurately monitor changes in function over time (including influences of pharmacological, surgical, or immunological interventions), detect malingering, and establish disability compensation. This work describes the clinical validation of an advanced rapid odor detection threshold test that standardizes odorant delivery and eliminates unsanitary sniff bottles, the need for blindfolds, and the possibility of touching an odorant stimulus to the nose. METHODS: Snap & Sniff® single-staircase phenyl ethyl alcohol detection thresholds (S&S-Ts) were assessed bilaterally in 736 patients with chemosensory complaints; 421 received both bilateral and unilateral testing. The results were correlated with scores from the University of Pennsylvania Smell Identification Test (UPSIT) and the Smell Threshold Test (STT), a widely-used standardized threshold test. Test-retest reliability data were obtained for 50 patients. RESULTS: S&S-Ts were highly reliable (Spearman r = 0.84), correlated with the other olfactory test measures (rs > 0.65, ps < 0.0001), and required significantly shorter administration times than the STT (<10 minutes). Bilateral thresholds were systematically lower than unilateral thresholds, a phenomenon independent of presentation order but dependent upon the better functioning side of the nose. The S&S-Ts were sensitive to age and sex. No systematic left:right nasal side threshold differences were evident. CONCLUSION: The present study validates the use of Snap & Sniff® technology in the clinic setting. High test-retest reliability and brief administration times were evident. The S&S-T test allows for a reliable, valid, inexpensive, and rapid clinical means for quantitatively assessing human olfactory sensitivity.

Olfactory dysfunction and quality of life in patients with transfusion-dependent thalassemia.

Transfusion-dependent thalassemia (TDT) is a group of thalassemia syndromes that require regular blood transfusions for survival. It is unknown whether the sense of smell of patients with TDT is affected, and if so, whether smell loss has an adverse effect on quality of life (QOL). Olfactory thresholds were measured using Snap & Sniff® wands. QOL was assessed via the Short Form-36 (SF-36) questionnaire. Forty-two TDT patients from the Thalassemia Center in Istanbul Medical Faculty were tested (mean age 26.6 years), along with 42 healthy controls (mean age 28.0 years). Mean olfactory sensitivity was lower in the TDT patients than the controls (p < 0.0001). TDT was associated with lower mean QOL scores on the domains of physical function (p < 0.0001), physical role limitation (p = 0.011), and general health (p < 0.0001). Within the TDT group, significant correlations were present between the threshold scores and physical function, physical role limitation, emotional role limitation, and general health. Patients with TDT are less sensitive to odors than healthy controls and the lower olfactory test scores are related to lower quality of life, suggesting that decreased smell function is an additional complication of this disease.

The Retinoblastoma family member p107 regulates the rate of progenitor commitment to a neuronal fate.

The Retinoblastoma protein p107 regulates the neural precursor pool in both the developing and adult brain. As p107-deficient mice exhibit enhanced levels of Hes1, we questioned whether p107 regulates neural precursor self-renewal through the repression of Hes1. p107 represses transcription at the Hes1 promoter. Despite an expanded neural precursor population, p107-null mice exhibit a striking reduction in the number of cortical neurons. Hes1 deficiency rescues neurosphere numbers in p107-null embryos. We find that the loss of a single Hes1 allele in vivo restores the number of neural precursor cells at the ventricular zone. Neuronal birthdating analysis reveals a dramatic reduction in the rate of neurogenesis, demonstrating impairment in p107(-/-) progenitors to commit to a neuronal fate. The loss of a single Hes1 allele restores the number of newly generated neurons in p107-deficient brains. Together, we identify a novel function for p107 in promoting neural progenitor commitment to a neuronal fate.