Assessing the Reliability and Validity of the Sheehan Irritability Scale in Patients With Major Depressive Disorder.

OBJECTIVE: Irritability is a significant component in the clinical manifestation of major depressive disorder (MDD). The Sheehan Irritability Scale (SIS) was developed to assess irritability-related symptoms in patients with psychiatric disorders. Data from a phase 2 clinical trial (June 2008-July 2009) was utilized to evaluate the psychometric properties of the SIS. The trial population included patients diagnosed with MDD, according to DSM-IV and confirmed via the MINI diagnostic scale, who had inadequate response to citalopram. METHOD: The secondary analyses included 586 patients from the United States and India. Data from the SIS, depression severity measures (17-item Hamilton Depression Rating Scale [HDRS-17], Montgomery-Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR]), and other measures (Sheehan Disability Scale [SDS], Clinical Global Impressions-Severity of Illness scale [CGI-S]) were used in the psychometric evaluation. All statistical tests used a significance level of .05 unless otherwise noted. RESULTS: Internal consistency (0.92-0.99) and test-retest reliability (0.83 to 0.98) were excellent. Concurrent validity was demonstrated through strong correlations between the SIS total score and HDRS-17, QIDS-SR, SDS, CGI-S, and MADRS scores. SIS total scores were significantly different by clinical severity level (P < .001). Minimally important difference estimates suggest that a 7- to 8-point change in the SIS total score may be clinically meaningful. CONCLUSIONS: The SIS has excellent reliability, acceptable validity, and good responsiveness, making the SIS appropriate for use in clinical research and practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00692445.

Content validity of the Sheehan Irritability Scale in patients with major depressive disorder.

The Sheehan Irritability Scale (SIS) measures the frequency, severity, and impairment associated with irritability in psychiatric patients. The content validity of the SIS in patients with major depressive disorder (MDD) has not been evaluated. A cross-sectional, qualitative research study was conducted to assess the content validity of the SIS among patients with MDD. One-on-one interviews were conducted, starting with open-ended questions to evaluate the consistency of the SIS content with patient experiences of irritability. Participants then completed the SIS and cognitive interviews around the comprehension of the SIS content (instructions, items, response options). Participants included 24 patients diagnosed with MDD who had an inadequate response to an antidepressant treatment. The sample was: 50.4 mean years, 66.7% female, and 91.7% white racial background. All concepts on the SIS were spontaneously mentioned by at least one participant, and when probed about the symptoms, the majority of participants (66.7-100%) reported the concepts being part of their experience. The majority of participants (70.8-100%) understood the SIS instructions, items, and response scales. This study provides evidence of content validity of the SIS in patients diagnosed with MDD, supporting the use as a measure of irritability in patients with depression.

Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia.

OBJECTIVES: This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia. METHODS: In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18-65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50 mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score. RESULTS: SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5 mg, 2-tailed P = .159; 50 mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated. CONCLUSION: These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.

A randomized double-blind study comparing 25 and 50 mg TC-1734 (AZD3480) with placebo, in older subjects with age-associated memory impairment.

Cognitive decline is a feature of ageing and can be defined as normal (age-associated memory impairment) or pathological (mild cognitive impairment/Alzheimer's disease). Stimulation of selective brain-specific neuronal nicotinic acetylcholine receptors might offer symptomatic treatment for normal ageing. The objective of this study was to assess the safety, tolerability and efficacy of TC-1734 (AZD3480), a selective α4ß2 nicotinic agonist, in the treatment of age-associated memory impairment. A randomized placebo-controlled trial was conducted in 16 community-based centers within the USA. Subjects who met objective criteria for age-associated memory impairment were recruited between November 2004 and December 2005. Subjects were randomly assigned to receive orally 25 mg (n = 59), 50 mg (n = 68) TC-1734 (AZD3480) or placebo (n = 66) in a double-blind fashion for 16 weeks. Main outcome measures included routine clinical safety measures, tolerability, cognitive assessment via the Cognitive Drug Research computerized test battery and a Subject Global Impression Scale of Cognition (SCI-Cog). Two outcomes from the computerized test battery - a factor assessing attention and one assessing episodic memory, along with the SGI-Cog were defined as co-primary outcome variables. Baseline to Week 16 differences from placebo for 50 mg TC-1734 (AZD3480) were considered of primary importance. For 50 mg TC-1734 (AZD3480) attention factor the mean drug-placebo difference was 22.9 (95% confidence interval 4.8 to 41.4) p = 0.01 for episodic memory factor the difference was -7.6 (95% confidence interval -14.4 to -0.8), p = 0.029, and for the SGI-Cog the difference was 0.99 (95% confidence interval 0.2 to 1.8), p = 0.015. As all three co-primary outcomes were positive it can be concluded the compound likely had a beneficial effect on cognition. TC-1734 (AZD3480) appeared safe and well tolerated in this study.

Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).

Cognitive decline seen in the normal elderly is associated with selective loss of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine given either by inhalation or transdermally helps cognition, but unacceptable side effects limit its utility. The present study assessed the safety, tolerability and effect on cognition of ispronicline, a highly selective partial agonist at the 4beta2 nAChR, in elderly subjects (n =76) with age associated memory impairment (AAMI). This double-blind, placebo-controlled cross-over study explored ascending oral doses of ispronicline in the range 50-150 mg given as a single morning dose for a period of 3 weeks. Pharmacokinetics (PK) were assessed, as well as cognitive function measured by means of the Cognitive Drug Research (CDR) computerized test battery. Ispronicline had a favourable safety profile and was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, haematology, urine analysis, vital signs, electrocardiogram (ECG) or Holter monitoring. The most frequent drug induced adverse event was light-headedness (dizziness). A beneficial effect was seen on cognition across the dose range. This was most marked at 50 mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5-25/35 ng/ml ispronicline was associated with the most beneficial effect. These early results demonstrate ispronicline was well tolerated and did not display the side effects typical of nicotine. Ispronicline also had a beneficial effect on cognition in subjects with AAMI. This was seen most strongly in a Cmax range that had been predicted from pre-clinical animal studies.

Cognitive enhancement in man with ispronicline, a nicotinic partial agonist.

Cholinergic mechanisms are clearly involved in memory deficits associated with Alzheimer's disease (AD) (Perry et al., 1977). Recently, there has been growing interest in the nicotinic approach to the treatment of AD; however, compounds have failed in the clinic because of a lack of separation between central and peripheral nicotinic effects (Potter et al., 1999). Ispronicline (TC-1734) is an orally active, selective, partial agonist of the central alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR), with high binding affinity to membrane preparations from rat brain or mammalian cells expressing recombinant human alpha4beta2 receptor (Gatto et al., 2004). Ispronicline has no detectable effects on muscle or ganglionic nAChRs, indicating a marked CNS over PNS selectivity. In animal models ispronicline potently improved cognitive function. A long duration of memory enhancement was displayed in object recognition and radial arm maze tests. Ispronicline pharmacokinetics (half-life of 2 h in rats) contrasts with the long-lasting improvement of working memory (18 h to 2 d) (Gatto et al., 2004).