Phillip Branch Chappell

Ziprasidone treatment of children and adolescents with Tourette's syndrome : A pilot study

OBJECTIVE To evaluate the efficacy and tolerability of ziprasidone in children and adolescents with Tourettes syndrome and chronic tic disorders. METHOD Twenty-eight patients aged 7 to 17 years were randomly assigned to ziprasidone or placebo for 56 days. Ziprasidone was initiated at a dose of 5 mg/day and flexibly titrated to a maximum of 40 mg/day. RESULTS Ziprasidone was significantly more effective than placebo in reducing the Global Severity (p = .016) and Total Tic (p = .008) scores on the Yale Global Tic Severity Scale. Compared with placebo, ziprasidone significantly reduced tic frequencies as determined by blind videotape tic counts (p = .039). The mean (+/- SD) daily dose of ziprasidone during the last 4 weeks of the trial was 28.2 +/- 9.6 mg. Mild transient somnolence was the most common adverse event. No clinically significant effects were observed on specific ratings of extrapyramidal symptoms, akathisia, or tardive dyskinesia. CONCLUSIONS In this limited sample, ziprasidone (5-40 mg/day) appears to be effective and well tolerated in the treatment of Tourettes syndrome. Ziprasidone may be associated with a lower risk of extrapyramidal side effects in children. However, additional studies are necessary to evaluate more fully its safety and efficacy in children with tic disorders.

Impaired prepulse inhibition of acoustic startle in schizophrenia

BACKGROUND Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. METHODS PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. RESULTS Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. CONCLUSIONS These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.

Clinical and Sensorimotor Gating Effects of Ketamine in Normals

The clinical similarities between PCP psychosis and schizophrenia have contributed importantly to the development of the glutamate hypothesis of schizophrenia. Sensory gating, as measured by prepulse inhibition of the acoustic startle reflex (PPI), is impaired in patients with schizophrenia. In animals, the noncompetitive NMDA antagonists PCP and ketamine disrupt PPI in a way that resembles the defect seen in schizophrenia. The purpose of this work is to investigate the modulation of sensory gating in humans by subanaesthetic doses of ketamine. 16 healthy male subjects received a 60-min infusion of ketamine (0.5 mg/kg) or normal saline on two separate days in a randomized double-blind crossover design. Clinical ratings and PPI were done during the infusion on both days. Ketamine produced robust clinical effects. Dissociative symptoms as measured by the CADSS increased from 0 ± 0.0 to 29.3 ± 14.3; negative symptoms (Affect Rating Scale) increased from 17.2 ± 0.8 to 24.8 ± 3.1; and total BPRS scores increased from 18.3 ± 0.8 to 26.4 ± 5.1. ANOVAs for these ratings were all significant at the p < .000 level, although BPRS increases were not in the range seen in decompensated schizophrenic patients. The amplitudes of the startle responses to pulse-alone stimuli were not significantly different on ketamine and placebo days. Ketamine did not cause disruption in PPI as expected. On the contrary, in the first block of the PPI session ketamine significantly enhanced PPI (ANOVA; F=6.15, p = .026). These results indicate that the clinical effects of ketamine are not coupled with schizophrenic-like disruption of PPI in normal controls.

Voice Acoustical Measurement of the Severity of Major Depression.

A number of empirical studies have documented the relationship between quantifiable and objective acoustical measures of voice and speech, and clinical subjective ratings of severity of Major Depression. To further explore this relationship, speech samples were extracted from videotape recordings of structured interviews made during the administration of the 17-item Hamilton Depression Rating Scale (HDRS; ). Pilot data were obtained from seven subjects (five males, two females) from videotapes that have been used to train expert raters on the administration and scoring of the HDRS. Several speech samples were isolated for each subject and processed to obtain the acoustic measurements. Acoustic measures were selected on the basis that they were correlated with HDRS ratings of symptom severity as seen under ideal voice recording conditions in previous studies. Our findings corroborate earlier reports that speaking rate is well correlated (negatively) with HDRS scores, with a strong correlation and nearly significant trend seen for the measure of pitch variability. A moderate pairwise correlation between percent pause time and HDRS score was also revealed, although this relationship was not statistically significant. The results from this cross-sectional study further demonstrate the ability of voice and speech signal analyses to objectively track severity of depression. In the present case, it is suggested that this relationship is robust enough to be found despite the less than ideal recording conditions and equipment used during the original videotape recording. Voice acoustical analyses may provide a powerful compliment to the standard clinical interview for depression. Use of such measures increases the range of techniques that are available to explore the neurobiological substrates of Major Depression, its treatment, and the dynamic interplay of the systems that govern the motor, cognitive, and emotional aspects of speech production.

Patterns of response to acute naloxone infusion in Tourette's syndrome.

The purpose of this study was to replicate findings from an earlier pilot study in which we found a dose‐related effect of the opioid antagonist naloxone on tic behavior in patients with Tourettes syndrome (TS). Fifteen subjects with TS were challenged with randomized doses (30 and 300 μg/kg) of naloxone at 3‐day intervals. Videotaped recordings of tic behavior were counted in a “blind” fashion. We found that naloxone had opposite effects on tics at different dosages. The low dose caused a significant decrease in tics, whereas the high dose caused a significant increase in tics. Therefore, activity at opioid receptors appears to influence the expression of TS, and the difference in response to naloxone in TS subjects may be based on a dose‐response effect.

Switching from Quetiapine to Ziprasidone: A Sixteen-week, Open-label, Multicenter Study Evaluating the Effectiveness and Safety of Ziprasidone in Outpatient Subjects with Schizophrenia or Schizoaffective Disorder

Objective The objectives of this study were to evaluate the effects of switching from quetiapine to ziprasidone on weight, safety, and effectiveness Methods In this study, 241 subjects with schizophrenia or schizo affective disorder who had been treated with quetiapine (≥300 mg/day) for ≥3 months with either suboptimal efficacy or poor tolerability were enrolled in a 16-week, open-label, flexible-dose trial, with a 16-week follow-up (total 32 weeks). Quetiapine was tapered and discontinued over the course of 2 weeks, while ziprasidone was titrated up and dosed at 40–80 mg b.i.d. The primary endpoint was weight change (kg) from baseline at 16 weeks. Secondary endpoints were change in waist/hip circumference, lipid profile, fasting glucose, and glycosylated hemoglobin (HbA1c). Additional secondary endpoints included changes in scores on the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impres sions Improvement and Severity Scales (CGI-I and CGI-S), the Calgary Depression Scale for Schizophrenia (CDSS), the Schizophrenia Cognition Rating Scale (ScoRS), and the Global Assessment of Functioning (GAF). Safety measures included adverse event (AE) reporting and administration of the Abnormal Involuntary Movement Scale (AIMS). Results At week 16, there was a small but statistically significant decrease in weight, with a mean change from baseline of −0.73 kg (1–sided 95% upper confidence bound=−0.33) using the last observation carried forward [LOCF] approach. There were small mean decreases in levels of total cholesterol, low density lipoprotein (LDL), and triglycerides at week 16, but no change in fasting glucose or HbA1c. At week 16, there were also significant changes indicating improvement in the secondary clinical assessments, including the PANSS scores, CGI-S, CDSS, SCoRS and GAF. There was no change in the AIMS. AEs included insomnia (12.4%), somnolence (13.7%), and nausea (9.1%). Conclusion Subjects switching from quetiapine to ziprasidone showed a small but significant decrease in weight as well as improved lipid profiles, regardless of their metabolic status and disease severity at baseline. Subjects also showed improvement in clinical symptoms and in cognitive functioning. Ziprasidone, with a comparatively neutral metabolic profile relative to other antipsychotics, may be an effective treatment alternative for patients experiencing weight gain or lack of tolerability with quetiapine. (Journal of Psychiatric Practice 2011;17:100–109).

Assessment of Suicidal Ideation and Behavior: Report of the International Society for CNS Clinical Trials and Methodology Consensus Meeting.

OBJECTIVE To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials. PARTICIPANTS Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17-18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting. EVIDENCE Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting. CONSENSUS PROCESS Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded. CONCLUSIONS All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions.

Suicidal ideation and behavior assessment in dementia studies: An Internet survey

The AARR task force on suicidal ideation and behavior (SI/SB) in dementia conducted an online survey on the extent of SI/SB in individuals diagnosed with mild cognitive impairment (MCI) or dementia who were participating in clinical trials.

Considerations for the assessment of suicidal ideation and behavior in older adults with cognitive decline and dementia

Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence.

Towards a Biological Understanding of ADHD and the Discovery of Novel Therapeutic Approaches

Publisher Summary Attention-Deficit/Hyperactivity Disorder (ADHD) is recognized as a priority clinical and public health concern because of its prevalence, chronicity, and associated morbidity and impairment in children, adolescents, and adults. It is one of the most common neurobehavioral disorders of childhood with worldwide prevalence rates conservatively estimated at 4–10%. It is also common in adults and in general, it affects more males than females. ADHD is one of the most extensively investigated mental health disorders of childhood and adolescence. Nonetheless, it lacks specific biomarkers and remains underspecified. Moreover, it is undergoing re-conceptualization and the emerging neuroscientific understanding of ADHD challenges current targets for treatment. This chapter provides an update on the clinical and neuroscientific perspectives on ADHD and highlights the historical and current development of pharmacological treatment approaches. It also discusses the potential utility of biomarkers in drug development and the clinical challenges in pursuing novel pharmacological approaches for ADHD, given its primacy as a pediatric disorder.