Symptomatic and Functional Response and Remission From the Open-Label Treatment-Optimization Phase of a Study With DR/ER-MPH in Children With ADHD.

Objective: Delayed-release and extended-release methylphenidate (DR/ER-MPH), the first stimulant predicted to be absorbed primarily in the colon, demonstrated significant improvements in attention-deficit/hyperactivity disorder (ADHD) symptoms and functional impairment from awakening until evening versus placebo in clinical trials. The clinical significance of these improvements was explored post hoc by examining response and remission thresholds as well as safety in the context of dose optimization.Methods: Data from the open-label, treatment-optimization phase of a phase 3 study of DR/ER-MPH in children (aged 6-12 years) with ADHD, as diagnosed by DSM-5 criteria and enrolled between July 2015 and March 2016, were analyzed. Thresholds for response (anchored to Clinical Global Impressions-Improvement scale [CGI-I] score of 1 or 2) and remission were applied to ADHD Rating Scale-IV (ADHD-RS-IV), Before School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior, Revised, Morning Subscale (PREMB-R AM) and Evening Subscale (PREMB-R PM) scores. Rates of response, remission, and treatment-emergent adverse events by starting dose were examined.Results: Mean DR/ER-MPH dose increased from 29.7 mg/d at baseline (51% on 20 mg/d; 49% on 40 mg/d) to 66.2 mg/d at week 6. At week 6, most participants achieved response/remission thresholds (response/remission: ADHD-RS-IV: 97%/89%; BSFQ: 98%/94%; PREMB-R AM: 94%/98%; PREMB-R PM: 91%/84%). More participants starting on a 40-mg versus 20-mg dose achieved thresholds at week 1 (P < .02). Weekly treatment-emergent adverse event rates over the open-label period were similar between starting doses.Conclusions: When DR/ER-MPH dosing was optimized for ADHD symptom control throughout the day, the majority of participants achieved thresholds indicating all-day control of ADHD symptoms and functional impairment to the level of their non-ADHD peers.Trial Registration: Data used in this post hoc analysis came from the study with ClinicalTrials.gov identifier: NCT02493777.

Remission in schizophrenia: 196-week, double-blind treatment with ziprasidone vs. haloperidol.

To compare the remission rate and its time-course over 196 wk of double-blind treatment with an atypical antipsychotic, ziprasidone (80-160 mg/d given b.i.d., or 80-120 mg/d given q.d.), or a conventional antipsychotic, haloperidol (5-20 mg/d). Outcome assessments included attainment of remission (Andreasen criteria) by longitudinal analysis. Positive and Negative Syndrome Scale (PANSS) scores, Global Assessment of Functioning Scale (GAF) scores, and quality-of-life (QLS) were also assessed in the initial 40-wk study phase (n=599) and the 3-yr extension study (n=186). Discontinuation rates in the initial 40-wk core and follow-up extension studies were comparable between groups: 64% and 65% for the 80-160 mg/d ziprasidone group, 65% and 58% for the 80-120 mg/d ziprasidone group, and 60% and 66% for the 5-20 mg/d haloperidol group, respectively. Mean change scores from baseline to LOCF endpoint (week 40 or early termination) for PANSS negative and GAF (primary efficacy variables) were not statistically significantly different between ziprasidone and haloperidol. During the 3-yr extension study, ziprasidone-treated subjects (80-160 mg/d) were more likely to achieve remission (51%) than haloperidol-treated (40%) subjects (p=0.04), while there was a favourable trend associated with 80-120 mg/d ziprasidone (48%). Compared to the haloperidol group, subjects assigned to the 80-160 mg/d ziprasidone group showed a gradual and persistent improvement in remission (p=0.006) and quality-of-life (p=0.004) in the longitudinal analyses. Significant differences in the trajectory of PANSS total and GAF scores favouring the 80-160 mg/d ziprasidone group were also observed. In this long-term, double-blind study, ziprasidone treatment was more likely to result in remission than haloperidol treatment, and was associated with greater improvement in quality-of-life.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study.

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders.

OBJECTIVE: While the efficacy of antipsychotic medications for the treatment of psychosis is generally established, the speed of onset of antipsychotic action remains controversial. The objective of this study was to evaluate the early response (within the first 24 h) in psychosis with ziprasidone IM treatment, and to determine whether this early effect is distinct from a reduction in agitation symptoms. METHODS: In a 24-h, double-blind study, hospitalized patients with psychotic disorder and acute agitation were randomized to treatment with fixed doses of IM ziprasidone: 2 mg (N=38) or 20 mg (N=41). Efficacy assessments were based on the PANSS positive subscale and PANSS early psychosis factor score (conceptual disorganization, hallucinatory behavior, and unusual thought content) at 4 and 24 h. RESULTS: Ziprasidone IM demonstrated a significant dose-related effect (20 mg vs. 2 mg) on both the PANSS early psychosis factor score and the PANSS positive subscale at the first post-baseline time point (4 h), and at 24 h (all p<0.05). There was a significant direct effect of ziprasidone IM on early psychosis at 24 h (p<0.05), distinct from improvement in agitation symptoms. CONCLUSIONS: These findings suggest, in addition to an early reduction in acute agitation, ziprasidone IM may be associated with a more rapid improvement in psychotic symptoms than previously reported, thus lending further support to the emergent hypothesis of early psychosis improvement in antipsychotic treatment.

Ziprasidone for the treatment of acute manic or mixed episodes associated with bipolar disorder.

Ziprasidone, a benzisothiazolyl piperazine-type atypical antipsychotic agent, has a unique receptor-binding profile. A potent antagonist of serotonin 5-HT(2A) and dopamine D(2) receptors, ziprasidone has an affinity for 5-HT(2A) receptors >10-fold higher than its affinity for D(2) receptors. Ziprasidone has been shown to be effective in the treatment of bipolar disorder in patients experiencing manic or mixed episodes. It was significantly more effective than placebo in improving manic symptoms as early as day 2 of treatment in two 3-week placebo-controlled trials as monotherapy. In a 12-week, placebo-controlled trial of patients with acute mania, ziprasidone as monotherapy showed comparable efficacy with, and fewer movement-related adverse events than, haloperidol. It has demonstrated efficacy in two 1-year open-label extension trials, both as monotherapy and in combination with lithium. Ziprasidone has a generally favourable adverse effect profile. In short-term placebo-controlled trials, there were similar discontinuation rates in active treatment and placebo recipients. While twice as many patients treated with ziprasidone compared with placebo discontinued therapy because of adverse events, the number of events was small and adverse effects were generally mild or moderate. The favourable tolerability of ziprasidone has been confirmed in long-term extension studies and its use was not associated with weight gain or dyslipidaemia. Ziprasidone-related movement disorders occurred infrequently.

Comparison of ziprasidone and aripiprazole in acutely ill patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, 4-week study.

We compared the efficacy and safety of ziprasidone and aripiprazole in the treatment of acutely ill patients with schizophrenia. Patients were randomized to receive double-blind treatment with ziprasidone (80-160 mg/day), or aripiprazole (10-30 mg/day) for up to 4 weeks. Primary efficacy measures were the Clinical Global Impression of Severity scale (CGI-S) and Brief Psychiatric Rating Scale (BPRSd) total (derived from the Positive and Negative Syndrome Scale). Noninferiority for ziprasidone (N=125) relative to aripiprazole (N=128) was established for CGI-S score (P=0.007), but was not confirmed for BPRSd total score (P=0.248). Effect sizes for within-group improvement, however, were robust for both ziprasidone and aripiprazole (effect size range 1.0-1.1 for CGI-S; and range 1.1-1.2 for BPRSd total). A mixed model repeated measures analysis of BPRSd total score favored ziprasidone at day 4 compared with aripiprazole (P=0.04), with no significant differences between treatment groups at other visits (P=0.001 for interaction between treatment and visit). No statistically significant difference was found in CGI-S score between groups across all visits. Our findings suggest that ziprasidone and aripiprazole exhibit similar efficacy and tolerability profiles in the treatment of acute schizophrenia. Differences between the two drugs in the onset of therapeutic effect warrant further investigation.

Selective tolerance to the hypothermic and anticataleptic effects of a neurotensin analog that crosses the blood-brain barrier.

NT69L, a neurotensin analog that crosses the blood-brain barrier, reduces body temperature, reverses apomorphine-induced climbing, haloperidol-induced catalepsy, and D-amphetamine- and cocaine-induced locomotor activity in rats. In this study we tested the development of tolerance to these effects of NT69L in rats. The blockade of apomorphine-induced climbing behavior and D-amphetamine- and cocaine-induced hyperactivity seen after a single acute injection did not show significant change with repeated daily injections of NT69L. Thus, for example, NT69L after five daily injections at a fixed dosage was as effective at reversing cocaine-induced hyperactivity as after the first injection. On the other hand, repeated daily injections of NT69L resulted in a diminished hypothermic response and a diminished anticataleptic effect against haloperidol. The effect of NT69L on blood glucose, cortisol, and thyroxine (T(4)) were all back to control levels after five daily injections. Thus, tolerance developed to NT69L after the first injection, when it was tested for causing hypothermia, blockade of haloperidol-induced catalepsy, and change in blood glucose, cortisol and T(4) levels. Since tolerance did not develop to the effects of drugs acting as direct (apomorphine) or indirect (D-amphetamine and cocaine) agonists at dopamine receptors over the course of 5 days, these findings suggest a selective role of neurotensin in the modulation of dopamine neurotransmission. Furthermore, due to the lack of development of tolerance, NT69L or similar analogs might be useful in modulating certain behavioral effects of psychostimulants or have potential use as an antipsychotic drug in humans.

Neurotensin analogs indications for use as potential antipsychotic compounds.

This review will be an update, focusing on the central nervous system (CNS) roles of the neurotransmitter, neurotensin. We will provide a summary of current knowledge about neurotensin, why it is an important peptide to study, and where the field is heading. Special emphasis is placed on the development of neurotensin analogs, which has been a major effort of our group, the potential role of neurotensin in Parkinson's disease, and the interaction of neurotensin with other neurotransmitters as evidenced by microdialysis studies.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study.

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or= 80, and CGI-S score >or= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Long-term safety and efficacy of ziprasidone in subpopulations of patients with bipolar mania.

OBJECTIVE: To evaluate long-term safety and efficacy of ziprasidone. METHOD: Subjects completing a 21-day placebo-controlled trial of ziprasidone in DSM-IV acute bipolar mania (N = 65) were enrolled in a 52-week open-label extension of flexibly dosed ziprasidone 40 to 160 mg/day, administered b.i.d. Three subjects had missing evaluations (N = 62) but still provided demographic data. Subpopulations with manic (N = 43) or mixed (N = 19) episodes, and with (N = 37) or without (N = 25) psychotic symptoms, were identified. Safety evaluations included adverse event monitoring, electrocardiography, and standard laboratory assessments. Efficacy measures included change from initial study baseline in Mania Rating Scale (MRS) and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores, as well as MRS responder rates (> or = 50% reduction from initial study baseline). The study was conducted from March 1998 to September 1999. RESULTS: Almost all adverse events (98%) were mild to moderate in severity. The mean +/- SD reduction in MRS score at week 55 (last observation carried forward [LOCF]) was -23.5 +/- 1.5 (p <.0001) from a baseline of 29.4. CGI-S score decreased by 2.32 +/- 0.25 at week 55 (LOCF, p <.0001) from a baseline of 5.0. MRS and CGI-S reductions were comparable across the subpopulations. The overall MRS responder rate was 86%; subpopulation responder rates were 88% (manic), 79% (mixed), 84% (psychotic), and 88% (nonpsychotic). Long-term improvement within subpopulations was comparable to the overall study population. CONCLUSION: Sustained and comparable improvements in symptoms were seen with up to 55 weeks of ziprasidone treatment for patients initially treated for bipolar mania, regardless of whether the baseline episode was manic or mixed or involved psychotic symptoms.