Assessment of human abuse potential of dasotraline compared to methylphenidate and placebo in recreational stimulant users.

AIMS: The aim of this study was to evaluate the abuse potential of dasotraline, a novel dopamine and norepinephrine reuptake inhibitor with slow absorption (tmax, 10-12h) and elimination (t1/2=47-77 h) that is in development for the treatment of attention deficit hyperactivity disorder (ADHD). METHODS: Recreational stimulant users (N=48) who had specific experience with cocaine, and who were able to distinguish methylphenidate (60 mg) versus placebo in a qualification session, were randomized, in a 6-period, double-blind, crossover design, to receive single doses of dasotraline 8 mg, 16 mg, and 36 mg, methylphenidate (MPH) 40 mg and 80 mg, and placebo. The primary endpoint was the Drug Liking Visual Analog Scale (VAS) score at the time of peak effect (Emax). RESULTS: There were no significant differences between the 3 doses of dasotraline and placebo on the drug liking VAS at Emax, and on most secondary endpoints. Both doses of MPH had significantly higher VAS-drug liking scores at Emax relative to both placebo (P<0.001 for all comparisons) and dasotraline 8 mg (P<0.001), 16 mg (P<0.001) and 36 mg (P<0.01). The increase in heart rate for MPH and dasotraline 36 mg showed a time-course that closely matched subject-rated measures such as Any Effects VAS. CONCLUSIONS: In this study, dasotraline was found to have low potential for abuse, which may be, in part, related to its established pharmacokinetics (PK) profile, which is characterized by slow absorption and gradual elimination.

Time course and biologic correlates of treatment response in first-episode schizophrenia.

OBJECTIVE: To examine the course and potential predictors of treatment response in the early phase of schizophrenia. DESIGN: Prospective study of an inception cohort. SETTING: Psychiatric division of an academic medical center with a suburban metropolitan catchment area. PATIENTS AND INTERVENTION: Seventy first-episode patients who had undergone four biologic assessment procedures (brain magnetic resonance imaging, behavioral response to methylphenidate hydrochloride, growth hormone levels, eye tracking) were treated with a standardized antipsychotic drug protocol until recovery. Response was measured in terms of psychopathology and degree of remission. RESULTS: Using survival analysis, the proportion of patients remitting by 1 year was estimated at 83%. Mean and median times to remission were 35.7 weeks and 11 weeks, respectively. No baseline demographic or psychopathologic measure significantly predicted time to or level of remission. However, males tended to be nonresponders to treatment and have diagnoses of schizophrenia rather than schizoaffective disorder. Brain pathomorphology and abnormal basal growth hormone significantly predicted time to remission. CONCLUSIONS: These results indicate that the antipsychotic treatment response of first-episode schizophrenics is better than chronic multiepisode patients and suggest that specific pathobiologic markers reflect pathophysiologic processes that mediate antipsychotic treatment response.

Plasma homovanillic acid levels in first-episode schizophrenia. Psychopathology and treatment response.

OBJECTIVES: To examine plasma homovanillic acid (pHVA) levels in first-episode schizophrenia, to compare pHVA levels in patients and controls, and to assess the association of pHVA levels with psychopathology and treatment response. METHODS: Forty-one patients entered the study, and pHVA levels were measured at baseline and on a weekly basis for up to 6 weeks of open standardized neuroleptic treatment. Psychopathology was evaluated with the Schedule for Affective Disorders and Schizophrenia, the Scale for Assessment of Negative Symptoms, and the Clinical Global Impressions scale. Ten healthy controls were used for comparison of baseline pHVA levels. RESULTS: No differences were observed between patients and controls. Baseline pHVA level was not associated with psychopathology but was associated with time to reach remission. Baseline pHVA levels and week-1 pHVA levels were higher in responders than nonresponders. Regardless of responsiveness, female participants had higher pHVA levels than male participants throughout the study. The pattern of pHVA levels with treatment was similar in all patients with a short-term rise initially and then a decrease toward baseline values. CONCLUSIONS: These findings suggest that pHVA levels have prognostic significance for response and time to reach remission. Qualitative and quantitative differences between first-episode patients' pHVA levels and studies using a long-term, neuroleptic-exposed population suggest that changes occur with neuroleptic treatment or the progression of the illness.

Efficacy of lurasidone across five symptom dimensions of schizophrenia: pooled analysis of short-term, placebo-controlled studies.

OBJECTIVE: To evaluate the efficacy of lurasidone for schizophrenia using an established five-factor model of the Positive and Negative Syndrome Scale (PANSS). METHODS: Patient-level data were pooled from five randomized, double-blind, placebo-controlled, 6-week studies of lurasidone (fixed doses, 40-160mg/d) for patients with an acute exacerbation of schizophrenia. Changes in five established PANSS factors were assessed using mixed-model repeated measures analysis. RESULTS: Compared with placebo (n=496), lurasidone (n=1029, dose groups pooled) significantly improved the PANSS total score at Week 6 (-22.6 vs. -12.8; P<0.001; effect size, 0.45), as well as all factor scores (P<0.001 for each): positive symptoms (-8.4 vs. -6.0; effect size, 0.43), negative symptoms (-5.2 vs. -3.3; effect size, 0.33), disorganized thought (-4.9 vs. -2.8; effect size, 0.42), hostility/excitement (-2.7 vs. -1.6; effect size, 0.31), and depression/anxiety (-3.2 vs. -2.3; effect size, 0.31). Separation from placebo occurred at Week 1 for the positive symptoms, disorganized thought, and hostility/excitement factors and at Week 2 for the other factors. CONCLUSIONS: In this pooled analysis of short-term studies in patients with acute schizophrenia, lurasidone demonstrated significant improvement for each of the five PANSS factor scores, indicating effectiveness across the spectrum of schizophrenia symptoms.

Relation of plasma fluphenazine levels to treatment response and extrapyramidal side effects in first-episode schizophrenic patients.

OBJECTIVE: The aim of this study was to determine the relation between plasma fluphenazine levels and clinical response in first-episode schizophrenic patients. METHOD: Data from 36 first-episode schizophrenic or schizoaffective inpatients diagnosed according to the Research Diagnostic Criteria were evaluated. The patients received open, standardized treatment with fluphenazine, 20 mg/day, for at least 4 weeks. Psychopathology was assessed biweekly, and plasma fluphenazine levels were ascertained weekly. Patients were classified as responders or nonresponders, and correlations between their neuroleptic levels and ratings of psychopathologic and extrapyramidal symptoms were computed. RESULTS: Plasma fluphenazine levels for weeks 1 through 4 were significantly correlated with each other but were not correlated with age, gender, diagnosis, or race. Mean neuroleptic levels (weeks 3 and 4) were not different between responders and nonresponders and were not correlated with measures of psychopathology or extrapyramidal symptoms. CONCLUSIONS: These results do not indicate an association between plasma fluphenazine levels and response to treatment or extrapyramidal side effects in first-episode schizophrenia. The disparity between the results of this study and those of previous studies may be due to methodological differences or to a biologically based difference between first-episode and chronic patients.

Duration of psychosis and outcome in first-episode schizophrenia.

OBJECTIVE: This study was undertaken to assess the potential effect of duration of untreated illness on outcome in a group of first-episode schizophrenic patients. METHOD: Seventy patients with schizophrenia diagnosed according to the Research Diagnostic Criteria entered the study and were followed for up to 3 years. All patients received standardized treatment and uniform assessments both during the acute phase of their illness and throughout the follow-up period. Outcome was measured in terms of time to remission of acute psychotic symptoms as well as degree of symptom remission. RESULTS: The mean duration of psychotic symptoms before initial treatment was 52 weeks, preceded by a substantial prepsychotic period. According to survival analysis, duration of illness before treatment was found to be significantly associated with time to remission as well as with level of remission. The effect of duration of illness on outcome remained significant when diagnosis and gender variables, themselves associated with outcome, were controlled in a regression analysis. Duration of illness was not correlated with age at onset, mode of onset, premorbid adjustment, or severity of illness at entry into the study. CONCLUSIONS: Duration of psychosis before treatment may be an important predictor of outcome in first-episode schizophrenia. Acute psychotic symptoms could reflect an active morbid process which, if not ameliorated by neuroleptic drug treatment, may result in lasting morbidity. Further implications of these findings are discussed.

The deficit state in first-episode schizophrenia.

OBJECTIVE: The prevalence, clinical correlates, and outcome of the deficit syndrome were determined for 70 patients ascertained in their first episode of schizophrenia and then followed through their recovery. METHODS: Patients were treated in a standardized manner and underwent baseline assessments of symptoms and adverse effects that were repeated at intervals throughout their inpatient and subsequent outpatient course. Forty-seven patients were followed for a minimum of 6 months after remission of their positive symptoms, allowing for an assessment of their deficit syndrome status. RESULTS: Using modified criteria of Carpenter et al. for the deficit syndrome, the authors found that two patients (4%) met all criteria for the deficit syndrome, nine (19%) had deficit symptoms (questionable deficit state), and 36 (77%) had no deficit symptoms. When patients who had not fully remitted or had remitted for less than 6 months were included, seven (10%) met deficit syndrome criteria, 11 (16%) had deficit symptoms, and 52 (74%) had no deficit symptoms. CONCLUSIONS: The prevalence of the deficit syndrome in first-episode schizophrenia varies depending on the criteria used and is lower than that previously described in more chronic patient samples. Patients without deficit symptoms had better premorbid functioning and a better global outcome than patients with deficit symptoms.

Gender differences in onset of illness, treatment response, course, and biologic indexes in first-episode schizophrenic patients.

OBJECTIVE: Gender differences in onset of illness, response to treatment, course, and biologic measures have been consistently reported in patients with chronic schizophrenia. Patients with first-episode schizophrenia were examined to determine whether gender differences also occur in these patients. METHOD: Fifty-four neuroleptic-naive schizophrenic patients (29 men and 25 women) were studied beginning in an initial stage of the first hospitalization for psychosis while undergoing treatment with a standardized medication regimen. Before antipsychotic drug treatment and during 1 year of follow-up each patient was rated on the Schedule for Affective Disorders and Schizophrenia--Change Version (psychosis and disorganization items), Scale for the Assessment of Negative Symptoms, Clinical Global Impression, modified Simpson Tardive Dyskinesia Scale, and Simpson-Angus Rating Scale for extrapyramidal side effects. Methylphenidate challenge testing was done at study entry. Plasma neuroleptic, homovanillic acid (HVA), and prolactin levels were determined weekly for the first 6 weeks. RESULTS: The female schizophrenic patients had a later onset and better treatment response than the men. Plasma HVA levels at baseline and week 1 and changes in prolactin levels from baseline to weeks 1 through 6 were greater among the women. CONCLUSIONS: Gender differences in onset and degree of treatment response in first-episode schizophrenic patients are similar to those of chronic patients and are apparent at early stages of the illness. The greater pharmacologic responsivity of the female patients, as indicated by the neuroendocrine results, is consistent with the gender difference in degree of symptom improvement with medication.

Early placebo response in anxious and depressed patients.

Specific subgroups of anxiety disorder patients (N = 130) and depression patients (N = 105), defined according to DSM-III criteria, were given 1 week of placebo treatment as part of ongoing clinical drug trials. Placebo responses and dropout rates were assessed at the end of the placebo trial period. The results indicate a comparable dropout rate between depression and anxiety disorder groups due to positive placebo response, negative placebo response, and "nonsymptomatic" reasons. In addition, male anxiety disorder patients dropped out at a significantly higher rate than male depression patients.

Dopaminergic mechanisms in idiopathic and drug-induced psychoses.

Stimulant drugs such as cocaine and amphetamine are among the most commonly abused substances by schizophrenic patients. This may be due in part to aspects of the illness and treatment side effects that impel patients to use dopamine agonist drugs. Dopaminergic neural systems have been shown to mediate both stimulant drug effects and schizophrenia. Because of the hypothesized overlap in the pathophysiology of schizophrenia and the neurobiological effects of chronic stimulant use, the potential for serious complication of the primary disease by substance abuse exists. This article reviews the neurobiological mechanisms of behavioral sensitization and neurotoxicity associated with chronic stimulant administration in the context of pathophysiological theories of schizophrenia. Discussion focuses on the potential impact of stimulant use on the disease process as well as the manifest phenomenology and course of schizophrenia.

Prospective study of psychobiology in first-episode schizophrenia at Hillside Hospital.

Heterogeneity has been a consistent problem in the research and treatment of schizophrenia. Despite marked variation in the onset, phenomenology, treatment response and outcome of schizophrenic patients, our ability to identify subtypes is remarkably limited. A major problem in schizophrenia research has been the use of cross-sectional study designs and heterogeneous patient samples at different stages of the illness and who have been previously exposed to neuroleptics which have potentially confounding effects on the disease. This study intends to identify biologic correlates of the phenomenology and course of schizophrenia by using a prospective, longitudinal, repeated measures design assessing biologic and clinical parameters including measures of psychopathology, side effects, and social adjustment to examine clinical variables of treatment response, illness course, and outcome; measures of central nervous system dopamine activity and brain morphology in patients, from the onset of their illness. Patients were ascertained at hospital admission and assessed with a battery of clinical, neuropsychologic, and biologic measures before undergoing standardized treatment for the acute and maintenance phases of the illness. Upon completion, approximately 120 first-episode patients will have entered the study and will have been followed prospectively for up to 5 years and assessed at specific time intervals. Preliminary results reveal significant abnormalities in brain morphology, growth hormone secretion, eye movement function, and psychotogenic response to dopamine agonists in first-episode, treatment-naive patients which are associated with treatment response and outcome. This article describes the study's rationale, design, and methods, and a summary of the published results to date. These are discussed in terms of their significance for putative clinical subtypes and pathophysiological models of schizophrenia.

Atypical antipsychotics in the managed care era.

Over the past decade, a new class of atypical antipsychotic drugs has been developed for the treatment of schizophrenia and related conditions. This new generation of antipsychotic agents represents the first significant breakthrough in the treatment of schizophrenia since the advent of chlorpromazine in the early 1950s. Although the designation "atypical" is currently the most widely used term for referring to these drugs, they are not likely to be viewed as atypical in the future--given their rapidly increasing use as first-line agents. Increased acceptance of these drugs early in the course of schizophrenia holds the promise of real long-term benefits in outcome. Although the acquisition cost of these drugs is significantly higher than that of older agents, pharmacoeconomic analysis suggests the possibility of substantial reductions in the overall financial burden posed by schizophrenic illness. This review summarizes the role of atypical antipsychotics in the treatment of schizophrenia, their merits compared to conventional medications, and their cost effectiveness.

Efficacy of ziprasidone in dysphoric mania: pooled analysis of two double-blind studies.

BACKGROUND: Dysphoric mania is a common and often difficult to treat subset of bipolar mania that is associated with significant depressive symptoms. OBJECTIVE: This post hoc analysis was designed to evaluate the efficacy of ziprasidone in the treatment of depressive and other symptoms in a cohort of patients with dysphoric mania. METHODS: Pooled data were examined from two similarly designed, 3-week placebo-controlled trials in acute bipolar mania. Patients scoring >/=2 on at least two items of the extracted Hamilton Rating Scale for Depression (HAM-D) met criteria for dysphoric mania and were included in the post hoc analysis. Changes from baseline in symptom scores were evaluated by a mixed-model analysis of covariance. RESULTS: 179 patients with dysphoric mania were included in the post hoc analysis (ziprasidone, n=124; placebo, n=55). Beginning at day 4, HAM-D scores were significantly lower at all visits in patients treated with ziprasidone compared with those treated with placebo (p<0.05). Ziprasidone-treated patients also demonstrated significant improvements on the Mania Rating Scale and all secondary efficacy measures, and had significantly higher response and remission rates compared with placebo. LIMITATIONS: The main limitations are the use of a post hoc analysis and the pooling of two studies with slightly different designs. CONCLUSION: In this analysis, ziprasidone significantly improved both depressive and manic mood symptoms in patients with dysphoric mania, suggesting that it might be a useful treatment option in this patient population. Further prospective controlled trials are needed to confirm these findings.

Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study.

This 12-week, double-blind, two-part study in 438 adults with bipolar-associated acute mania began with a 3-week period comparing ziprasidone (80-160 mg/day) and placebo with haloperidol (8-30 mg/day) as active reference. Changes from baseline Mania Rating Scale (MRS) scores for ziprasidone and haloperidol were superior to placebo from day 2 (P = 0.001) to week 3 (P < 0.001); change from baseline at week 3 was greater for haloperidol than ziprasidone (P or=50% decrease from baseline MRS score) was 36.9, 54.7 and 20.5% for ziprasidone, haloperidol and placebo, respectively (P

Shedding of transferrin receptor from rat reticulocytes during maturation in vitro: soluble transferrin receptor is derived from receptor shed in vesicles.

Measurements of circulating transferrin (Tf) receptor are useful in assessing erythropoiesis; however, steps involved in the generation of soluble Tf receptor from cellular receptor are incompletely understood. To obtain a better understanding of this process, we investigated the loss of Tf receptor during terminal maturation of rat reticulocytes in vitro. Previous studies have identified Tf receptor-containing vesicles in the culture medium of maturing reticulocytes. In the present study, vesicle-free reticulocyte culture medium was found to contain functional and immunoreactive soluble Tf receptor, which increased over time. During a 44-hour incubation, Tf receptor on reticulocytes decreased by approximately 69%, while, of the Tf receptor shed to the medium, 65% was present in vesicles and 35% was in a soluble form. Isolated vesicles reincubated in fresh medium released soluble Tf receptor to the medium. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the isolated soluble receptor protein was mainly 190 Kd and 95 Kd under nonreducing and reducing conditions, respectively, similar in size to the vesicular and cellular receptor. Our studies show that loss of Tf receptor from rat reticulocytes during maturation in vitro involves shedding of cellular Tf receptor in vesicles and release of soluble receptor from these vesicles.

Incidence and correlates of acute extrapyramidal symptoms in first episode of schizophrenia.

The incidence and correlates of extrapyramidal symptoms (EPS) in neuroleptic treatment of schizophrenic patients have been reported for chronic patients but not for first-episode patients. We examined the incidence and correlates of extrapyramidal symptoms in a cohort of 70 treatment-naive patients who received fluphenazine at 20-40 mg/day for the first 10 weeks of treatment. Thirty-four percent of our sample developed parkinsonism, 18 percent developed akathisia, and 36 percent developed dystonia. Acute EPS were associated with greater baseline psychopathology. Acute EPS were also associated with better treatment outcome in terms of time to and level of remission. These findings suggest that the EPS response of neuroleptic-naive patients may differ from that of chronically ill patients and that acute EPS status may be an indicator of pharmacologic responsivity in this group.

Complement-mediated T-cell depletion of bone marrow: comparison of T10B9.1A-31 and Muromonab-Orthoclone OKT3.

BACKGROUND: T10B9.1A-31 (T(10)B(9)) and Muromonab-Orthoclone OKT3 (OKT3) are both murine MAb with a narrow specificity for T lymphocytes. Over the past 10 years, we have used each for T-cell depletion (TCD) of BM. In this report we describe similarities and differences using these antibodies, as well as their effects on patient outcome. METHODS: We compared BM mononuclear cells (BMMC) prepared using a Cobe Spectra apheresis machine with density gradient (DG) separation to remove RBC and enrich for CD34(+) cells prior to TCD. FACS and limiting dilution assays (LDA) were used to measure the efficiency of TCD, the subsets of cells removed and CD34 content. Univariate statistics were used to assess graft outcome, including GvHD, graft failure, post-transplant lymphoproliferative disease (PTLD), relapse, DFS, and TRM. RESULTS: BMMC preparation on the Cobe Spectra resulted in superior recovery of CD34(+) cells. However, this method could not be used with OKT3 due to inhibition of T-cell lysis. Optimal TCD required two rounds of complement at room temperature for OKT3, compared with one or two rounds for T(10)B(9). TCR(gamma delta)(+) T-cells, but not natural killer cells, were spared to a greater degree with T(10)B(9). Further T-cell loss occurred during culture with T(10)B(9) but not with OKT3. Overall efficiency of TCD was superior using T(10)B(9). The risk of acute GvHD was higher with OKT3-mediated TCD, independent of T-cell content, and may have led to a higher incidence of PTLD. A decreased risk of relapse for patients with high-risk disease was seen with OKT3-treated grafts, but engraftment, TRM and DFS did not significantly differ. DISCUSSION: TCD using OKT3 results in higher T-cell content and higher rates of acute GvHD and PTLD compared with T(10)B(9). Cobe Spectra cannot be used for BMMC processing with OKT3, fewer CD34(+) are therefore infused. Technical, as well as biological, differences between narrow specificity MAbs can affect graft outcome.