High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study.

Uncontrolled studies have suggested that increasing the dose of ziprasidone above the standard maximum daily dose of 160 mg may be more effective for some patients with schizophrenia. To test this hypothesis, we conducted an 8-week, placebo-controlled, fixed-dose escalation trial comparing ziprasidone 160 versus 320 mg/d in individuals with schizophrenia or schizoaffective disorder who remained symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks. Of 75 randomized patients, 42 completed the study. Serum ziprasidone concentrations increased significantly in the high-dose group compared with the standard-dose group at week 4 but did not differ between groups at week 8. Both treatment groups exhibited significant symptomatic improvement. Response did not differ between treatment groups; however, in the high-dose group, higher ziprasidone serum concentrations were associated with better response at a trend level. Higher ziprasidone concentrations were also associated with reductions in diastolic blood pressure and, at a trend level, with more prominent negative symptoms and greater QTc prolongation. In summary, increasing the ziprasidone dose to 320 mg/d did not produce a sustained elevation in serum concentrations or symptomatic improvement compared with a standard ziprasidone dose of 160 mg/d.

Neurological soft signs in individuals with schizotypal personality features.

OBJECTIVE: The current study attempted to examine the prevalence of neurological soft signs and their relationships with schizotypal traits in individuals with psychometrically defined schizotypal personality disorder (SPD) features. METHOD: Sixty-four individuals with SPD-proneness and 51 without SPD-proneness were recruited for the present study. The soft signs subscales of the Cambridge Neurological Inventory were administered to all participants; the Schizotypal Personality Questionnaire (SPQ) was administered to SPD-proneness and non-SPD-proneness participants. RESULTS: The SPD-proneness participants demonstrated significantly higher prevalence of soft signs than those without SPD-proneness. SPQ subscales were significantly associated with ratings of motor coordination, sensory integration and total soft signs. CONCLUSION: These findings suggest that neurological soft signs are trait markers of schizophrenia.

Schizotypy and individual differences in the frequency of normal associations in verbal utterances.

BACKGROUND: Recent empirical evidence [Maher, B.A., Manschreck, T.C., Linnert, J., Candela, S., 2005. Quantitative assessment of the frequency of normal associations in the utterances of schizophrenia patients and healthy controls. Schizophrenia Research 78, 219-224] shows that schizophrenia patients produce an elevated rate of normative thought associations in verbal utterances as measured by an objective computerized procedure. An important theoretical question concerns whether such an elevated rate of associative activity is due merely to psychosis, or can it be found in schizotypic subjects with no prior history of psychosis. METHODS: We hypothesized that schizotypic features should be correlated with associative performance, especially the positive symptom-like schizotypic features. The present study examined associative performance in psychometrically-identified schizotypic subjects (n=25) and normal control (n=29) subjects. We studied individual differences in schizotypal personality features in relation to the associative performance index. RESULTS: Level of normative associations was correlated with total schizotypic features, particularly those involving reality distortion and disorganization. Regression analysis revealed higher levels of disorganization features and lower levels of negative schizotypal features uniquely accounted for variation in the associative performance index. Partial correlation analysis suggested that the negative schizotypic features dimension may function as a suppressor variable moderating the relationship between disorganization and level of normative associations. CONCLUSIONS: Disorganization-related schizotypal features among individuals with no prior history of psychosis are correlated with elevated levels of normative associations. This relationship is most likely moderated by negative schizotypic features. These data support the presence of hyperassociative processes in those deemed to be at elevated risk for schizophrenia (or, more broadly perhaps, psychosis). Our findings support the utility of measuring associative performance using an objective measure and suggest that associative performance may be an endophenotype [Gottesman, I., Gould, T., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636-645] for schizophrenia.

The CATIE schizophrenia trial: results, impact, controversy.

The CATIE (Clinical Antipsychotic Trials for Intervention Effectiveness) Schizophrenia Trial was designed to examine fundamental issues about second-generation antipsychotic (SGA) medications (olanzapine, risperidone, quetiapine, and ziprasidone) - their relative effectiveness and their effectiveness compared to a first-generation antipsychotic (FGA), perphenazine. This article reviews these and other findings from this important trial and offers a perspective regarding their meaning for practice and their significance for the advancement of research in psychiatry. The primary outcome measure, time to discontinuation, served as an index of effectiveness and was remarkably short; only 26% of subjects completed the 18-month trial on the medicine to which they were initially randomized. Subjects receiving olanzapine experienced a slightly longer time to discontinuation. Based on this single criterion, olanzapine showed greater effectiveness than the other agents despite its association with significant metabolic disturbance, especially weight gain. Perphenazine unexpectedly showed comparable levels of effectiveness and produced no more extrapyramidal side effects than the other agents. Despite modest prolactin elevation, risperidone was the best-tolerated medication. Ziprasidone was associated with weight loss and with positive impact on lipids and blood glucose. In Phase 2, clozapine demonstrated better effectiveness compared to other SGAs for subjects who discontinued their Phase 1 medication because of efficacy. Olanzapine and risperidone showed greater effectiveness in the tolerability pathway. CATIE secondary outcomes are currently being examined. Improvements in cognition were modest among all the agents in Phase 1, and perphenazine was no less effective in improving cognitive performance than the SGAs. Cost-effectiveness analysis revealed a significant advantage for perphenazine, due to the impact of the high-priced, brand-name SGAs on overall health care costs.

Baseline neurocognitive deficits in the CATIE schizophrenia trial.

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An 'all-comer' approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13-0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an 'all-comer' clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Prolongation of ERP latency and reaction time (RT) in simultaneous EEG/fMRI data acquisition.

BACKGROUND: Recording EEG and fMRI data simultaneously inside a fully-operating scanner has been recognized as a novel approach in human brain research. Studies have demonstrated high concordance between the EEG signals and hemodynamic response. However, a few studies reported altered cognitive process inside the fMRI scanner such as delayed reaction time (RT) and reduced and/or delayed N100 and P300 event-related brain potential (ERP) components. NEW METHOD: The present study investigated the influence of electromagnetic field (static magnetic field, radio frequency (RF) pulse, and gradient switching) and experimental environment on posterior N100 and P300 ERP components in four different settings with six healthy subjects using a visual oddball task: (1) classic fMRI acquisition inside the scanner (e.g., supine position, mirror glasses for stimulus presentation), (2) standard behavioral experiment outside the scanner (e.g., seated position, keyboard response), (3) controlled fMRI acquisition inside the scanner (e.g., organic light-emitting diode (OLED) goggles for stimulus presentation) inside; and (4) modified behavioral experiment outside the scanner (e.g., supine position, OLED goggles). RESULTS: The study findings indicated that the experimental environment in simultaneous EEG/fMRI acquisition could substantially delay N1P, P300 latency, and RT inside the scanner, and was associated with a reduced N1P amplitude. COMPARISON WITH EXISTING METHODS: There was no effect of electromagnetic field in the prolongation of RT, N1P and P300 latency inside the scanner. N1P, but not P300, latency was sensitive to stimulus presentation method inside the scanner. CONCLUSION: Future simultaneous EEG/fMRI data collection should consider experimental environment in both design and analysis.

Comparison of Injectable and Oral Antipsychotics in Relapse Rates in a Pragmatic 30-Month Schizophrenia Relapse Prevention Study.

OBJECTIVE: In a pragmatic clinical trial, this study sought to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics. METHODS: PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy), a prior 30-month relapse prevention study, compared use of a long-acting injectable second-generation antipsychotic with use of an oral second-generation antipsychotic by 305 patients with schizophrenia or schizoaffective disorder and found similar rates of first relapse between groups (42% with injectable medication, 32% with oral medication). This study examined subsequent relapses among patients who had relapsed in PROACTIVE and who continued in treatment, follow-up, or both. RESULTS: Thirty-two patients (11%) experienced two relapses, and 13 patients (4%) had three relapses. Neither rate of relapse nor time to successive relapses differed between treatment groups. CONCLUSIONS: There was an impressively low rate of subsequent relapses in this pragmatic clinical trial. Because all patients had a clinic visit according to the biweekly long-acting injectable medication administration schedule, frequent contact may have contributed to low relapse rates. Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment.

Quantitative assessment of the frequency of normal associations in the utterances of schizophrenia patients and healthy controls.

BACKGROUND: The intrusion of associations into the utterances of schizophrenic individuals typically disrupts the coherence of the patient's utterances. Recent theoretical formulations of these phenomena have emphasized the hyperactivity) of associational networks in such language disturbance (e.g., Maher, B.A. 2003 Schizophrenia, aberrant utterance and delusions of control: the disconnection of speech and thought, and the connection of experience and belief. Mind and Language, 18, 1-22). There has been only limited effort to quantify such features in patient populations. METHODS: We hypothesized that (1) coherent utterances elicited from a sample of schizophrenia patients will present a higher mean frequency of normative associations than in normal controls; and (2) there is a positive association between total associations in utterances and hyperassociative activity (positive facilitation) as assessed by a semantic priming task. Participants included 43 schizophrenic patients and 25 healthy controls. Three measures were employed, a new computer program, Computed Associations in Sequential Text (CAST), to quantify normative associations; a picture description technique for eliciting speech samples; and a semantic priming task to measure associative facilitation. RESULTS: In coherent utterances, schizophrenia patients produced higher mean totals of associations compared to controls. Patients with positive facilitation scores in the controlled processing interval (1250 ms) of the semantic priming procedure, there was a correlation between facilitation scores and total frequency of associations. This effect was absent in controls. CONCLUSIONS: These results are consistent with models of language disturbance in schizophrenia that posit hyperactivity of associational networks.

Review of antipsychotic medication administration: a proposal of intermittent dosing.

Despite advances in the treatment of schizophrenia, there are substantial gaps in systematically established knowledge concerning the application of antipsychotic agents. We still do not know how antipsychotic drugs work, where they work, how much to prescribe, or how often to prescribe. No consensus exists on the definition of relapse or recovery. Based on new knowledge of delayed onset and offset of pharmacological response in schizophrenia, of signal transduction, of time-delayed effects at the neuronal level, and of the complexities of etiologic and clinical heterogeneity in these disorders, we propose an alternative dosing strategy. Fixed intermittent dosing for initiation and maintenance of remission of clinical symptoms holds promise for improving response to medication, reducing side effects, increasing compliance, and limiting cost. It may help clarify the taxonomic conundrum of schizophrenia by providing a probe for identifying discrete pathophysiologic substrates in these disorders.

Earlier age of first diagnosis in schizophrenia is related to impaired motor control.

We examined the control of motor behavior in relation to age of first diagnosis (AFD; an approximation of age of onset) in schizophrenia. We hypothesized that earlier AFD reflects increased vulnerability to the disorder, vulnerability that may be indexed by elevated levels of motor abnormality. AFD, symptom and demographic features, motor performance on a line drawing task, and the presence and severity of dyskinesia and extrapyramidal side effects were evaluated in 65 chronic schizophrenia subjects. More severely impaired motor control was significantly related to an earlier age of diagnosis. Potential confounds, including age, gender, education, length of illness, current medication dosage, symptom status, and motor side effects, did not appear to influence this relationship, although greater chronicity appeared to be independently related to more severely impaired motor control. In summary, the data are consistent with the hypothesis that an earlier AFD is associated with more pronounced motor impairment.

Verbal and visual-spatial memory impairment in youth at familial risk for schizophrenia or affective psychosis: a pilot study.

BACKGROUND: Schizophrenia and affective psychoses share several common biological origins, particularly genetic susceptibility. Kraepelin posited that differing clinical expressions in these disorders reflect different etiopathologies. We tested a neuropsychological component of this hypothesis by evaluating verbal memory and visual memory performance in nonpsychotic youth at familial risk for psychosis, taking into account contributions to memory dysfunction including executive processing and psychopathology. METHODS: Teenage and young adults (ages 13-25) at familial high-risk (FHR) for schizophrenia (HR-SCZ, n=41) or affective psychosis (HR-AFF, n=24) were compared to community controls (CC, n=54) on verbal (Miller-Selfridge Context Memory) and visual (Rey-Osterrieth Complex Figure) memory tests in which the roles of strategy and contextual processing on distinct recall domains could be assessed. Effects of psychopathology, vigilance and working memory were investigated to determine their influence on memory performance. RESULTS: HR-AFF and HR-SCZ exhibited similarly impaired memory profiles and elevated levels of psychopathology compared to CC. HR-SCZ were significantly impaired on both verbal memory and visual-spatial memory, while HR-AFF in verbal memory only. However, effect sizes, in the medium range, were largely comparable between the two HR groups. Deficits in verbal recall and in visual memory organization remained significant after adjustment for confounders. CONCLUSIONS: Youth at FHR for psychosis present relatively common memory deficits across both visual-spatial and verbal modalities that are not explained by current psychopathology, vigilance or working memory deficits. Deficits in organizing information to be recalled represent a promising trait of psychosis vulnerability.

Genetics of the schizophrenias: a model accounting for their persistence and myriad phenotypes.

This article addresses the classic enigma about schizophrenia (SZ). The disease occurs with a lifetime prevalence of 1%, 80% of which is attributable to genetic factors. Females with SZ produce 50% as many children as normals, and males with SZ produce 25%. Genetic factors responsible for SZ should behave like lethal genes. Yet the prevalence of SZ remains around 1% throughout the world. How can that be? Additionally, CATIE concluded that the response of each individual with SZ to treatment with antipsychotic agents (effectiveness, side-effect profile, or long-term prognosis) cannot be predicted. Every case seems to be unique. Several recent publications have reported increased frequencies of single-nucleotide polymorphisms (SNPs) and of copy-number variants (CNVs) containing large regions of DNA in patients with SZ. These genetic perturbations often include neurodevelopmental genes. The overwhelming majority of SNPs and CNVs are post-fertilization mutations, occurring in somatic tissue, not germinal tissue. These mutations are a normal aspect of somatic cell division but occur more frequently in patients with SZ. Somatic mutations are not passed on to subsequent generations and therefore cannot account for the inheritance of SZ. Our speculation is that the genetic platform for SZ is the gene or genes that increase the number of de novo mutations in patients with SZ. We argue that balanced polymorphism is the most plausible hypothesis to account for the preservation of non-adaptive genes in nature-and, in particular, in SZ. Maladaptive genes in different combinations can confer increased fitness to the entire population, thus insuring their preservation in the gene pool. Somatic mutations explain both the sporadic occurrence of SZ within families and the wide variations in phenotypic expression of SZ. Increased frequency of somatic mutations may confirm greater overall fitness via balanced polymorphism to explain the maintenance of the SZ gene or genes within the human population.

Longitudinal consent-related abilities among research participants with schizophrenia: results from the CATIE study.

OBJECTIVE: Research participants must have adequate consent-related abilities to provide informed consent at the time of study enrollment. We sought to determine if research participants with schizophrenia maintain adequate consent-related abilities during a longitudinal study. If participants lose abilities during a trial they may not be able to judge and protect their interests. If reduced abilities are common or can be predicted, special protections can be targeted appropriately. METHOD: We examined longitudinal consent-related abilities of participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study using the MacArthur Competence Assessment Tool-Clinical Research (MacCAT-CR) at protocol-specified times over 18 months. RESULTS: Of 1158 research participants in this analysis, most (n=650, 56%) had a stable pattern of MacCAT-CR Understanding scores, 235 (20%) improved substantially with no evidence of decline, 273 (24%) had at least one assessment with substantial worsening. During the course of the trial, 43 (4%) fell below the initial threshold for adequate capacity, which was predicted by lower Understanding scores, more severe positive symptoms, and poorer neurocognitive functioning at baseline, and by increases in negative symptoms and deteriorating global status. CONCLUSIONS: Most participants in this long-term study had stable or improved consent-related abilities, but almost one-fourth experienced substantial worsening and 4% of participants fell below the study's capacity threshold for enrollment. Clinical investigators should monitor with special care individuals with marginal capacity or higher levels of psychotic symptoms at study entry and those who exhibit clinical worsening during a study.

Prevalence of neurological soft signs and their neuropsychological correlates in typically developing Chinese children and Chinese children with ADHD.

This study examined prevalence of soft signs in 214 typically developing Chinese children and investigated whether soft signs are associated with attention deficit hyperactivity disorder (ADHD) in this population. Chinese children with ADHD (N = 54) scored significantly higher than age-matched controls on all three soft signs subscales and motor coordination correlated significantly with Stroop interference. Logistic regression supported the utility of the soft sign scales in discriminating children with ADHD and controls. Children with ADHD had a significant excess of soft signs, which may be a useful marker of developmental disruption in this clinical condition.

Neurological soft signs and their relationships to neurocognitive functions: a re-visit with the structural equation modeling design.

BACKGROUND: Neurological soft signs and neurocognitive impairments have long been considered important features of schizophrenia. Previous correlational studies have suggested that there is a significant relationship between neurological soft signs and neurocognitive functions. The purpose of the current study was to examine the underlying relationships between these two distinct constructs with structural equation modeling (SEM). METHODS: 118 patients with schizophrenia and 160 healthy controls were recruited for the current study. The abridged version of the Cambridge Neurological Inventory (CNI) and a set of neurocognitive function tests were administered to all participants. SEM was then conducted independently in these two samples to examine the relationships between neurological soft signs and neurocognitive functions. RESULTS: Both the measurement and structural models showed that the models fit well to the data in both patients and healthy controls. The structural equations also showed that there were modest to moderate associations among neurological soft signs, executive attention, verbal memory, and visual memory, while the healthy controls showed more limited associations. CONCLUSIONS: The current findings indicate that motor coordination, sensory integration, and disinhibition contribute to the latent construct of neurological soft signs, whereas the subset of neurocognitive function tests contribute to the latent constructs of executive attention, verbal memory, and visual memory in the present sample. Greater evidence of neurological soft signs is associated with more severe impairment of executive attention and memory functions. Clinical and theoretical implications of the model findings are discussed.

Recent advances in the treatment of delusional disorder.

OBJECTIVE: Often considered difficult to treat in the past, even treatment-resistant, delusional disorder is now regarded as a treatable condition that responds to medication in many instances. Munro and Mok previously reviewed the published record of its treatment to 1994. This review aims to update and extend their observations and to examine the impact of new second-generation antipsychotic agents on the treatment of this condition. METHOD: We attempted to gather all published reports of delusional disorder from 1994 to 2004, using various database strategies. We then assessed the reports for clarity and completeness, treatment, and outcome descriptions, thereby selecting a patient sample for analysis. RESULTS: Of 224 cases identified as delusional disorder, only 134 case descriptions provided sufficient treatment and outcome data to inform this review. The demographics of this sample were similar to those of the earlier review. Depression as a comorbid condition was more frequent than before. Adherence to medication regimens was seldom explicitly addressed. Most cases showed improvement regardless of which antipsychotic medication the patients received. Pimozide and other conventional antipsychotics, as well as second-generation antipsychotics, and even clozapine, were used in many of the case reports. Family history of delusional disorder was seldom recorded. CONCLUSIONS: A positive response to medication treatment occurred in nearly 50% of the cases in our review, which is consistent with the earlier review.

Paul E. Meehl's influence on experimental psychopathology: fruits of the nexus of schizotypy and schizophrenia, neurology, and methodology.

Paul E. Meehl made numerous contributions to clinical science and a hallmark of many of these contributions was their integrative nature. Meehl's positions on complex topics, especially one such as schizophrenia, were reflective of input from a variety of disciplines and levels of analysis. In this essay the authors focus on Meehl's uniquely rich contribution to our understanding of schizophrenia through his theoretical model of schizotypy, his abiding interest in exploring neurologically based indicators of schizophrenia liability and encouragement to others to pursue such indicators, and his passion for rigorous research methodology. Meehl's contributions in each of these areas continue to influence the direction and research strategies used in experimental psychopathology to illuminate the fundamental nature of schizophrenia. These contributions have also shaped inquiry into many other psychopathological entities.