The effects of antipsychotic medication on sequential inhibitory processes.

The authors used a Stroop negative priming paradigm to examine the effects of antipsychotic medication on selective attentional processes. The performance of 14 patients with schizophrenia who were withdrawn from neuroleptic medication was compared with that of 10 medicated patients and 16 matched controls. Results demonstrated an increase in negative priming to normal levels with neuroleptic therapy. In contrast, within-trial interference and facilitation effects appeared to be less sensitive to medication therapy. The sustainment of inhibitory processes over time may differentiate the inhibitory mechanisms of the medication-withdrawn patients from both the medicated patients and the matched controls. The study of sequential inhibitory processes and their response to neuroleptic treatment could be important methods for understanding the temporal parameters associated with inhibition in schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Recent developments in antipsychotic medication

The development of new neuroleptics aims to reduce unwanted extrapyramidal motor side effects as well as the non-response rate, and to achieve a greater effect on negative symptoms. Preferential binding of neuroleptics to D2-receptors in the limbic system, as well as the combination of dopamine D2- and serotonin S2-antagonism proved to be effective. A potent D2-S2-antagonism as was realized with positive results in risperidone serves as a model for a whole class of new neuroleptics.     

Quetiapine: a new atypical antipsychotic for the treatment of schizophrenia

In the first of a new series of updates on recent advances in medication, RICHARD GRAY outlines the dibenzothiazepine quetiapine, which offers an alternative to conventional antipsychotics for the treatment of schizophrenia, with fewer side effects.     

Determinants of medication compliance in schizophrenia: empirical and clinical findings

Advances in psychopharmacology have produced medications with substantial efficacy in the treatment of positive and negative symptoms of schizophrenia and the prevention of relapse or symptom exacerbation after an acute episode. In the clinical setting, the individual patient's acceptance or rejection of prescribed pharmacological regimens is often the single greatest determinant of these treatments' effectiveness. For this reason, an understanding of factors that impede and promote patient collaboration with prescribed acute and maintenance treatment should inform both pharmacological and psychosocial treatment planning. We review the substantive literature on medication adherence in schizophrenia and describe a modified health belief model within which empirical findings can be understood. In addition to factors intrinsic to schizophrenia psychopathology, medication-related factors, available social support, substance abuse comorbidity, and the quality of the therapeutic alliance each affect adherence and offer potential points of intervention to improve the likelihood of collaboration. Because noncompliance as a clinical problem is multidetermined, an individualized approach to assessment and treatment, which is often best developed in the context of an ongoing physician-patient relationship, is optimal. The differential diagnosis of noncompliance should lead to interventions that target specific causal factors thought to be operative in the individual patient.     

Attention orienting effects of hesitations in speech: Evidence from ERPs.

Filled-pause disfluencies such as um and er affect listeners' comprehension, possibly mediated by attentional mechanisms (J. E. Fox Tree, 2001). However, there is little direct evidence that hesitations affect attention. The current study used an acoustic manipulation of continuous speech to induce event-related potential components associated with attention (mismatch negativity [MMN] and P300) during the comprehension of fluent and disfluent utterances. In fluent cases, infrequently occurring acoustically manipulated target words gave rise to typical MMN and P300 components when compared to nonmanipulated controls. In disfluent cases, where targets were preceded by natural sounding hesitations culminating in the filled pause er, an MMN (reflecting a detection of deviance) was still apparent for manipulated words, but there was little evidence of a subsequent P300. This suggests that attention was not reoriented to deviant words in disfluent cases. A subsequent recognition test showed that nonmanipulated words were more likely to be remembered if they had been preceded by a hesitation. Taken together, these results strongly implicate attention in an account of disfluency processing: Hesitations orient listeners' attention, with consequences for the immediate processing and later representation of an utterance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinical assessment of extrapyramidal signs in nursing home patients given antipsychotic medication

BACKGROUND: We sought to quantify the relationship between antipsychotic drug use and clinical evidence of extrapyramidal dysfunction in a large population of elderly nursing home patients. METHODS: Subjects were 251 residents (mean age, 84.1 years; range, 65 to 105 years) who were taking psychoactive drugs in 12 long-term care facilities. Patient characteristics and all medication use (both scheduled and as needed) were measured during a 1-month observation period. We then performed neuropsychological and functional testing on residents who received any psychoactive medications during the study month. The presence of rigidity, bradykinesia, or masklike facies was assessed in each patient by a research assistant who was unaware of diagnoses and medication use. RESULTS: The parkinsonian signs studied were found in 127 (50.6%) of these residents. Using logistic regression modeling to adjust for potential confounding, we found this outcome to be increased more than threefold in patients who took low-potency neuroleptics (odds ratio [OR], 3.49 for > or = 50 mg/d of chlorpromazine-type drugs; 95% confidence interval [CI], 1.28 to 9.57) and more than sixfold for use of 1 mg/d or more of haloperidol (OR, 6.42; 95% CI, 2.16 to 19.04). Age, gender, and use of nonneuroleptic psychoactive drugs were not associated with an increase in parkinsonian signs. CONCLUSIONS: Clinical evidence of extrapyramidal dysfunction is three to six times more common in institutionalized elderly patients given antipsychotic medication than in comparable patients not using such drugs. Its risk is substantially increased even in patients given low-potency chlorpromazine-type drugs, as well as those taking haloperidol. The effect is not explained by age or mental status and is not seen with other psychoactive medications. The expected frequency of parkinsonian symptoms can help to inform the balancing of risks vs therapeutic effect when the use of all drugs in this class is considered.     

Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension

OBJECTIVE: The authors sought to replicate and extend previous observations of improvement in some EEG sleep measures during the course of antipsychotic treatment in schizophrenia patients. METHOD: Fourteen medication-free patients with schizophrenia underwent 2 nights of sleep EEG monitoring before and after 3-4 weeks of treatment with clinically determined doses of haloperidol or thiothixene. RESULTS: Measures of sleep continuity improved consistently. REM latency increased, although five of 14 patients continued to exhibit short REM latencies (less than 60 minutes). Stage 3 sleep increased during neuroleptic treatment, while stage 4 sleep did not change. CONCLUSIONS: These data demonstrate partial improvement of some but not all EEG sleep measures in schizophrenic patients through the course of neuroleptic treatment. They suggest that shortened REM latency and disturbed sleep continuity might represent reversible state abnormalities, while reduced slow-wave sleep may represent a more persistent trait abnormality in schizophrenia.     

P300 delay and attenuation in schizophrenia: reversal by neuroleptic medication

PURPOSE: To examine parental influences on two transitions in the adolescent smoking uptake process: from never having smoked to experimentation and from experimentation to established smoking. METHODS: Using data from the longitudinal Teenage Attitudes and Practices Survey of 1989-1993, we related perceived parental concern about their adolescents' future smoking, parental smoking status, problem-solving communication between parent and adolescent, demographics, and other factors at baseline to experimentation by follow-up among those who had never puffed on a cigarette (n = 4149). We also related these factors at baseline to reaching a lifetime level of smoking of at least 100 cigarettes by follow up among those who had experimented but smoked < 100 cigarettes (n = 2684) in univariate and multivariate analyses. RESULTS: Among never-smokers, baseline susceptibility to smoking and having male best friends who smoke predicted experimentation in the next 4 years. Among experimenters, susceptibility to smoking, having male or female best friends who smoked, and lack of parental concern about future smoking distinguished those who progressed to established smoking by follow-up. Furthermore, communicating with parents first about serious problems was protective against progression from experimentation to established smoking. CONCLUSION: Interventions aimed at reducing adolescent smoking should encourage cessation for parents who smoke and help parents communicate strong anti-smoking norms to children and adolescents and maintain strong lines of communication with them.     

CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder

OBJECTIVE: The relationship between CSF neurotensin concentrations and measures of psychopathology in patients with schizophrenia or schizoaffective disorder was examined before and after treatment with antipsychotic drugs. METHOD: CSF neurotensin concentrations were measured in 42 drug-free patients with schizophrenia or schizoaffective disorder. For 18 of these patients, CSF neurotensin was measure again after 4 weeks of antipsychotic treatment. RESULTS: Significantly higher levels of pretreatment psychopathology were observed in the patients with the lowest CSF neurotensin concentrations. Furthermore, improvements in overall psychopathology and, particularly, negative symptoms were correlated with increases in CSF neurotensin concentrations during treatment. CONCLUSIONS: These findings provide further evidence for a role of neurotensin the pathophysiology of psychosis and in the mechanism of action of antipsychotic drugs.     

Fast and slow reaction times and associated ERPs in patients with schizophrenia and controls

A number of studies have examined across-trial averaged late component. Event Related Potentials (EPR) and Reaction Times (RT) in response to multiple target stimuli. In this study, within-trial relatively fast and slow sub averages are additionally examined, in 20 patients with schizophrenia and 20 age and sex matched controls. A conventional auditory oddball paradigm. Across-trial ERP average analysis showed smaller N200 amplitude and delayed latency (but larger P200 amplitude) in patients with schizophrenia compared with controls. Within-trial ERP analysis revealed a number of additional findings. Controls showed distinctive differences in fast compared with slow ERP sub averages (smaller P200 amplitude, increased N200/P300 amplitudes and earlier latencies). The schizophrenic group on the other hand, showed relatively similar fast versus slow subaverages (no differences in P200 amplitude and N200 latency). In addition, between-group (within-trial) analyses highlighted significant differences in earlier stages of processing (compared with across-trial averages) in both fast and slow subaverages (increased N100 amplitude in controls). The complementary within-trial (compared with across-trial) data are interpreted with respect to a possible disturbance in inhibitory function in patients with schizophrenia.     

Leukocyte differentials predict short-term clinical outcome following antipsychotic treatment in schizophrenia

PURPOSE: The purpose of the test-retest phase of the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study was to determine the repeatability of the various parts of the CLEK Study protocol. This paper presents the test-retest parameters of the refraction protocol. METHODS: We examined 138 CLEK Study-eligible patients on two occasions (median, 90 days; range, 22 to 268 days). All patients underwent subjective refraction on two occasions, and contact lens over-refractions were performed either over the patient's habitual rigid contact lenses or over a trial rigid contact lens equal in base curve to the steep keratometric reading in nonrigid contact lens wearers. RESULTS: Mean interoccasion differences +/- SD were -0.32 +/- 2.91 D and -0.17 +/- 1.39 D for subjective refraction sphere and cylinder power, respectively, and the mean absolute difference for subjective refraction cylinder axis was 18.1 +/- 20.2 degrees. The mean interoccasion difference +/- SD for high-contrast visual acuity with subjective refraction was 0.38 +/- 10.9 letters correct. Mean interoccasion differences +/- SD were -0.11 +/- 0.81 D and 0.02 +/- 0.67 D for contact lens over-refraction sphere and cylinder power, respectively, and the mean absolute difference for contact lens over-refraction cylinder axis was 11.6 +/- 9.9 degrees. The mean interoccasion difference +/- SD for visual acuity with contact lens over-refraction was 0.50 +/- 5.2 letters correct and 0.71 +/- 6.9 letters correct for high- and low-contrast visual acuity, respectively. CONCLUSIONS: The repeatability of subjective refraction in keratoconus patients is good but somewhat lower than that found in nondiseased eyes. Only 36% of our repeat measures of sphere power from subjective refraction fell within 0.50 D of each other, compared with more than 90% in studies of normal eyes.     

Auditory ERPs during rhyme and semantic processing: effects of reading ability in college students

Event-related potential (ERP), reaction time (RT), and response accuracy measures were obtained during the phonological and semantic categorization of spoken words in 14 undergraduates: 7 were average readers and 7 were reading-impaired. For the impaired readers, motor responses were significantly slower and less accurate than were those of the average readers in both classification tasks. ERPs obtained during rhyme processing displayed a relatively larger amplitude negativity at about 480 ms for the impaired readers as compared to the average readers, whereas semantic processing resulted in no major group differences in the ERPs at this latency. Also, N480 amplitude was larger during semantic relative to phonological classification for the average readers but not for the impaired readers. Results are compared to a previous study of reading-impaired children on the same tasks.     

Sertindole, a new atypical antipsychotic for the treatment of schizophrenia

Recent studies have shown that at least some of the functional effects of serotonin (5-HT) on motoneuron excitability are direct and are mediated via postsynaptic 5-HT receptors on motoneurons. To determine the spatial distribution of direct inputs from the serotonin system on the proximal and distal dendrites of individual motoneurons, we examined identified motoneurons in vivo with a combination of immunohistochemical localization of 5-HT-immunoreactive boutons and intracellular staining with horseradish peroxidase. Seventeen intracellularly stained motoneurons from 12 adult cats were analyzed with light microscopy. Quantitative analysis of 5-HT boutons apposed to dendrites of five representative motoneurons that were entirely reconstructed in three dimensions (each from the lumbosacral spinal cord of a different animal) revealed a total of 7,848 contacts (1,570+/-487 contacts/postsynaptic neuron; mean +/- SD) over the dendrites of these cells. Analysis of contacts on the soma of two of these cells, and on the somas of an additional 12 intracellularly stained motoneurons, revealed a wide range of somatic contacts (11-211 contacts/cell) on motoneuron cell bodies, with an average of 52 contacts/cell. These results indicate that the vast majority of 5-HT-immunoreactive boutons are apposed to dendritic branches rather than to the somatic surface of motoneurons. The spatial distribution of contacts essentially matched the distribution of surface membrane area of the postsynaptic neuron, resulting in a relatively uniform density of contacts (<1/100 microm2) on proximal and distal dendrites. Consequently, the frequency of contacts was higher on the proximal dendritic compartments where available membrane area is greater. There was no preferential distribution of contacts to particular dendrites. Light/electron microscopic correlations were performed on 21 boutons that contacted dendrites (n = 7) of three motoneurons from different animals. At the electron microscope level, most appositions (18/21; 85.7%) selected by our light microscopic criteria were confirmed as direct contacts when the 5-HT boutons were examined through serial sections. Synaptic junctions, generally small and symmetric, were positively identified in only a subset of these cases (n = 6; 28.6%), in part due to the obscuring effects of the peroxidase histochemical precipitate present in both pre- and postsynaptic profiles. A few 5-HT boutons (3/21; 14.3%) selected as contacts by our light microscopic criteria were in fact separated from the adjacent labeled dendrites; in two of these three cases, the separation was due to intrusion of very thin glial lamellae (<0.3 microm in cross section). These results indicate that the bulbospinal serotonergic system(s) provide a significant, direct synaptic input to spinal motoneurons that innervate hindlimb muscles. The nature of the modulatory actions exerted by such widespread synaptic inputs will affect all regions of the somatodendritic membrane and will ultimately depend on the nature of the 5-HT receptors present over different parts of the postsynaptic neuron's dendritic tree.     

Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action

Syncope is by definition a transient event, and its cause has usually resolved by the time the patient is examined. Electrophysiologic testing provides a method for assessing a patient's risk for future arrhythmias based on the known sensitivity and specificity of the analyses of sinus node function, atrioventricular conduction, and responses to programmed atrial and ventricular stimulation. Interpretation of these data must always be made in the context of the patient's total clinical situation.     

Do atypical antipsychotic medications favorably alter the long-term course of schizophrenia?

Schizophrenia is characterized by the greatest degree of clinical deterioration in the first decade following onset of psychosis; in fact, deterioration begins even prior to the onset of frank psychotic symptomatology. While somewhat controversial, it appears that effective early antipsychotic treatment might limit the extent of such deterioration. The newer, atypical antipsychotics such as clozapine, risperidone, olanzapine and quetiapine appear to have antipsychotic efficacy at least equal to the traditional neuroleptics, but with a much more favorable side effect profile. Clozapine is also effective in treating neuroleptic-refractory schizophrenic patients. Data suggest that in comparison to conventional agents, treatment with atypical antipsychotics may be associated with a more benign course of schizophrenic illness. Whether these atypical antipsychotics are associated with greater efficacy in limiting clinical deterioration in schizophrenic illness than traditional neuroleptics is, however, unclear. The following questions will be addressed in this paper: (i) Do atypical antipsychotics differ from traditional neuroleptics in modifying the natural course of symptomatology in schizophrenic illness? (ii) Do atypical antipsychotics differ from typical neuroleptics in modifying the natural course of neurobiological and cognitive abnormalities in schizophrenic illness? (iii) Do atypical antipsychotics differ from typical neuroleptics in modifying the natural course of psychosocial dysfunction in schizophrenic illness? (iv) Are there differences between typical and atypical antipsychotics with regard to their effects on the cost of care and resource utilization? The implications of the answers to these questions for the long-term treatment of schizophrenia will be discussed.     

The effects of between-source discriminability on attended and unattended auditory ERPs

Event-related potentials (ERPs) for tone pips from attended and unattended sources, which varied on discriminability, were compared with ERPs for the same stimuli recorded during performance of a visual task. This comparison revealed that Nd, the negative shift of attended relative to unattended ERPs, consisted of three components: a negativity in the attended ERP from 100 to 270 ms, a positivity in the unattended ERP from 170 ms to the end of the epoch, and a second negativity in the attended ERP from 270 to 700 ms. In general, the later onset of early Nd with more difficult between-source discriminations could be attributed to the later onset of the positivity in unattended ERPs. A number of hypotheses were advanced for the origin of the unattended positivity: the suppression of the later of two negative components in the 100-220-ms range, an enhanced P2 component, an endogenous positivity, or the resolution of a protracted negativity elicited by preceding attended stimuli.     

Perceptual anomalies in schizophrenia co-occur with selective impairments in the gamma frequency component of midlatency auditory ERPs.

This study aimed to establish concordance between phenomenological and psychophysiological indices of sensory gating disturbance in schizophrenia. Perceptually normal and deviant subgroups of schizophrenia (SZ) and healthy comparison (HC) participants were empirically determined on the basis of self-rated Sensory Gating Inventory scores. Contrasts by diagnosis and subgroup classification were conducted on event-related brain potential (ERP) response attenuation to paired auditory stimuli, measured in time (P50 ERP) and frequency (low frequency, 1-20 Hz; gamma band, 20-50 Hz) domains. The SZ sample evidenced significantly less low-frequency response attenuation than did HC but comparable P50 and gamma responses. The low-frequency response, however, appeared insensitive to variation in perceptual experience between SZ subgroups. Conversely, smaller P50 amplitude and weaker gamma response attenuation distinguished deviant SZ (n=17) from normal SZ (n=9) and normal HC (n=29) subgroups. Perceptually normal SZ and normal HC subgroups were statistically equivalent across all comparisons. These findings support hypotheses relating perceptual disturbance in schizophrenia to an early sensory input dysfunction, which is thought to involve gamma-mediated thalamocortical integration of sensory stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia.

In this article, we review research designed to examine the influence of neuroleptic and anticholinergic drugs on cognitive processes in schizophrenia. The review is motivated by the recognition that pharmacotherapy is an important factor in psychological research in schizophrenia, given that the great majority of patients studied in investigations of cognition receive both of these drugs. We find that neuroleptic treatment is associated with limited normalization on many psychological measures, whereas anticholinergics appear to disrupt some aspects of memory. Subject selection criteria, research designs, and drug measurement methods important in the evaluation of possible drug effects in psychological studies are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

For how long should antipsychotic medication be continued after the first psychotic episode in schizophrenics?

Four patients, two women aged 24 and 62 years and two men aged 25 and 24, respectively, were admitted because of psychosis. A Dutch consensus paper advises treating patients with a first episode of schizophrenia or schizophreniform disorder with neuroleptics for two years as secondary prophylaxis. However, this advice should be tailored to the individual patient's characteristics. Thus, the first patient was given prophylactic medication for five years because she had many schizophrenic symptoms and a positive family history. In the second patient, the diagnosis was much less certain and, because of her advanced age, the risk of developing tardive dyskinesia was considerable. Prophylaxis was given for three months only. The third patient used drugs and did not really want to be treated. In the fourth patient the affective symptoms could not be interpreted for certain as part of a basic schizophrenic defect. In addition, he would be seriously handicapped professionally if he developed tardive dyskinesia. In his case, two years of secondary prophylaxis was advised.