Transcranial Magnetic Stimulation at M1 disrupts cognitive networks in schizophrenia.

Transcranial Magnetic Stimulation (TMS) is rapidly gaining acceptance as a non-invasive probe into brain functionality. We utilize TMS to study the connectivity of a simple motor network in patients of schizophrenia (N=19), and in healthy control subjects (N=9). TMS was used in an externally paced finger tapping task, perturbing the internal network oscillations invoked by the finger motion as it keeps pace with a metronome. TMS perturbations were synchronized to the metronome and applied to the network at the level of the primary motor cortex (M1). Contrary to initial expectations, TMS did not affect the sensorimotor synchronization of subjects with schizophrenia or their tapping accuracy. TMS did cause extreme deviations in the finger's trajectory, and altered the timing perceptions of subjects with schizophrenia. Additionally, it invoked high-level deficiencies related to attention and volition in the form of lapses, implying that the connectivity between modules in the brain that underlie motor control, sensorimotor synchronization, timing perception and awareness of action, can be disrupted by TMS in subjects with schizophrenia, but not in healthy subjects. The ability to disrupt high level network functions with perturbations to the lower level of M1 supports models describing deficits in connectivity of distributed networks in the brains of schizophrenia patients. It also demonstrates the use of TMS to probe connectivity between components of such networks.

State and trait related predictors of serum cortisol to DHEA(S) molar ratios and hormone concentrations in schizophrenia patients.

OBJECTIVE: In previous studies we have demonstrated high serum molar ratios of cortisol to dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) [together abbreviated DHEA(S)], and the value of both cortisol/DHEA(S) molar ratios for prediction of responsivity to antipsychotic treatment in schizophrenia patients. The present study aimed to examine the contribution of anxiety, and severity of symptoms to the prediction of serum cortisol, DHEA(S) levels and two molar ratios across three examinations. METHOD: Serum concentrations of cortisol and DHEA(S)were examined in 43 schizophrenia inpatients and in 20 age matched healthy controls at baseline, and after 2 and 4 weeks. The Positive and Negative Symptom Scale and the State-Trait Anxiety Inventory scores were used as independent variables for multiple regression analysis. RESULTS: Despite clinical improvement during the study period cortisol/DHEA(S) molar ratios were found persistently elevated as compared to healthy controls. Multiple regression analysis revealed that across three examinations cortisol/DHEA(S) molar ratios negatively associated with trait-anxiety (partial R(2)=7-14%) rather than with negative symptoms (partial R(2)=3-6%). Age and age of onset account for 12.7% for variability of cortisol/DHEAS ratio. Serum cortisol concentrations are predicted by trait and state-anxiety, activation symptoms and daily doses of antipsychotics. A small portion of variability in serum DHEA levels (R(2)=9%) is associated with symptom severity, while DHEAS levels were predicted by age at examination and age of onset. CONCLUSION: Elevated serum cortisol/DHEA(S) molar ratios were attributed to trait-anxiety and age rather than to clinical symptoms. The findings may indicate persistent dysfunction of the hypothalamic-pituitary-adrenal axis that is independent of the patients' clinical state.

Improving the accuracy of the diagnosis of schizophrenia by means of virtual reality.

OBJECTIVE: The authors' goal was to improve the diagnosis of schizophrenia by using virtual reality technology to build a complex, multimodal environment in which cognitive functions can be studied (and measured) in parallel. METHOD: The authors studied sensory integration within working memory by means of computer navigation through a virtual maze. The simulated journey consisted of a series of rooms, each of which included three doors. Each door was characterized by three features (color, shape, and sound), and a single combination of features--the door-opening rule--was correct. Subjects had to learn the rule and use it. The participants were 39 schizophrenic patients and 21 healthy comparison subjects. RESULTS: Upon completion, each subject was assigned a performance profile, including various error scores, response time, navigation ability, and strategy. A classification procedure based on the subjects' performance profile correctly predicted 85% of the schizophrenic patients (and all of the comparison subjects). Several performance variables showed significant correlations with scores on a standard diagnostic measure (Positive and Negative Syndrome Scale), suggesting potential use of these measurements for the diagnosis of schizophrenia. On the other hand, the patients did not show unusual repetition of response despite stimulus cessation (called "perseveration" in classical studies of schizophrenia), which is a common symptom of the disease. This deficit appeared only when the subjects did not receive proper explanation of the task. CONCLUSIONS: The ability to study multimodal performance simultaneously by using virtual reality technology opens new possibilities for the diagnosis of schizophrenia with objective procedures.

Characterization of the serotonin transporter in lymphocytes and platelets of schizophrenia patients treated with atypical or typical antipsychotics compared to healthy individuals.

A rapidly growing body of data suggests that abnormalities in serotonergic function might be involved in the pathophysiology of schizophrenia and that serotonergic mechanisms play a role in the therapeutic effects of antipsychotics. The activity of the serotonin transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 38 medicated schizophrenia patients (15 of them treated with typical antipsychotics and 23 treated with atypical antipsychotics) and 15 healthy control subjects. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the three groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. There were no significant differences in the maximal uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes between the three groups. The affinity (K(m)) values of 5-HT to the 5-HTT were significantly higher in schizophrenia patients treated with typical antipsychotics compared with control subjects. The K(m) values in schizophrenia patients treated with atypical antipsychotics were significantly lower compared with those observed in the group of schizophrenia patients treated with typical antipsychotics; however, they were comparable to values in the control group. The high values of K(m) associated with typical antipsychotic treatment may be relevant to the high risk of developing extrapyramidal side effects (EPS). The role of the various components of the serotonergic system in the etiopathology of schizophrenia and the mechanisms by which antipsychotics achieve their therapeutic effects need to be further evaluated.

Serotonin transporter characteristics in lymphocytes and platelets of male aggressive schizophrenia patients compared to non-aggressive schizophrenia patients.

A large body of literature indicates that disturbances of central serotonin (5-HT) function play an important role in aggressive behavior. Results from open-label and placebo-controlled trials as well as the reported inverse relationship between 5-HT function and aggression in human subjects, suggest that reduced 5-HT activity is associated with aggressive behavior. The activity of the 5-HT transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 20 currently aggressive and 20 non-aggressive male schizophrenia patients. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the two groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. The maximum uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes and the K(m) values of the 5-HT to the transporter were significantly higher in currently aggressive compared to the non-aggressive schizophrenia patients. The association of high V(max) values with current aggressive behavior provides further support to the involvement of the 5-HTT in aggressive behavior as well as to the efficacy of 5-HTT blockers in the control of aggression. The role of the various components of the serotonergic system in the pathophysiology and treatment of aggressive behavior in schizophrenia needs to be further evaluated.

Cortisol/dehydroepiandrosterone ratio and responses to antipsychotic treatment in schizophrenia.

Dehydroepiandrosterone (DHEA) or their sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) exert multiple effects in the central nervous system, and may be involved in the pathophysiological processes in schizophrenia. This prospective study aimed to investigate whether serum cortisol/DHEA(S) molar ratios are associated with response to antipsychotic treatment during the exacerbation of schizophrenia. Serum DHEA(S) and cortisol were determined at baseline, and 2 and 4 weeks later for 43 medicated schizophrenia inpatients with acute exacerbation. The patients were treated with stable doses of antipsychotic agents up to 2 weeks prior to entering the study and for the 4-week duration of the study after which they were classified as either responders or nonresponders to treatment. Findings suggest that responders had significantly higher serum cortisol levels and cortisol/DHEA(S) ratios compared with nonresponders. These differences remained significant at three time points controlling for gender, age, severity of symptoms and emotional distress, benzodiazepines, type or dosage of antipsychotic agents, and background variables. The logistic regression model shows advantages of both cortisol/DHEA(S) molar ratios vs serum cortisol and DHEA(S) concentrations for prediction of responsivity to antipsychotic treatment. No significant canonical correlations were observed between changes from baseline through end-of-study in hormonal values and severity of symptoms and emotional distress among responders and nonresponders. Thus, these data provide evidence that elevated serum cortisol and cortisol/DHEA(S) ratios may serve as markers of biological mechanisms that are involved in responsivity of schizophrenia patients to antipsychotic treatment.

Schizophrenia patients with a history of severe violence differ from nonviolent schizophrenia patients in perception of emotions but not cognitive function.

BACKGROUND: Impaired processing of emotions may relate to violent behavior in schizophrenia patients. We compared emotional function in schizophrenia patients with and without a history of severe violent behavior. METHOD: Tests of identification and differentiation of facial emotions were performed to compare 35 patients with chronic schizophrenia or schizoaffective disorder (DSM-IV criteria) and a history of severe violent behavior with 35 non-violent schizophrenia patients and 46 healthy controls. Tests of executive function, attention, visual orientation, working memory, memory for faces and objects, and motor function were also administered. RESULTS: Violent and nonviolent schizophrenia patients showed impaired emotional and cognitive function compared with controls. Violent patients showed a significantly better ability to identify facial emotional expressions but a poorer ability to discriminate between intensity of emotions than nonviolent schizophrenia patients. There was no difference in cognitive performance between the 2 patient groups. CONCLUSION: Violent schizophrenia patients may have a better ability to identify facial emotional cues than nonviolent schizophrenia patients but may be less able to assess the intensity of these cues. This trait may contribute to conflict generation and failure to recognize resolution signals, leading to conflict escalation and violence in violence-prone schizophrenia patients.

A double-blind, cross-over comparison of the effects of amantadine or placebo on visuomotor and cognitive function in medicated schizophrenia patients.

The present study aimed to test the hypothesis that dopamine agonists may enhance cognitive function. The effect of amantadine on neuropsychological function in medicated schizophrenia patients was investigated. The study comprised an add-on, double-blind, placebo-controlled, cross-over 6-week trial. Participants comprised 29 inpatients at Sha'ar Menashe Mental Health Center who were diagnosed with chronic schizophrenia or schizoaffective disorder. Amantadine 200 mg/day or identical placebo was added to ongoing antipsychotic treatment for 3 weeks. Study medications were then switched for an additional 3 weeks. Assessments were performed at baseline, and weeks 3 and 6, including cognitive and visuomotor assessments. Clinical ratings included positive, negative and depressive symptoms and extrapyramidal side-effects. Blood prolactin levels were assayed. A mixed model was used to examine differences in the data at the three assessment points. Amantadine was associated with improved visuomotor coordination compared to placebo. No significant changes in cognitive functions were noted. Clinical symptoms, extrapyramidal side-effects and blood prolactin levels were not altered. Amantadine improved visuomotor coordination independently of extrapyramidal side-effects but not cognitive function. Because prolactin concentrations were unchanged, the mechanism is more likely to involve glutaminergic NMDA than dopaminergic mechanisms. Further studies of amantadine with different doses and treatment duration, as well as more glutamate selective agents such as memantine, are indicated.

An association of CAG repeats at the KCNN3 locus with symptom dimensions of schizophrenia.

BACKGROUND: In 1999 Cardno et al reported that long CAG repeats in the calcium-activated potassium channel gene hSKCa3/KCNN3 are associated with higher negative symptom dimension scores in schizophrenia patients. There has been no attempt to replicate the results. In this study, we investigated whether a symptom polymorphism of schizophrenia is associated with both the CAG repeat numbers and the difference in allele sizes. METHODS: We tested the association of CAG repeats with symptom models of schizophrenia in 117 unrelated Jewish patients. A multivariate analysis (MANOVA) of two models of schizophrenia with the repeat distribution and the difference in allele sizes was performed. RESULTS: We found a significant positive association of the number of CAG repeats with negative syndrome, anergia, activation, and paranoid symptoms. In addition, nonparanoid schizophrenia patients who had differences in allele sizes were characterized by earlier onset of illness. CONCLUSIONS: The study supports the hypothesis that the combined effect of long CAG repeats and the differences in allele sizes contribute to symptom expression of schizophrenia, particularly on the anergia-activation-paranoid axis.

Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia.

Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined.

Somatosensory evoked potentials during a rubber-hand illusion in schizophrenia.

The rubber-hand illusion (RHI), an illusion in which tactile sensations are referred to a synthetic alien limb, is enhanced in schizophrenia patients. Somatosensory evoked responses of the illusion were compared between schizophrenia patients and normal control subjects. Schizophrenia patients had significant alterations in long latency evoked responses during the illusion. These findings support the hypothesis of alterations in associative higher-level neuronal activity in schizophrenia. The findings support previous results pointing to alterations in associative brain regions in schizophrenia.

Decreased platelet peripheral-type benzodiazepine receptors in persistently violent schizophrenia patients.

Peripheral-type benzodiazepine receptors (PBR) have been shown to be sensitive to stressful conditions. This study aimed to explore a possible association of platelets PBR binding with aggressive behavior and homicidal history in schizophrenia patients. The authors compared [(3)H] PK 11195 binding to platelet membrane among 11 currently aggressive schizophrenia patients, 15 schizophrenia patients with homicidal history, 14 nonaggressive schizophrenia patients, and 15 healthy volunteers. Subjects were assessed for aggressive behavior, psychopathology, anxiety, anger, and emotional distress using standardized instruments. We found that currently aggressive patients had significantly lower (-30%) platelet PBR density (B(max)), and scored significantly higher on hostility, anxiety, state anger, and emotional distress compared to homicidal and nonaggressive schizophrenia patients and healthy controls. Predominance of positive or negative symptoms, homicidal or suicidal attempt history, emotional distress levels, and conventional or atypical antipsychotic therapy is not associated with the expression of platelet PBR binding sites. Significant negative correlations emerged between PBR density and scores for aggressive behavior, hostility and anxiety. Thus, decreased platelet PBR density in aggressive schizophrenia patients is associated with higher scores for overt aggression, hostility and anxiety, but independent of illness subtype, homicidal and suicidal attempt history, distress level and type of antipsychotic treatment.

Schizophrenic patients who smoke have a faster finger tapping rate than non-smokers.

The increased rate of smoking in schizophrenia patients remains unexplained and may reflect attempts at self-treatment. The effect sought from smoking may be related to nicotine's stimulating action. We tested this hypothesis by examining the relationship between smoking status and finger tapping rate, a measure of central processing, in schizophrenia patients treated with atypical antipsychotics. Smokers showed significantly faster finger tapping rates than non-smokers. This was not related to clinical state, illness chronicity, medication side-effects, antipsychotic dose or plasma concentrations. Nicotine can improve central processing in medicated schizophrenia patients and this may constitute part of the incentive for smoking.

The impact of side-effects of antipsychotic agents on life satisfaction of schizophrenia patients: a naturalistic study.

This study compared the impact of side-effects of antipsychotic treatment, clinical and psychosocial factors on the subjective quality of life (QOL) of hospitalized patients. We surveyed 161 patients meeting DSM-IV criteria for schizophrenia stabilized on conventional and atypical antipsychotic drugs using standardized measures of adverse events, psychopathology, psychosocial variables, and perceived QOL. We found that patients with adverse events reported less satisfaction with life domains of subjective feelings and general activities than asymptomatic patients. Patients treated with conventional and novel antipsychotic agents had comparable QOL ratings. Multiple regression analysis showed total variance in QOL ratings as follows: psychosocial factors, 20.9%; clinical symptoms and associated distress, 10.1%; adverse effects, 3.2%. Thus, medication side-effects influence subjective quality of life of schizophrenia inpatients significantly less than other clinical and psychosocial factors. Patient's subjective response to these events rather than their number is more predictive of QOL.

Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients.

Dehydroepiandrosterone (DHEA) and its sulfate derivative DHEA-S are neurosteroids, produced in the brain, and neuroactive steroids, produced in the adrenals and affecting the brain. We compared the ratios of serum cortisol/DHEA or DHEA-S in schizophrenia patients with normal subjects, and determined the correlation of these ratios with psychopathology and distress. Early morning plasma concentrations of DHEA, DHEA-S, and cortisol were determined by radioimmunassay in 40 medicated schizophrenia inpatients, and 15 healthy subjects with similar age and sex distribution. Subjects were assessed for psychopathology using the Positive and Negative Syndrome Scale (PANSS) and the Montgomery and Asberg Depression Rating Scale (MADRS), anxiety, anger, emotional and somatic distress levels. Schizophrenia inpatients demonstrated significantly higher levels of state and trait anxiety, anger expression index, emotional and somatic self-reported distress scores. Cortisol/DHEA and cortisol/DHEA-S ratios were significantly higher in schizophrenia patients than in healthy comparison subjects. Both ratios correlated positively with age and duration of illness; cortisol/DHEA-S ratio also showed positive association with age of illness onset. When age, illness duration and age of onset were controlled, cortisol/DHEA-S ratio significantly correlated with severity of depression (MADRS, r=0.33, p=0.048), state and trait anxiety (r=0.43, p=0.008 and r=0.40, p=0.014, respectively), trait anger (r=0.41, p=0.012), angry temperament (r=0.46, p=0.004), anger expression index (r=0.36, p=0.033), and hostility (r=0.42, p=0.010). No significant association was found between these ratios and severity of psychopathology, and type or dosage of antipsychotic agents. Thus, elevated cortisol/DHEA and/or cortisol/DHEA-S ratios in schizophrenia patients are positively associated with higher scores for anxiety and anger, depression and hostility, age and age of onset/duration of illness, but are independent of severity of psychopathology (PANSS) and antipsychotic treatment.

A computerized patient information system in a psychiatric hospital.

The authors describe a computerized patient information system at a psychiatric hospital in Israel. The system is a fully implemented work instrument that promotes clinical safety and cost containment. It allows interactive online consultations, clinical cross-checking, the production of computerized reports and schedules, fast response to laboratory results, and safer drug administration, all of which help improve the quality of care. Cost savings have been achieved in areas such as pharmacy and food distribution. The initial investment in the system was $400,000, which is expected to be recouped after 11.4 years.

Interpersonal distance in schizophrenic patients: relationship to negative syndrome.

BACKGROUND: Personal space is the area individuals maintain around themselves into which others cannot intrude without arousing discomfort. OBJECTIVE: We tested the hypotheses that psychological distancing of patients with schizophrenia would be a characteristic of 1) diagnosis and/or 2) syndrome. METHODS: For this aim, 30 schizophrenic and 30 age matching normal males established comfortable interpersonal distances for 20 word-stimuli representing family members, significant others, self-images, emotionally neutral and threatening surroundings. The distances were assessed by a paper-and-pencil projective measure, the Comfortable Interpersonal Distance scale and the patients' psychopathological symptoms were quantified by the Positive and Negative Syndrome Scale. t-tests and correlational analyses were employed to examine the relationships between the parameters of interest. RESULTS: The rank order (hierarchy) of preferable interpersonal distances of patients with schizophrenia was similar to that of normal subjects. At the same time, psychological distance from family members and themselves was substantially larger among the patients. There were no significant correlations between any kind of interpersonal distance and positive syndrome of schizophrenia, while negative syndrome showed significant inverse association with distances from emotionally neutral and threatening figures and positive correlation with family member and self-image distances. CONCLUSION: The results suggest that the negative syndrome of schizophrenia attenuates the differences between interpersonal distances from generally close and distant persons.

Transcranial magnetic stimulation in a finger-tapping task separates motor from timing mechanisms and induces frequency doubling.

We study the interplay between motor programs and their timing in the brain by using precise pulses of transcranial magnetic stimulation (TMS) applied to the primary motor cortex. The movement of the finger performing a tapping task is periodically perturbed in synchronization with a metronome. TMS perturbation can profoundly affect both the finger trajectory and its kinematics, but the tapping accuracy itself is surprisingly not affected. The motion of the finger during the TMS perturbation can be categorized into two abnormal behaviors that subjects were unaware of: a doubling of the frequency of the tap and a stalling of the finger for half the period. More stalls occurred as the tapping frequency increased. In addition, an enhancement of the velocity of the finger on its way up was observed. We conclude that the timing process involved in controlling the tapping movement is separate from the motor processes in charge of execution of the motor commands. We speculate that the TMS is causing a release of the motor plan ahead of time into activation mode. The observed doubles and stalls are then the result of an indirect interaction in the brain, making use of an existing motor plan to correct the preactivation and obtain the temporal goal of keeping the beat.

Cost effectiveness, safety, and satisfaction with video telepsychiatry versus face-to-face care in ambulatory settings.

Videoconference telepsychiatry provides an alternative for the psychiatric treatment of mental health patients who reside in remote communities. The objective of this study was to compare institutional ambulatory and hospitalization costs, treatment adherence, patient and physician satisfaction, and treatment safety between mental healthcare via videoconferencing and care provided in person. Data collected for 1 year of telepsychiatry treatment was compared to that of the preceding year and a matched comparison group. Twenty-nine patients from Or Akiva and 20 patients from Reut Hostel in Hadera who met the inclusion criteria agreed to participate; 24 and 15 patients, respectively, completed the study. Forty-two matched patients, who continued face-to-face interviews, comprised the comparison group. Drop-out patients and those who did not consent to telepsychiatry treatment were not involved. During the year of telepsychiatry treatment, patients and physicians were satisfied and treatment was safe. However, 1 hour of telepsychiatry treatment was more expensive than face-to-face care, and a tendency of increased hospitalizations was noted. Adherence ratios before and during telepsychiatry treatment were similar, but were twice as high versus the comparison group. The limited sample size precludes the drawing of definite conclusions, and further studies involving a larger study population and longer duration of investigation is warranted.

Rating of textual associations in organized and nonorganized sentences for the assessment of semantic networks in schizophrenia.

BACKGROUND: Collins and Quillian ( Acta Psychol 1970;33:304-314) proposed that semantic representations in the human brain could have a "networklike" theoretical construct. Thought disorders in schizophrenia have been described as disturbances in the spread of activation within semantic networks. Semantic networks are typically evaluated indirectly via reaction times of priming tasks. Medications may interfere with the reaction time of patients, thus, we sought to investigate semantic networks, independent of time, by having patients and controls rate textual associations in sentences organized to various degrees. METHODS: Twenty-eight schizophrenic patients (17 non-thought-disordered and 11 thought-disordered) and 27 healthy controls performed a rating of textual associations task in which they were asked to rate the associative relationship between concepts in sentences on a scale from 1 (totally dissociated) to 10 (completely associated). The task contained 3 sets of sentences; organized meaningful sentences, vague sentences (intermediately disorganized), and completely disorganized sentences. To avoid order effects, sentences were randomly mixed at presentation. RESULTS: Analysis of variance calculations indicated significant differences among the 3 groups (controls, thought-disordered, and non-thought-disordered). The differences were greater for the vague sentences. Compared with controls, schizophrenic patients demonstrated increased SDs in rating associative values between concepts in the sentences, which is higher in disorganized sentences. Inadequate ability to identify and rate associations in disorganized sentences is discussed in the context of disordered semantic networks of schizophrenic patients.