Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine.

INTRODUCTION: Agitation is a major problem in acute schizophrenia. Only a few studies have tested antipsychotic agents in severely agitated patients, mainly because of legal issues. Furthermore, most studies were limited to the first 24 hours. We aimed to investigate the efficacy of oral haloperidol, risperidone, and olanzapine in reducing psychotic agitation in severely agitated patients with schizophrenia or schizophreniform or schizoaffective disorder over 96 hours using a prospective, randomized, rater-blinded, controlled design within a naturalistic treatment regimen. METHODS: In total, 43 severely agitated patients at acute care psychiatric units were enrolled. Participants were randomly assigned to receive either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 to 6 mg over 5 days. Positive and Negative Syndrome Scale psychotic agitation subscale score was the primary outcome variable. A mixed-model analysis was applied. RESULTS: All drugs were effective for rapid tranquilization within 2 hours. Over 5 days, the course differed between agents (P < 0.001), but none was superior. Dropouts occurred only in the risperidone and olanzapine groups. Men responded better to treatment than did women during the initial 2 hours (P = 0.046) as well as over the 5-day course (P < 0.001). No difference between drug groups was observed regarding diazepam or biperiden use. CONCLUSIONS: Oral haloperidol, risperidone, and olanzapine seem to be suitable for treating acute severe psychotic agitation in schizophrenia spectrum disorders. Response to oral antipsychotics demonstrated a gender effect with poorer outcome in women throughout the study.

Glucocorticoids enhance in vivo exposure-based therapy of spider phobia.

BACKGROUND: Preclinical and clinical studies indicate that the administration of glucocorticoids may promote fear extinction processes. In particular, it has been shown that glucocorticoids enhance virtual reality based exposure therapy of fear of heights. Here, we investigate whether glucocorticoids enhance the outcome of in vivo exposure-based group therapy of spider phobia. METHODS: In a double blind, block-randomized, placebo-controlled, between-subject study design, 22 patients with specific phobia of spiders were treated with two sessions of in vivo exposure-based group therapy. Cortisol (20 mg) or placebo was orally administered 1 hr before each therapy session. Patients returned for a follow-up assessment one month after therapy. RESULTS: Exposure-based group therapy led to a significant decrease in phobic symptoms as assessed with the Fear of Spiders Questionnaire (FSQ) from pretreatment to immediate posttreatment and to follow-up. The administration of cortisol to exposure therapy resulted in increased salivary cortisol concentrations and a significantly greater reduction in fear of spiders (FSQ) as compared to placebo at follow-up, but not immediately posttreatment. Furthermore, cortisol-treated patients reported significantly less anxiety during standardized exposure to living spiders at follow-up than placebo-treated subjects. Notably, groups did not differ in phobia-unrelated state-anxiety before and after the exposure sessions and at follow-up. CONCLUSIONS: These findings indicate that adding cortisol to in vivo exposure-based group therapy of spider phobia enhances treatment outcome.

Spider phobia is associated with decreased left amygdala volume: a cross-sectional study.

BACKGROUND: Evidence from animal and human studies imply the amygdala as the most critical structure involved in processing of fear-relevant stimuli. In phobias, the amygdala seems to play a crucial role in the pathogenesis and maintenance of the disorder. However, the neuropathology of specific phobias remains poorly understood. In the present study, we investigated whether patients with spider phobia show altered amygdala volumes as compared to healthy control subjects. METHODS: Twenty female patients with spider phobia and twenty age-matched healthy female controls underwent magnetic resonance imaging to investigate amygdala volumes. The amygdalae were segmented using an automatic, model-based segmentation tool (FSL FIRST). Differences in amygdala volume were investigated by multivariate analysis of covariance with group as between-subject factor and left and right amygdala as dependent factors. The relation between amygdala volume and clinical features such as symptom severity, disgust sensitivity, trait anxiety and duration of illness was investigated by Spearman correlation analysis. RESULTS: Spider phobic patients showed significantly smaller left amygdala volume than healthy controls. No significant difference in right amygdala volume was detected. Furthermore, the diminished amygdala size in patients was related to higher symptom severity, but not to higher disgust sensitivity or trait anxiety and was independent of age. CONCLUSIONS: In summary, the results reveal a relation between higher symptom severity and smaller left amygdala volume in patients with spider phobia. This relation was independent of other potential confounders such as the disgust sensitivity or trait anxiety. The findings suggest that greater spider phobic fear is associated with smaller left amygdala. However, the smaller left amygdala volume may either stand for a higher vulnerability to develop a phobic disorder or emerge as a consequence of the disorder.

Frontal white matter integrity is related to psychomotor retardation in major depression.

Altered frontal white matter integrity has been reported in major depression. Still, the behavioral correlates of these alterations are not established. In healthy subjects, motor activity correlated with white matter integrity in the motor system. To explore the relation of white matter integrity and motor activity in major depressive disorder, we investigated 21 medicated patients with major depressive disorder and 21 matched controls using diffusion tensor imaging and wrist actigraphy at the same day. Patients had lower activity levels (AL) compared with controls. Fractional anisotropy (FA) differed between groups in frontal white matter regions and the posterior cingulum. AL was linearly associated with white matter integrity in two clusters within the motor system. Controls had an exclusive positive association of FA and AL in white matter underneath the right dorsal premotor cortex. Only patients had a positive association within the posterior cingulum. Furthermore, patients had negative associations of FA and AL underneath the left primary motor cortex and within the left parahippocampal gyrus white matter. These differences in the associations between structure and behavior may contribute to well-known impaired motor planning or gait disturbances in major depressive disorder. Therefore, signs of psychomotor slowing in major depressive disorder may be linked to changes of the white matter integrity of the motor system.

Semantic network disconnection in formal thought disorder.

BACKGROUND: Structural and functional findings in schizophrenic patients with formal thought disorder (FTD) show abnormalities within left-side semantic areas. The present study investigate the network function of the involved brain regions as a function of FTD severity. METHODS: We examined a group of 16 schizophrenia patients differing in FTD, but not in overall symptom severity, and 18 matched healthy controls. A passive word reading paradigm was applied during functional MRI (fMRI). A concatenated independent component analysis approach separated the fMRI signal into independent components, and spatial similarity was used to estimate the individual differences in spatial configuration of networks. RESULTS: The semantic network was identified for both groups encompassing structures of the left inferior frontal gyrus, the left angular gyrus and the left middle temporal gyrus. The differences between the semantic networks of patients and controls increased with increasing severity of FTD. This difference was due to a decreasing contribution of the left inferior frontal gyrus (Brodmann area 45 and 47). CONCLUSION: Severity of FTD was correlated with a disruption of the left semantic network in schizophrenic patients. We suggest that FTD is a consequence of a frontal-parietal/temporal disconnection due to a complex interaction between structural and functional abnormalities within the left semantic network.

Semantic memory involvement in the default mode network: a functional neuroimaging study using independent component analysis.

The Default Mode Network (DMN) is a higher order functional neural network that displays activation during passive rest and deactivation during many types of cognitive tasks. Accordingly, the DMN is viewed to represent the neural correlate of internally-generated self-referential cognition. This hypothesis implies that the DMN requires the involvement of cognitive processes, like declarative memory. The present study thus examines the spatial and functional convergence of the DMN and the semantic memory system. Using an active block-design functional Magnetic Resonance Imaging (fMRI) paradigm and Independent Component Analysis (ICA), we trace the DMN and fMRI signal changes evoked by semantic, phonological and perceptual decision tasks upon visually-presented words. Our findings show less deactivation during semantic compared to the two non-semantic tasks for the entire DMN unit and within left-hemispheric DMN regions, i.e., the dorsal medial prefrontal cortex, the anterior cingulate cortex, the retrosplenial cortex, the angular gyrus, the middle temporal gyrus and the anterior temporal region, as well as the right cerebellum. These results demonstrate that well-known semantic regions are spatially and functionally involved in the DMN. The present study further supports the hypothesis of the DMN as an internal mentation system that involves declarative memory functions.

Alterations of white matter integrity related to motor activity in schizophrenia.

Altered structural connectivity is a key finding in schizophrenia, but the meaning of white matter alterations for behavior is rarely studied. In healthy subjects, motor activity correlated with white matter integrity in motor tracts. To explore the relation of motor activity and fractional anisotropy (FA) in schizophrenia, we investigated 19 schizophrenia patients and 24 healthy control subjects using Diffusion Tensor Imaging (DTI) and actigraphy on the same day. Schizophrenia patients had lower activity levels (AL). In both groups linear relations of AL and FA were detected in several brain regions. Schizophrenia patients had lower FA values in prefrontal and left temporal clusters. Furthermore, using a general linear model, we found linear negative associations of FA and AL underneath the right supplemental motor area (SMA), the right precentral gyrus and posterior cingulum in patients. This effect within the SMA was not seen in controls. This association in schizophrenia patients may contribute to the well known dysfunctions of motor control. Thus, structural disconnectivity could lead to disturbed motor behavior in schizophrenia.

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia.

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

Measuring motor activity in major depression: the association between the Hamilton Depression Rating Scale and actigraphy.

Despite the use of actigraphy in depression research, the association of depression ratings and quantitative motor activity remains controversial. In addition, the impact of recurring episodes on motor activity is uncertain. In 76 medicated inpatients with major depression (27 with a first episode, 49 with recurrent episodes), continuous wrist actigraphy for 24h and scores on the Hamilton Depression Rating Scale (HAMD) were obtained. In addition, 10 subjects of the sample wore the actigraph over a period of 5 days, in order to assess the reliability of a 1-day measurement. Activity levels were stable over 5 consecutive days. Actigraphic parameters did not differ between patients with a first or a recurrent episode, and quantitative motor activity failed to correlate with the HAMD total score. However, of the motor-related single items of the HAMD, the item activities was associated with motor activity parameters, while the items agitation and retardation were not. Actigraphy is consistent with clinical observation for the item activities. Expert raters may not correctly rate the motor aspects of retardation and agitation in major depression.

Higher motor activity in schizophrenia patients treated with olanzapine versus risperidone.

There are indications that atypical antipsychotics differ in the probability of causing motor retardation. Whereas olanzapine seems to exert sedation, risperidone might slow patients because of parkinsonism or increased negative symptoms. Objective data on gross motor activity are not available. We present actigraphic data of 16 schizophrenia patients treated with olanzapine (mean dose, 21.1 mg/d) and 23 with risperidone (mean dose, 4.7 mg/d) to investigate possible differences in their effects on motor activity. Participants wore actigraphs continuously for 24 hours at the nondominant arm. Groups did not differ in age, Positive and Negative Syndrome Scale scores, duration of illness, and number of episodes. Patients treated with olanzapine had higher activity levels than those treated with risperidone (P = 0.024); this effect was robust and also present after covarying for chlorpromazine equivalents and Positive and Negative Syndrome Scale scores. Movement index (proportion of active episodes) and the average duration of immobility, however, failed to show any difference between groups. The results indicate that patients on olanzapine are more active during the day than patients on risperidone. It remains unclear whether this difference is due to subthreshold parkinsonism with risperidone or stronger beneficial effects of olanzapine on psychomotor slowing. Because the average duration of immobility remained unaffected, sedation is not likely to be the cause for the observed differences.

The Bern psychopathology scale for the assessment of system-specific psychotic symptoms.

The translation from psychiatric core symptoms to brain functions and vice versa is a largely unresolved issue. In particular, the search for disorders of single brain regions explaining classical symptoms has not yielded the expected results. Based on the assumption that the psychopathology of psychosis is related to a functional imbalance of higher-order brain systems, the authors focused on three specific candidate brain circuitries, namely the language, and limbic and motor systems. These domains are of particular interest for understanding the disastrous communication breakdown during psychotic disorders. Core symptoms of psychosis were mapped on these domains by shaping their definitions in order to match the related brain functions. The resulting psychopathological assessment scale was tested for interrater reliability and internal consistency in a group of 168 psychotic patients. The items of the scale were reliable and a principal component analysis (PCA) was best explained by a solution resembling the three candidate systems. Based on the results, the scale was optimized as an instrument to identify patient subgroups characterized by a prevailing dysfunction of one or more of these systems. In conclusion, the scale is apt to distinguish symptom domains related to the activity of defined brain systems. PCA showed a certain degree of independence of the system-specific symptom clusters within the patient group, indicating relative subgroups of psychosis. The scale is understood as a research instrument to investigate psychoses based on a system-oriented approach. Possible immediate advantages in the clinical application of the understanding of psychoses related to system-specific symptom domains are also discussed.

Gray matter volume differences specific to formal thought disorder in schizophrenia.

Formal thought disorder (FTD) is one of the main symptoms of schizophrenia. To date there are no whole brain volumetric studies investigating gray matter (GM) differences specifically associated with FTD. Here, we studied 20 right-handed schizophrenia patients that differed in the severity of formal thought disorder and 20 matched healthy controls, using voxel-based morphometry (VBM). The severity of FTD was measured with the Scale for the Assessment of Thought, Language, and Communication. The severity was negatively correlated with the GM volume of the left superior temporal sulcus, the left temporal pole, the right middle orbital gyrus and the right cuneus/lingual gyrus. Structural abnormalities specific for FTD were found to be unrelated to GM differences associated with schizophrenia in general. The specific GM abnormalities within the left temporal lobe may help to explain language disturbances included in FTD.

Performance during face processing differentiates schizophrenia patients with delusional misidentifications.

BACKGROUND: Delusional misidentification syndrome (DMS) is of considerable interest, but rarely diagnosed clinically. It is supposed to occur relatively frequently in schizophrenia, and to be related to the pathophysiology of face processing. Two antagonistic forms of DMS are the hypoidentification (Capgras) and hyperidentification (Fregoli) syndromes. We aimed to highlight differences between these subtypes using a face recognition memory task. METHODS: Twenty schizophrenia patients (10 with DMS) and 21 healthy controls memorized the images of unknown neutral faces (targets). After a 10-min interval, accuracy and reaction times were recorded during a recognition task consisting of targets (newly learned faces), as well as familiar and unfamiliar face images. The 10 DMS patients could be further subdivided into 6 patients with Fregoli syndrome and 4 with Capgras syndrome. RESULTS: Patients with DMS had longer reaction times than controls or patients without DMS (p < 0.001). Fregoli patients had longer reaction times (p < 0.001) and lower discrimination accuracy than Capgras patients (p = 0.019). These results were independent of other clinical variables. CONCLUSIONS: Face recognition differs between clinically identified subgroups of schizophrenia and between types of DMS. The results indicate independent pathophysiological mechanisms for Capgras (hypoidentification) and Fregoli (hyperidentification) syndromes in schizophrenia.

Structural and metabolic changes in language areas linked to formal thought disorder.

BACKGROUND: The role of the language network in the pathophysiology of formal thought disorder has yet to be elucidated. AIMS: To investigate whether specific grey-matter deficits in schizophrenic formal thought disorder correlate with resting perfusion in the left-sided language network. METHOD: We investigated 13 right-handed patients with schizophrenia and formal thought disorder of varying severity and 13 matched healthy controls, using voxel-based morphometry and magnetic resonance imaging perfusion measurement (arterial spin labelling). RESULTS: We found positive correlations between perfusion and the severity of formal thought disorder in the left frontal and left temporoparietal language areas. We also observed bilateral deficits in grey-matter volume, positively correlated with the severity of thought disorder in temporoparietal areas and other brain regions. The results of the voxel-based morphometry and the arterial spin labelling measurements overlapped in the left posterior superior temporal gyrus and left angular gyrus. CONCLUSIONS: Specific grey-matter deficits may be a risk factor for state-related dysfunctions of the left-sided language system, leading to local hyperperfusion and formal thought disorder.

Quantitative motor activity differentiates schizophrenia subtypes.

BACKGROUND: Motor symptoms are frequent in schizophrenia and relevant to the diagnosis of subtypes. However, the assessment has been limited to observations recorded in scales and experimental designs. The aim of this study was to use wrist actigraphy to obtain motor activity data in 3 schizophrenia subtypes. METHODS: In total, 60 patients with schizophrenia (35 paranoid, 12 catatonic, 13 disorganized) were investigated using continuous wrist actigraphy over 24 h in an inpatient setting on average 38 days after admission. Data of the wakeful hours of the day were analyzed. RESULTS: The activity level was predicted by schizophrenia subtype and by the type of antipsychotic medication. The movement index and mean duration of uninterrupted immobility were found to be predicted only by the schizophrenia subtype. Age, gender, duration of illness and chlorpromazine equivalents did not contribute to the variance of the activity data. A MANOVA demonstrated the significant differences in the 3 parameters between schizophrenia subtypes (p = 0.001). Patients with catatonic schizophrenia had lower activity levels, a lower movement index and a longer duration of immobility than those with paranoid schizophrenia. CONCLUSIONS: Schizophrenia subtypes can be differentiated using objective measures of quantitative motor activity. The increased duration of immobility appears to be the special feature of catatonic schizophrenia.

Objectively measured motor activity in schizophrenia challenges the validity of expert ratings.

Motor symptoms are frequent in schizophrenia and relevant to diagnosis. They are usually assessed by clinical observation and ratings based on psychometric scales. However, investigations with quantitative measurements are rare. To understand the relationship between the objective parameters of a quantitative motor activity measurement and the items related to motor symptoms of the Positive and Negative Syndrome Scale (PANSS), 55 schizophrenia patients were studied with 24-h continuous wrist actigraphy. Activity level, movement index, and mean duration of uninterrupted immobility periods were analyzed for wakeful periods. Actigraphic parameters were strongly inter-correlated. High PANSS negative syndrome subscale scores predicted low activity levels. Single PANSS items, such as suspiciousness, hallucinatory behavior, and emotional withdrawal, contributed largely to the variance in activity level and movement index. Age, gender, medication, and duration of illness had no significant impact on the actigraphic parameters. Interestingly, correlations between the specific motor symptoms of the PANSS and the actigraphic parameters were only found as a non-significant trend. We conclude that the objectively measured quantity of movement is related to the clinically assessed negative syndrome in schizophrenia. In contrast, PANSS items related to psychomotor behavior imprecisely reflect real quantitative motor activity.

Encoding deficit during face processing within the right fusiform face area in schizophrenia.

Face processing is crucial to social interaction, but is impaired in schizophrenia patients, who experience delays in face recognition, difficulties identifying others, and misperceptions of affective content. The right fusiform face area plays an important role in the early stages of human face processing and thus may be affected in schizophrenia. The aim of the study was therefore to investigate whether face processing deficits are related to dysfunctions of the right fusiform face area in schizophrenia patients compared with controls. In a rapid, event-related functional magnetic resonance imaging (fMRI) design, we investigated the encoding of new faces, as well as the recognition of newly learned, famous, and unfamiliar faces, in 13 schizophrenia patients and 21 healthy controls. We applied region of interest analysis to each individual's right fusiform face area and tested for group differences. Controls displayed higher blood oxygenation level dependent (BOLD) activation during the memorization of faces that were later successfully recognized. In schizophrenia patients, this effect was not observed. During the recognition task, schizophrenia patients exhibited lower BOLD responses, less accuracy, and longer reaction times to famous and unfamiliar faces. Our results support the hypothesis that impaired face processing in schizophrenia is related to early-stage deficits during the encoding and recognition of faces.

Inferior frontal gyrus gray matter volume is associated with aggressive behavior in schizophrenia spectrum disorders.

We aimed to assess potential gray matter (GM) alterations for aggressive patterns of behavior in a sample of in- and outpatients with schizophrenia spectrum disorders. Eighty-four patients previously participating in brain volumetric studies were included. Aggression was assessed using the Modified Overt Aggression Scales (MOAS) based upon review of clinical records of the hospital register. Multiple regression analyses for total MOAS and each MOAS subscale separately were conducted correcting for age, sex, history of addiction, chlorpromazine equivalents, illness duration, and total intracranial volume. Significant effects were reported in two cases; the total MOAS scores and MOAS verbal aggression scores were associated with GM volume in left inferior frontal gyrus. From the demographic/clinical characteristics, only the number of episodes correlated with the subscales and the total MOAS scores. Our results highlight the role of GM volume in left inferior frontal gyri in patients with history of aggression. This evidence ties in well with previous data reporting involvement of these regions in response control and semantic networks.

The early context effect reflects activity in the temporo-prefrontal semantic system: evidence from electrical neuroimaging of abstract and concrete word reading.

Spatial and temporal characteristics of lexico-semantic retrieval are frequently examined with semantic context (i.e., priming) paradigms. These paradigms measure context (i.e., priming) effects in word processing evoked by semantically related context. Besides the well-known attention-dependent N400 context effect (>250 ms), recent studies demonstrate early automatic context effects in the P1-N1 time period (<200 ms). However, in visual word presentation the semantic origin of these early effects remains debated. This study examined spatio-temporal activation dynamics of the early context effect as well as the modulation of the effect by differences in structure and accessibility of verbal semantics existent in abstract and concrete words. The early context effect was measured in visually displayed words that followed semantically related single-word context. Spatial and temporal aspects of the effect were analyzed by applying topographic and source analyses on the word-triggered Event Related Potentials. The early context effect was enhanced in abstract compared to concrete words as indicated by a difference in the occurrence of P1-N1 transition map and a corresponding topographic dissimilarity (116-140 ms). This concreteness-dependent modulation demonstrates the sensitivity of the early context effect to structural differences in verbal semantics. Furthermore, the topographic difference was explained by enhanced activation in the left inferior prefrontal cortex for related compared to unrelated words in addition to temporo-parietal generators recruited in both conditions. The result suggests automatic feedforward processing of context-related information in temporo-prefrontal brain regions critical to semantic analysis. Taken together our findings show that the early context effect reflects activation processes in verbal semantic memory.

Formal thought disorder is related to aberrations in language-related white matter tracts in patients with schizophrenia.

This study examined the hypothesis that a fronto-temporal disconnection in the language network underpins formal thought disorder (FTD) in schizophrenia. Forty-nine patients with a schizophrenia spectrum disorder (27 with mild FTD, 22 with severe FTD) and 26 healthy controls (HC) were included. Overall psychopathology and FTD were assessed by the Positive and Negative Syndrome Scale and the Thought, Language, and Communication scale, respectively. White matter (WM) microstructure was analysed using Tract-Based Spatial Statistics. In patients, severity of overall FTD (TLC Sum Score) was predicted by decreased fractional anisotropy (FA) in the right superior longitudinal fasciculus (SLF), and severity of negative FTD (TLC Emptiness subscale) was predicted by increased FA in the left SLF and arcuate fasciculus (AF). Notably, these results were no longer significant after correction for multiple comparisons. Compared with HC, patients showed lower FA in all the investigated language-related WM tracts as well as across the whole WM skeleton. No difference in FA was found between patients with severe and patients with mild FTD. Our results are compatible with earlier studies reporting impairments in widely spread WM tracts including those related to language processing in patients with schizophrenia.