Cherise Rosen

Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial.

BACKGROUND Many severely depressed patients do not benefit from or tolerate existing treatments. Repetitive transcranial magnetic stimulation (rTMS) has been reported to benefit depression. We compared rTMS to electroconvulsive therapy (ECT) in severely ill, depressed patients. METHODS Twenty-five patients with a major depression (unipolar or bipolar) deemed clinically appropriate for ECT were randomly assigned to rTMS (10-20 treatments, 10 Hz, 110% motor threshold applied to the left dorsolateral prefrontal cortex for a total of 10,000-20,000 stimulations) or a course of bitemporal ECT (4-12 treatments). The primary outcome measure was the 24-item Hamilton Depression Rating Scale (HDRS). The Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMS), and Clinical Global Impression scale (CGI) were secondary measures. Minimal rescue medications were utilized. RESULTS Mean percent improvement on the baseline HDRS score did not significantly differ between the two treatments (i.e., 55% for the rTMS group vs. 64% for the ECT group [p = ns]). With response defined as a 50% reduction from baseline and a final score < or = 8 on the HDRS, there was also no significant difference between the two groups. We did not observe any differences between groups on the secondary measures. CONCLUSIONS A 2-4 week randomized, prospective trial comparing rTMS to ECT produced comparable therapeutic effects in severely depressed patients.

A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia.

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n=41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.

Periods of Recovery in Deficit Syndrome Schizophrenia: A 20-Year Multi–follow-up Longitudinal Study

Periods of recovery were examined in patients with and without deficit syndrome schizophrenia. Fifty-six patients with schizophrenia were studied, 39 of whom were divided into deficit and nondeficit syndrome schizophrenia subtypes using a proxy method. We also studied 39 nonpsychotic depressive comparison patients. Patients were evaluated as part of the Chicago Follow-up Study, which prospectively examined patients at regular intervals over a 20-year period. Using standardized instruments, patients were evaluated for the deficit syndrome, global recovery, rehospitalization, social dysfunction, occupational disability, and symptom presentation. Recovery was examined at 6 time points measured at 2-, 4.5-, 7.5-, 10-, 15-, and 20-year postindex hospitalization. Cumulatively, over the 20-year period, 13% of patients classified as meeting criteria for the deficit syndrome showed 1 or more 1-year periods of global recovery, in comparison to 63% of nondeficit schizophrenia patients and 77% of depressed patient controls. Results indicate that the deficit syndrome represents a persistently impaired subsample of schizophrenia patients, with continuous social, occupational, and symptom impairment. In contrast, nondeficit syndrome schizophrenia patients showed at least some periods of remission or recovery, with the likelihood of these periods increasing as they became older. Findings provide further support for the validity of the deficit syndrome concept and suggest that deficit status is characterized by a more persistently impaired course of illness and particularly poor long-term prognosis.

Failure of positive but not negative emotional valence to enhance memory in schizophrenia.

Abnormalities in the integration of emotion and cognition have long been considered hallmark characteristics of schizophrenia. Study authors used a well-established emotional memory model from the neuroscience literature to assess the facilitative impact of emotional valence of information on long-term memory consolidation in schizophrenia. Participants with schizophrenia (n=33) indicated somewhat higher levels of emotional intensity in response to emotional images than did healthy (n=28) participants. However, when recognition memory was tested 24 hr later, schizophrenia participants did not show enhancement of memory for positive images as was found in healthy participants. Their memory enhancement for negative images did not differ from that of healthy participants. Correlations between self-reported physical and social anhedonia were significantly inversely correlated with intensity ratings of positive stimuli during the encoding phase for healthy participants but were negligible for schizophrenia participants. These results suggest a failure to adequately integrate positive emotional experience in memory consolidation processes in schizophrenia participants, despite appropriate initial response to positive stimuli, which may contribute to symptoms such as anhedonia by reducing the long-term impact of positive experiences in motivating hedonic behavior in day-to-day life.

Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal study of psychosis and recovery

This longitudinal study was designed to provide data on sex differences in the course of schizophrenia and other psychotic disorders. Ninety-seven participants (43 women and 54 men) were assessed during index hospitalization when they were in the acute phase of illness and then reassessed prospectively at 6 consecutive follow-ups over a 20-year period. Patients were evaluated by a series of standardized measures on many aspects of illness including the presence of psychosis, global outcome, and rate of recovery. When women were compared to men in this sample, the data demonstrated a lower percentage of psychotic activity for women over the course of illness (significant at the 7.5- and 20-year follow-ups), and a significant improvement in psychotic activity over 20 years for women (P < .05), but not for men. In addition, women showed significantly better global functioning (P < .05) at 3 of the 6 follow-ups (the 2-, 7.5-, and 10-year follow-ups). Significantly higher percentages (P < .05) of women were in recovery at 2 of the 6 follow-up years (the 2- and 10-year follow-ups). Cumulatively, 61% of the women with schizophrenia showed a period of recovery at some point during the 20-year period compared to 41% of the men. The sex difference patterns were similar for patients with schizophrenia and for those with other types of psychotic disorders. Sex differences in this sample were specifically not attributable to differences in age of onset or premorbid developmental achievements.

Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depression.

OBJECTIVE Repetitive transcranial magnetic stimulation (rTMS) is being investigated as a potential treatment for depression. Few studies have addressed the neurocognitive effects of a course of rTMS in severely depressed patients. We evaluated neurocognitive effects of a 1-4 week course (mean 3 weeks) of rTMS using an aggressive set of parameters, in 15 severely depressed subjects. METHODS A battery of neurocognitive tests relevant to attention, working memory-executive function, objective memory and motor speed were administered to 15 subjects with treatment-resistant major depression (unipolar and bipolar), before and after a course of rTMS. Mean z scores were computed for each of 4 cognitive domains and analyzed using repeated measures multivariate analysis of covariance. Significant interactions were further clarified using univariate analysis of variance. RESULTS There was no worsening of performance on any of the cognitive domains over the baseline-post rTMS period. On the contrary, evidence of modest but statistically significant improvement in performance was noted in working memory-executive function, objective memory and fine motor speed domains over the rTMS treatment period. CONCLUSIONS There was no evidence of adverse neurocognitive changes over the baseline-post rTMS period in 15 treatment-resistant depressed subjects undergoing a 3 week (mean) trial of rTMS. Significant improvements in several domains observed over the rTMS treatment period could not be explained by improved mood. Practice effects as well as other factors potentially contributing to these findings are discussed. SIGNIFICANCE rTMS is being increasingly studied as a neurophysiological probe as well as for its potential antidepressive effects. The effects on neuronal function raise appropriate questions of safety of its use at varying stimulus parameters and durations. This study contributes to the small body of evidence of the cognitive effects of rTMS in severely depressed patients.

Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: Preliminary results from a clinical population

Levels of acetylated Histone 3 and 4 proteins are strongly predictive of a chromatin structure that is conducive to gene expression. In cell and animal studies, valproic acid is a potent inhibitor of histone deactylating enzymes, and consequently results in increased levels of acetylated Histone 3 (acH3) and acetylated Histone 4 proteins (acH4). To examine this effect in a clinical setting, 14 schizophrenic and bipolar patients were treated with valproic acid (Depakote ER), either as monotherapy or in combination with antipsychotics, over a period of 4 weeks. AcH3 and acH4 levels from lymphocyte nuclear protein extracts were measured by Western Blot. Treatment with Depakote ER resulted in a significant increase of acH3 and a trend-level increase of acH4. Levels of valproic acid were positively and significantly correlated with percent increase in acH3 but not acH4. Schizophrenia patients were significantly less likely to increase their acH3 and acH4 levels after 4 weeks on Depakote ER. The authors consider these results in the context of future application of HDAC inhibitors to the treatment of psychiatric disorders.

Diagnostic and prognostic significance of Schneiderian first-rank symptoms: a 20-year longitudinal study of schizophrenia and bipolar disorder

OBJECTIVE This research addresses the following questions: what is the prevalence and severity of first-rank symptoms (FRS) during an extended period of time in patients with schizophrenia and bipolar disorder with psychosis? Are the specific FRS listed in Diagnostic and Statistical Manual of Mental Disorders DSM, Third Edition, Revised/Fourth Edition Criterion A for schizophrenia diagnosis (a voice keeping a running commentary or voices conversing) more prevalent and severe in patients with schizophrenia than bipolar disorder with psychosis? Lastly, do FRS at index hospitalization in patients with schizophrenia predict the absence of later recovery? METHODS This research follows a sample of patients with psychotic disorders who were evaluated at index hospitalization and then prospectively followed-up at 6 evaluations during next 20 years (n = 86). All patients were evaluated as part of a prospective research study designed to measure multiple factors of phenomenology, severity of illness, course of illness, prognosis, and global outcome. RESULTS First-rank symptoms are not exclusive to schizophrenia; they also occur in some bipolar patients. However, they are more frequent and more severe in patients with schizophrenia than bipolar disorder. Schizophrenia patients with FRS during the acute phase are more likely to have poorer long-term outcome than schizophrenia patients who do not have FRS during the acute phase. CONCLUSIONS Our results indicate FRS at the acute phase are not a clinicopathologic correlate specific to schizophrenia. However, the presence and severity of any FRS and specifically of the 2 FRS associated with Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised/Fourth Edition Criterion A are more prevalent and more severe in patients with schizophrenia than patients with bipolar disorder.

Neurocognition in schizophrenia: A 20-year multi-follow-up of the course of processing speed and stored knowledge

Individuals with schizophrenia have relative deficits in cognition, although little is known regarding the course of such deficits across the life span and at various stages of the illness. Furthermore, the relationship between psychosis and cognition has not been adequately explored to this point. Prospective, longitudinal, multi-assessment studies of the same patients across time are rare in the field and provide a unique opportunity to examine long-term changes in cognition among individuals with schizophrenia. As part of The Chicago Follow-up Study, we prospectively assessed 244 psychiatric inpatients, including individuals with schizophrenia, other psychotic disorders, and nonpsychotic depression. Assessments were conducted 7 times (once at index hospitalization and then 6 times subsequently for the next 20 years) to provide longitudinal data about cognition and symptoms, with a focus on 2 aspects of cognition: processing speed and the ability to access general knowledge. The Digit Symbol-Coding and Information subtests from the Wechsler Adult Intelligence scale were used to measure the 2 cognitive domains at each assessment. At all 7 assessments, individuals with schizophrenia performed more poorly than the other diagnostic groups on the 2 cognitive measures. However, after the acute phase (index hospitalization), individuals with schizophrenia demonstrated significant improvements in cognition and did not show evidence of cognitive decline over the remaining 6 assessments spanning 20 years. Our data support the presence of relative cognitive impairment in schizophrenia, as well as a pattern of stability in some cognitive areas after the acute phase. In addition, we find evidence for an association between relative cognitive impairment and psychosis.

An fMRI study of visual attention and sensorimotor function before and after antipsychotic treatment in first-episode schizophrenia.

While much is known about receptor affinity profiles of antipsychotic medications, less is known about their impact on functional brain systems in patients with schizophrenia. We conducted functional magnetic resonance imaging (fMRI) studies with first-episode schizophrenia patients as they made saccades to unpredictable visual targets before and after 4-6 weeks of antipsychotic treatment. Matched healthy individuals were scanned at similar time intervals. Pretreatment, patients had less activation in frontal and parietal eye fields and cerebellum. After treatment these disturbances were not present, suggesting improved function in attentional and sensorimotor systems. Other pretreatment abnormalities were noted in sensory and ventromedial prefrontal cortex, but after treatment these abnormalities were absent or less prominent, in line with improved function in attentional systems. In addition, although not abnormal at baseline, there was reduced activity after treatment in dorsal prefrontal cortex, dorsal striatum, and dorsomedial thalamus, suggesting a potential adverse effect of treatment on frontostriatal systems, perhaps related to dopamine blockade in the caudate. These findings provide evidence for a complex impact of antipsychotic medication on functional brain systems in schizophrenia and illustrate the potential of neuroimaging biomarkers for both adverse and beneficial drug effects on functional brain systems.