David Printz

Resting neural activity distinguishes subgroups of schizophrenia patients

BACKGROUND Schizophrenia is etiologically heterogeneous. It is anticipated, but unproven, that subgroups will differ in neuropathology and that neuroimaging may reveal these differences. The optimal imaging condition may be at rest, where greater variability is observed than during cognitive tasks, which more consistently reveal hypofrontality. We previously demonstrated symptom and physiologic differences between familial and sporadic schizophrenia patients and hypothesized that the groups would show different resting regional cerebral blood flow (rCBF) patterns. METHODS Ten familial and sixteen sporadic schizophrenia patients and nine comparison subjects had single photon emission computed tomography imaging during passive visual fixation. Images were spatially normalized into Talairach coordinates and analyzed for group rCBF differences using SPM with a Z value threshold of 2.80, p < .001. RESULTS The subgroups had similar age, gender, illness duration, and medication treatment. Sporadic patients had hypofrontality (anterior cingulate, paracingulate cortices, left dorsolateral and inferior-orbitofrontal), whereas familial patients had left temporoparietal hypoperfusion; all of these regions show resting activity in healthy subjects. Both groups hyperperfused the cerebellum/pons and parahippocampal gyrus; additional hyperperfusion for sporadic patients was observed in the fusiform; familial patients also hyperperfused the hippocampus, dentate, uncus, amygdala, thalamus, and putamen. CONCLUSIONS Familial and sporadic schizophrenia patients had different resting rCBF profiles, supporting the hypothesis that certain subgroups have distinct neural underpinnings. Different neuropathologic processes among subgroups of schizophrenia patients may account for the prior contradictory results of resting imaging studies.

Prenatal protein deprivation in rats induces changes in prepulse inhibition and NMDA receptor binding

Epidemiological studies suggest that prenatal malnutrition increases the risk of developing schizophrenia. Animal models indicate that prenatal protein deprivation (PPD) affects many aspects of adult brain function. We tested the hypothesis that PPD in rats would alter prepulse inhibition (PPI), which is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. Additionally, we examined dopaminergic and glutaminergic receptor binding in the striatum and hippocampus, which have been suggested to play a role in the etiology of schizophrenia. Rat dams were fed normal (25%) or low (6%) protein diets beginning 5 weeks prior to, and throughout pregnancy. The pups were tested at postnatal days (PND) 35 and 56 for PPI. Striatal and hippocampal NMDA receptor, and striatal dopamine receptor binding were quantified post-mortem in a subset of these rats. Female rats exposed to PPD had reduced levels of PPI at PND 56, but not PND 35, suggesting the emergence of a sensorimotor gating deficit in early adulthood. Striatal NMDA receptor binding was increased in PPD females. A decrease in initial startle response (SR) was also observed in all PPD rats relative to control rats. These results suggest that PPD causes age- and sex-dependent decreases in PPI and increases in NMDA receptor binding. This animal model may be useful for the investigation of neurodevelopmental changes that are associated with schizophrenia in humans.

A pilot study of noradrenergic and HPA axis functioning in PTSD vs. panic disorder

The biological literature in the anxiety disorders has focused on comparisons between patient groups and normal volunteers, with relatively little comparative study of the anxiety disorders. We therefore conducted this pilot study to compare a group of patients with post-traumatic stress disorder (PTSD) (n = 7) to a contiguously studied panic disorder group (n = 17) and healthy control subjects (n = 16) on baseline levels of cortisol and 3-methoxy-4-hydroxyphenylglycol (MHPG), and response to clonidine challenge. Despite the small sample size, highly significant differences were found on the following measures: PTSD patients had lower cortisol, lower MHPG, reduced MHPG volatility to clonidine challenge, and marginally reduced cortisol volatility compared to patients with panic disorder. These biological findings support existing clinical, epidemiologic, family study, and clinical trial findings that distinguish these two disorders as distinct syndromes.

Elevation of CD5+ B lymphocytes in schizophrenia.

BACKGROUND A variety of immunologic alterations have been observed in patients with schizophrenia. These findings have lent support to theories that autoimmune mechanisms may be important in some patients with the illness. The CD5+ B lymphocyte, a B-cell subset associated with autoimmune disease, has been the subject of two previously published studies yielding disparate results. METHODS In this study, we used immunofluorescent flow cytometry to measure CD5+ B cells, total B and T cells, and CD4 and CD8 subsets in patients with schizophrenia and in normal control subjects. RESULTS A significantly higher percentage of patients with schizophrenia, relative to normal control subjects, exhibited an elevated level of CD5+ B cells (27.6% vs 6.7%). Antipsychotic withdrawal had no effect on CD5+ B-cell levels, suggesting that medication effects were not the cause of this difference. No other studied lymphocyte subsets differed between the two groups. CONCLUSIONS A subset of patients with schizophrenia have elevated levels of CD5+ B cells. This finding replicates an earlier study by another group and provides further evidence suggestive of autoimmune manifestations in schizophrenia.

Medication treatment of bipolar disorder 2000: a summary of the expert consensus guidelines.

&NA; The original Expert Consensus Guidelines on the Treatment of Bipolar Disorder were published in 1996. Since that time, a variety of new treatments for bipolar disorder have been reported; however, evidence for these treatments varies widely, with data especially limited regarding comparisons between treatments and how to sequence them. For this reason, a new survey of expert opinion was undertaken to bridge gaps between the research evidence and key clinical decisions. The results of this new survey, which was completed by 58 experts, are presented in The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000, which was published in April 2000 as a Postgraduate Medicine Special Report. In this article, the authors describe the methodology used in the survey and summarize the clinical recommendations given in the resulting guidelines. The expert panel reached consensus on many key strategies, including acute and preventive treatment of mania (euphoric, mixed, and dysphoric subtypes), depression, rapid cycling, and approaches to managing treatment resistance and comorbid psychiatric conditions. Use of a mood stabilizer is recommended in all phases of treatment. Divalproex (especially for mixed or dysphoric subtypes) and lithium are the primary mood stabilizers for both acute and preventive treatment of mania. If monotherapy with these agents fails, the next recommended intervention is to combine them. This combination of lithium and divalproex can then serve as the foundation to which other medications are added if needed. Carbamazepine is the leading alternative mood stabilizer for mania. The experts rated the other new anticonvulsants as second‐line options (i.e., their use is recommended if lithium, divalproex, and carbamazepine fail or are contraindicated). For milder depression, a mood stabilizer, especially lithium, may be used as monotherapy. Divalproex and lamotrigine are other first‐line choices. For more severe depression, the experts recommend combining a standard antidepressant with lithium or divalproex. Bupropion, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine are preferred antidepressants. The antidepressants should usually be tapered 2–6 months after remission. Monotherapy with divalproex is recommended for the initial treatment of either depression or mania in rapid‐cycling bipolar disorder. Antipsychotics are recommended for use in combination with the above regimens for mania or depression with psychosis, and as potential adjuncts in nonpsychotic episodes. Atypical antipsychotics, especially olanzapine and risperidone, were generally preferred over conventional antipsychotics. The guidelines also include recommendations concerning the use of electroconvulsive therapy (ECT), clozapine, thyroid hormone, stimulants, and various novel agents for patients with treatment‐refractory bipolar illness. The experts reached high levels of consensus on key steps in treating bipolar disorder despite obvious gaps in high‐quality data. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data; however, their recommendations are generally conservative. Experts give their strongest support to initial strategies and medications for which high‐quality research data or longstanding patterns of clinical usage exist. Within the limits of expert opinion and with the understanding that new research data may take precedence, these guidelines provide clear pathways for addressing common clinical questions and can be used to inform clinicians and educate patients about the relative merits of a variety of interventions.

Etiological heterogeneity and intelligence test scores in patients with schizophrenia

Previous research has indicated that patients with a family history of schizophrenia show a greater degree of cognitive and neuropsychological impairment than patients without a family history. We examined the neurocognitive performance, using the WAIS-R, of 51 patients with a family history (familial) and 103 patients without a family history (sporadic) to determine if differences exist that may help to explain the heterogeneous neuropsychological profile of the illness. The family history groups did not differ with respect to gender, diagnosis, ethnicity, age, age of onset, education or duration of illness. Multivariate analyses, covarying for age of onset and education, showed the sporadic group performed significantly better than the familial group on the digit symbol and object assembly subtests, with a trend level difference in overall performance IQ score. Additionally, we identified significant gender differences in favor of males for full scale and verbal IQ, the information, digit span, block design, and arithmetic subtests, and at a trend level, the picture assembly subtest. The family history group differences reflect relative dysfunction in visual attention and scanning, visuomotor control, and spatial processing and reasoning. Overall, the results suggest that sporadic patients have better perceptual-organizational skills and faster speed of processing.

Spiking fevers with clozapine treatment

Clozapine often causes low-grade fever and less frequently spiking fever. We describe three cases of spiking fever that occurred in the first 3 weeks of clozapine therapy. A new set of side effects of clozapine is identified, which includes spiking fever, respiratory and gastrointestinal symptoms, and neutrophilia. Possible mechanisms are discussed.