Kimberley P. Good

Extrapyramidal signs and clinical symptoms in first-episode schizophrenia : Response to low-dose risperidone

The purpose of this study was to determine the prevalence of extrapyramidal signs or symptoms (EPS) and clinical symptoms in first-episode schizophrenia, before any treatment, during and after treatment with a novel antipsychotic, risperidone. Twenty-two (17 men; 5 women) patients were examined using the Extrapyramidal Symptom Rating Scale, Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity of Illness and Improvement, and Global Assessment of Functioning. Three patients (14%) had distinct EPS at baseline, whereas all were free of EPS after treatment with risperidone. On the maximum dose of risperidone (5-8 mg), 32% of the total sample developed mild akathisia or parkinsonism, both of which diminished with dosage reduction. No clinically significant EPS were observed in patients receiving 2 to 4 mg of risperidone. Analysis of symptom response of the lower (2-4 mg) versus the higher (5-8 mg) doses of risperidone resulted in superior outcome in the 2- to 4-mg group for all three symptom clusters of the PANSS. In addition, 91% of the low-dose group achieved a 20% or greater reduction in total PANSS score compared with 27% for the high-dose group. These findings have clinical relevance directed at the early and longer-term treatment of schizophrenia.

Diffusion tensor imaging and olfactory identification testing in early-stage Parkinson's disease

Evidence from imaging, clinical studies, and pathology suggests that Parkinson’s disease is preceded by a prodromal stage that predates clinical diagnosis by several years but there is no established method for detecting this stage. Olfactory impairment, which is common in Parkinson’s disease and often predates clinical diagnosis, may be a useful biomarker for early Parkinson’s. Evidence is emerging that diffusion imaging parameters might be altered in olfactory tract and substantia nigra in the early stages of clinical Parkinson’s disease, possibly reflecting pathological changes. However, no study has examined olfaction and diffusion imaging in olfactory tract and substantia nigra in the same group of patients. The present study compared newly diagnosed Parkinson’s disease patients with a matched control group using both olfactory testing and diffusion tensor imaging of the substantia nigra and anterior olfactory structures. Fourteen patients with stage 1–2 Hoehn & Yahr Parkinson’s disease were matched to a control group by age and sex. All subjects then completed the University of Pennsylvania Smell Identification Test, as well as a series of MRI scans designed to examine diffusion characteristics of the olfactory tract and the substantia nigra. Olfactory testing revealed significant impairment in the patient group. Diffusion tensor imaging revealed significant group differences in both the substantia nigra and anterior olfactory region, with fractional anisotropy of the olfactory region clearly distinguishing the Parkinson’s subjects from controls. This study suggests that there may be value in combining behavioral (olfaction) and MRI testing to identify early Parkinson’s disease. Since loss of olfaction often precedes the motor symptoms in Parkinson’s disease, the important question raised is “will the combination of olfactory testing and MRI (DTI) testing identify pre-motor Parkinson’s disease?”

The relationship of neuropsychological test performance with the PANSS in antipsychotic naïve, first-episode psychosis patients.

BACKGROUND Chronic schizophrenia patients have been sampled for factor analytic studies to identify the factor structure of the Positive and Negative Syndrome Scale (PANSS). Many of these studies have identified a cognitive factor, which may provide useful information about patients for whom formal neuropsychological testing is unavailable. However, the relationship between the clinically rated cognitive factor and performance-based cognitive test scores has not been thoroughly examined, particularly in patients who are early in the course of illness. OBJECTIVES The validity of the PANSS cognitive factor was examined in a sample of antipsychotic naïve, first-episode psychosis patients and the PANSS items that best predicted cognitive functioning were identified. METHOD PANSS scores and performance on a battery of cognitive tests from the baseline assessment of a clinical trial of 167 neuroleptic naïve patients with schizophrenia-like illnesses were analyzed. RESULTS Factor analysis revealed a five-factor model that was consistent with previously described factor models from samples of chronically treated patients. There were modest correlations (less than r=0.44) between the derived cognitive factor and six of the neuropsychological test variables (Wisconsin Card Sorting Test total errors and number of categories correctly sorted, WMS-R immediate and delayed recall scores, Category Fluency total score, and WAIS-R digit symbol). Five PANSS items (P6, N5, N6, G2, and G10) were identified that predicted global cognitive functioning; however, 66% of the variance in cognitive functioning remained unexplained. CONCLUSIONS A PANSS cognitive factor can be identified in first-episode, neuroleptic naïve patients. However, clinical ratings of cognitive deficits lack sensitivity and specificity and thus should not be relied upon fully.

Symptoms in neuroleptic-naive, first-episode schizophrenia: response to risperidone.

Analysis of the treatment response of different groups of patients with schizophrenia may further define the range of applications and specificity of novel therapies. Clinical trials of risperidone have focused on patients with exacerbations of chronic illness, largely having had multiple previous admissions and years of prior treatment (Chouinard et al 1993; Lindstrom and von Knorring 1994; Marder and Meibach 1994). Other investigators have reported the response to clozapine by first-episode, treatment-refractory patients with schizophrenia (Szymanski et al 1994); however, no prior studies document the response of first-episode, drug-naive schizophrenia patients to another novel antipsychotic, risperidone.

Treatment of a first episode of psychotic illness with quetiapine : An analysis of 2 year outcomes

BACKGROUND The first episode of a psychotic disorder provides a unique opportunity to initiate optimal treatment but when a new medication becomes available, little data exist to guide the appropriate use in this population. OBJECTIVES The objectives were to determine the optimal doses and titration of quetiapine for this group and to measure outcomes (including symptom response, social functioning, mood alterations, motor symptoms, metabolic parameters and cognitive functioning) over 2 years of treatment with quetiapine. DESIGN Thirty nine subjects with a first episode of psychosis referred to the Nova Scotia Early Psychosis Program in Halifax, Canada, were invited to participate in this study. Standardized clinical, laboratory, and neuropsychological assessments were performed at baseline and following treatment with quetiapine at intervals out to 2 years. RESULTS Quetiapine was effective in treating the psychotic and mood symptoms while not causing extra-pyramidal signs or symptoms (EPSS). Pre-existing motor dysfunction improved. No anticholinergic medications were required. Several domains of cognitive function also improved (sustained attention, the number of perseverative errors, visuomotor speed and sequencing, verbal fluency and verbal memory). Weight gain was observed along with increases in cholesterol levels but there was no glucose dysregulation. CONCLUSIONS The results of this two year, naturalistic study of people with a first episode of psychosis indicated that quetiapine was well tolerated and effective for this population. Significant improvements in cognitive functioning also provided evidence for potential longer-term benefits of early and optimal treatment with this agent. However, monitoring metabolic parameters, as recommended for other atypicals, is likely prudent.

Unirhinal olfactory identification deficits in young male patients with schizophrenia and related disorders: association with impaired memory function

We have observed discreet subgroups of male patients with psychotic disorders who have unirhinal olfactory identification deficits (microsmia). The purpose of this study was to examine the relationship between left or right nostril microsmia and performance on literalised neuropsychological tests sensitive to lesions in brain areas implicated in the pathogenesis of schizophrenia. Sixty-six male patients diagnosed with schizophrenia or related disorders were assessed with a battery of neuropsychological tests, sensitive to literalised and regional (temporal and frontal lobe) dysfunction. The University of Pennsylvania Smell Identification Test (UPSIT) was administered unirhinally and resultant scores were used to classify patients into olfactory subgroups. Neuropsychological test scores were compared amongst subgroups. A mixed design MANOVA was performed on cognitive domains with olfactory status (right microsmic; RM, n=8, left microsmic; LM, n=20, and normosmic schizophrenic controls; NSzC, n=38) as the between subject factor while hemisphere (left versus right) and domain (executive/fluency versus memory) were within-subject factors. A three-way (olfactory subgroup by hemisphere by region) interaction was observed. Non-verbal memory impairment was observed in the right and left microsmic subgroups. Verbal memory deficits were demonstrated in patients with left nostril microsmia. These results indicate that unirhinal olfactory performance may provide a meaningful manner by which to subtype patients with schizophrenia. Moreover, the data suggest that olfactory deficits in patients with schizophrenia are associated with dysfunction of temporal lobe, rather than frontal lobe abnormalities. The data are consistent with reports linking the right temporal lobe integrity to adequate olfactory processing.

Left nostril olfactory identification impairment in a subgroup of male patients with schizophrenia

Abnormal structural brain asymmetries have been reported in schizophrenia in brain areas which overlap with olfactory processing regions, with abnormalities more often described within the left hemisphere. We attempted to determine whether the olfactory agnosia observed in some male patients with schizophrenia was more likely left-hemisphere based. We assessed unirhinal (single nostril) olfactory identification and detection threshold in 65 male patients who met DSM-IV criteria for the diagnosis of schizophrenia and 59 healthy male control subjects. A two-way, mixed-design ANCOVA with diagnosis as the between-group factor, nostril as the within-subject factor and age as covariate was used to compare olfactory identification ability. This analysis demonstrated that patients with schizophrenia performed more poorly than the healthy controls across nostrils, but no differences were observed in either group between nostrils. However, when patients were classified according to unirhinal olfactory status (impaired left < right, impaired right < left, normosmic left < right, normosmic right < left), impaired patients were more than twice as likely to be classified as having a left nostril disadvantage than right nostril disadvantage. In contrast, within the normosmic group of patients, this pattern was reversed. Moreover, when those patients whose unirhinal olfactory scores differed by less than two points were removed from the analysis, a 2:1 ratio of left < right versus right < left was observed in the impaired patients. These results suggest that for impaired male patients with schizophrenia, olfactory identification deficits are more likely found for the left nostril, perhaps indicative of abnormalities in olfactory processing within the left hemisphere.

Unirhinal norms for the University of Pennsylvania Smell Identification Test.

Adult normative data are presented for unirhinal administration of the University of Pennsylvania Smell Identification Test (UPSIT). Two-hundred and seventy healthy adults, aged 15-64, were administered half of the UPSIT (20 items) to each nostril. The main findings were: (1) unirhinal and birhinal performance are not equivalent necessitating the use of unirhinal norms, rather than prorated birhinal norms, (2) unirhinal performance does not differ according to nostril of presentation, (3) unirhinal performance does not differ according to sex, (4) within the age ranges studied, age accounted for only a minor proportion of the variability, and (5) being a current smoker and having lower levels of formal education contributed to reduced unirhinal UPSIT scores. Correction factors are suggested for the education and smoking variables. Unirhinal evaluation may assist in further delineating the structural integrity of specific ipsilateral brain regions and potentially aid in differential diagnosis for a number of disorders.

Olfaction and schizophrenia clinical risk status: Just the facts

Dear Editors, The recent meta-analysis by Cohen et al. (2012) offered a review of the evidence regarding olfactory dysfunction in both schizophrenia patients and individuals at risk for the illness. Their analysis supported the presence of a robust olfactory identification deficit in patients. However, concerning the study of at-risk individuals, they concluded as follows: “Overall, the present findings failed to find evidence that olfaction identification deficits are a meaningful vulnerability marker of schizophrenia pathology..(We) believe that conducting further studies…is not a particularly promising endeavor.” It is our opinion that this assertion could have an unwarranted and unfortunate chilling effect on future research, as it does not accurately reflect the current status of the field. In reviewing 16 studies purported to examine schizophrenia risk status, the authors conflate three very different categories of risk. Five were studies of otherwise-healthy individuals who scored high on a psychometric scale of schizotypal features (e.g. Schizotypal Personality Questionnaire). Nine were studies of unaffected family members of schizophrenia patients. Only two were studies of “ultra-high risk” individuals in the sub-psychotic or prodromal state, as assessed by the Structured Interview for Prodromal Syndromes (SIPS). The incidence of future conversion to overt psychosis is very different in these sub-categories. Grouping them together presents a distorted picture that can lead to erroneous conclusions. Conversion rates among prodromal individuals with symptoms severe enough to prompt clinical referral have been reported as approximately 35% within 2.5 years (Cannon et al., 2008). Unaffected first-degree relatives of schizophrenia patients, in contrast, have a lifetime psychosis incidence of approximately 10% (Karlsson, 1982). Since most of the published family studies were of older adults (i.e., parents and siblings of schizophrenia probands), many of whom were already past the peak ages of illness onset, the actual incidence in this group was likely substantially lower. In the two existing large-scale longitudinal studies of individuals with psychometrically defined schizotypy, one reported zero cases of psychosis among 91 “at-risk” subjects after 5 years (Gooding et al., 2005). The other reported 10 cases of psychosis among 182 subjects (5.5%) after 10 years (Chapman et al., 1994). Clearly, the risk for psychosis among ultra-high risk subjects greatly exceeds the risk among individuals in the other two categories. A sensitive and specific marker of disease vulnerability should, ideally, reflect this heightened risk profile. Indeed, any vulnerability marker that cannot distinguish among these three groups has very little predictive utility. The results for odor identification, as reported by Cohen, are entirely consistent with these expectations regarding an ideal vulnerability marker. He determined the effect size for the ultra-high risk group to be −0.67 (a moderate to large effect), whereas the effect sizes for unaffected family members and psychometrically defined schizotypals were −0.21 and −0.14, respectively (small to insignificant effects). The facts regarding olfaction and clinical high-risk status are the following. There have been a total of three published studies of olfactory deficits in clinical high-risk subjects relative to demographically comparably healthy individuals (Brewer et al., 2003; Kamath et al., 2012; Woodberry et al., 2010). The overall effect size in the Brewer study was −0.48 (Woods, S.J. Personal communication). The effect size, as listed in the Woodbury manuscript, was −0.89 (not −0.84 as reported by Cohen). The effect sizes in the Kamath study — which was not included in Cohen’s review due to its recent publication — were −1.26 for odor identification and −1.11 for odor discrimination. A meta-analysis of all available data from these three studies yields a composite effect size of −0.77, rather than −0.67. Importantly, the Brewer and Woodberry studies also included longitudinal follow-ups of their clinical high-risk participants, which allowed them to examine separately the baseline data from those subjects who subsequently became psychotic. The effect sizes for these future-psychosis subsamples were substantially higher than for the high-risk groups as a whole, −0.68 and −1.32, respectively. Brewer’s future-psychosis sample was large enough to be further parsed into those who developed schizophrenia and those who developed other psychotic illnesses. The effect size for odor identification deficits in those who subsequently developed schizophrenia was −1.12; for those who developed other psychoses, it was −0.24. So the facts, as opposed to the fiction, regarding olfaction and clinical high-risk status are these. There have been three independent studies to date, with three sets of positive findings, a large composite effect, and initial evidence to suggest that this impairment is indicative of a future schizophrenia-spectrum psychotic disorder. The magnitude, consistency and predictive potential of this deficit collectively establish olfactory impairment as one of the most viable biomarkers of the psychosis clinical high-risk state yet identified. Our confidence in making this assertion would, of course, be greater if it were based on a greater number of studies, and it may ultimately be proven false. But to conclude, based on current evidence, that further study is unwarranted would be a truly egregious error.

Olfactory deficits in patients with schizophrenia and severe polydipsia

BACKGROUND The present study was designed to assess olfactory function in severely polydipsic/hyponatremic patients with schizophrenia who also had intermittent water intoxication. METHODS The University of Pennsylvania Smell Identification Test and an olfactory acuity battery were administered to three groups of male subjects: 9 patients with schizophrenia and severe polydipsia/hyponatremia, 9 control nonpolydipsic/normonatremic patients with schizophrenia, and 9 normal controls. RESULTS Male patients with severe polydipsia/hyponatremia and intermittent water intoxication had marked olfactory acuity and identification deficits when compared to the patient control group of similar age and age at illness onset, and to normal controls. CONCLUSIONS The finding of deficient acuity (detection threshold) in the polydipsic/hyponatremic group but not the nonpolydipsic, normonatremic group suggests that for this subgroup, abnormalities of olfactory sensory function may occur in a pattern previously reported for other brain disorders such as Alzheimers disease.