Jeffrey B. Weilburg

The neuropsychiatry of the cerebellum - insights from the clinic.

A central aspect of the cerebellar cognitive affective syndrome is the dysregulation of affect that occurs when lesions involve the ‘limbic cerebellum’ (vermis and fastigial nucleus). In this case series we describe neuropsychiatric disturbances in adults and children with congenital lesions including cerebellar agenesis, dysplasia, and hypoplasia, and acquired conditions including cerebellar stroke, tumor, cerebellitis, trauma, and neurodegenerative disorders. The behaviors that we witnessed and that were described by patients and families included distractibility and hyperactivity, impulsiveness, disinhibition, anxiety, ritualistic and stereotypical behaviors, illogical thought and lack of empathy, as well as aggression and irritability. Ruminative and obsessive behaviors, dysphoria and depression, tactile defensiveness and sensory overload, apathy, childlike behavior, and inability to appreciate social boundaries and assign ulterior motives were also evident. We grouped these disparate neurobehavioral profiles into five major domains, characterized broadly as disorders of attentional control, emotional control, and social skill set as well as autism spectrum disorders, and psychosis spectrum disorders. Drawing on our dysmetria of thought hypothesis, we conceptualized the symptom complexes within each putative domain as reflecting either exaggeration (overshoot, hypermetria) or diminution (hypotonia, or hypometria) of responses to the internal or external environment. Some patients fluctuated between these two states. We consider the implications of these neurobehavioral observations for the care of patients with ataxia, discuss the broader role of the cerebellum in the pathogenesis of these neuropsychiatric symptoms, and revisit the possibility of using cerebellar stimulation to treat psychiatric disorders by enhancing cerebellar modulation of cognition and emotion.

Effect of computerized order entry with integrated decision support on the growth of outpatient procedure volumes: seven-year time series analysis.

PURPOSE To determine the effect of a computerized radiology order entry (ROE) and decision support (DS) system on growth rate of outpatient computed tomography (CT), magnetic resonance (MR) imaging, and ultrasonography (US) procedure volumes over time at a large metropolitan academic medical center. MATERIALS AND METHODS Institutional review board approval was obtained for this study of deidentified aggregate administrative data. The research was compliant with HIPAA; informed consent was waived. This was a retrospective study of outpatient advanced imaging utilization before, during, and after implementation of a Web-based ROE and DS system. Dependent variables were the quarterly volumes of outpatient CT, MR imaging, and US examinations from quarter 4 of 2000 through quarter 4 of 2007. Outpatient visits during each quarter were included as control variables. These data were analyzed as three separate time series with piecewise linear regression for simultaneous estimation of quarterly examination volume trends before and after ROE and DS system implementation. This procedure was repeated with log-transformed quarterly volumes to estimate percentage growth rates. RESULTS There was a significant decrease in CT volume growth (274 per quarter) and growth rate (2.75% per quarter) after ROE and DS system implementation (P < .001). For MR imaging, growth rate decreased significantly (1.2%, P = .016) after ROE and DS system implementation; however, there was no significant change in quarterly volume growth. With US, quarterly volume growth (n = 98, P = .014) and growth rate (1.3%, P = .001) decreased significantly after ROE implementation. These changes occurred during a steady growth in clinic visit volumes in the associated referral practices. CONCLUSION Substantial decreases in the growth of outpatient CT and US procedure volume coincident with ROE implementation (supplemented by DS for CT) were observed. The utilization of outpatient MR imaging decreased less impressively, with only the rate of growth being significantly lower after interventions were in effect.

Using electronic medical records to enable large-scale studies in psychiatry: treatment resistant depression as a model

BACKGROUND Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define treatment outcome. METHOD Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out-patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard. RESULTS Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross-sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non-Caucasian (p<0.001). CONCLUSIONS The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity.

Recommendations for additional imaging in radiology reports: multifactorial analysis of 5.9 million examinations.

PURPOSE To quantify the rates of recommendation for additional imaging (RAI) in a large number of radiology reports of different modalities and to estimate the effects of 11 clinically relevant factors. MATERIALS AND METHODS This HIPAA compliant research was approved by the institutional review board under an expedited protocol for analyzing anonymous aggregated radiology data. All diagnostic imaging examinations (n = 5 948 342) interpreted by radiologists between 1995 and 2008 were studied. A natural language processing technique specifically designed to extract information about any recommendations from radiology report texts was used. The analytic data set included three quantitative variables: the interpreting radiologists experience, the year of study, and patient age. Categoric variables described patient location (inpatient, outpatient, emergency department), whether a resident dictated the case, patient sex, modality, body area studied, ordering service, radiologists specialty division, and whether the examination result was positive. A multivariable logistic regression model was used to determine the effect of each of these factors on likelihood of RAI while holding all others equal. RESULTS Recommendations increased during the 13 years of study, with the unadjusted rate rising from roughly 6% to 12%. After accounting for all other factors, the odds of any one examination resulting in an RAI increased by 2.16 times (95% confidence interval: 2.12, 2.21) from 1995 to 2008. As radiologist experience increased, the odds of an RAI decreased by about 15% per decade. Studies that had positive findings were more likely (odds ratio = 5.03; 95% confidence interval: 4.98, 5.07) to have an RAI. The remaining factors also had significant effects on the tendency for an RAI. CONCLUSION The likelihood of RAI increased by 15% for each decade of radiologist experience and roughly doubled over 13 years of study.

An Electronic Health Records Study of Long-term Weight Gain Following Antidepressant Use

IMPORTANCE Short-term studies suggest antidepressants are associated with modest weight gain but little is known about longer-term effects and differences between individual medications in general clinical populations. OBJECTIVE To estimate weight gain associated with specific antidepressants over the 12 months following initial prescription in a large and diverse clinical population. DESIGN, SETTING, AND PARTICIPANTS We identified 22,610 adult patients who began receiving a medication of interest with available weight data in a large New England health care system, including 2 academic medical centers and affiliated outpatient primary and specialty care clinics. We used electronic health records to extract prescribing data and recorded weights for any patient with an index antidepressant prescription including amitriptyline hydrochloride, bupropion hydrochloride, citalopram hydrobromide, duloxetine hydrochloride, escitalopram oxalate, fluoxetine hydrochloride, mirtazapine, nortriptyline hydrochloride, paroxetine hydrochloride, venlafaxine hydrochloride, and sertraline hydrochloride. As measures of assay sensitivity, additional index prescriptions examined included the antiasthma medication albuterol sulfate and the antiobesity medications orlistat, phentermine hydrochloride, and sibutramine hydrochloride. Mixed-effects models were used to estimate rate of weight change over 12 months in comparison with the reference antidepressant, citalopram. MAIN OUTCOME AND MEASURE Clinician-recorded weight at 3-month intervals up to 12 months. RESULTS Compared with citalopram, in models adjusted for sociodemographic and clinical features, significantly decreased rate of weight gain was observed among individuals treated with bupropion (β [SE]: -0.063 [0.027]; P = .02), amitriptyline (β [SE]: -0.081 [0.025]; P = .001), and nortriptyline (β [SE]: -0.147 [0.034]; P < .001). As anticipated, differences were less pronounced among individuals discontinuing treatment prior to 12 months. CONCLUSIONS AND RELEVANCE Antidepressants differ modestly in their propensity to contribute to weight gain. Short-term investigations may be insufficient to characterize and differentiate this risk.

Fluoxetine versus trazodone in depressed geriatric patients.

A total of 27 subjects began active treatment in this double-blind study comparing the efficacy and safety of trazodone and fluoxetine in geriatric depressed patients, but only 13 completed 6 weeks on study medication. Both agents were effective according to weekly and endpoint analyses, and there was no evidence of significant effects on blood pressure, pulse, or weight. Separate analysis of patients who had received an adequate trial of medication indicated a trend toward relatively more fluoxetine-treated patients meeting clinical criteria for resolved depression. (J Geriatr Psychiatry Neurol 1989;2:208-214.)

Antidepressant Response in Patients With Major Depression Exposed to NSAIDs: A Pharmacovigilance Study

OBJECTIVE It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system. METHOD Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed. RESULTS NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21-2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables. CONCLUSIONS These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding.

Tricyclic Augmentation of Fluoxetine

AbstractThe addition of low-dose tricyclic antidepressant (e.g., 10-50 mg of DMI) was employed as a treatment adjunct for 20 outpatients with major depressive disorder and/or dysthymia whose response to fluoxetine alone had been inadequate. Retrospective assessment revealed complete resolution of depression (full response) in 13 patients (65%) after adjunct was added. Improvement was evident within seven days of introduction of the adjunct in seven of the responders (54.8%). One patient worsened, experiencing increased agitation. No treatment-emergent side effects were observed in the other 19 patients. TCA plasma levels obtained in nine patients while combination treatment was ongoing were higher than would be expected for that dose of TCA used alone, but none of the levels were in the toxic range.

Low-level sensory processing in obsessive-compulsive disorder: An evoked potential study

This study used visual and auditory evoked potentials (VEP and AEP) to study low-level sensory processing in a group of 15 unmedicated subjects with obsessive-compulsive disorder (OCD) and 30 age-matched, gender-matched, and handedness-matched normal controls. EPs were recorded to flash (VEP) and binaural click (AEP) stimulation. OCD subjects were found to have significantly shorter latencies on N1 and P2 of the AEP, and no differences were found in the VEP. Results indicate abnormal information processing states in OCD during low-level auditory processing, but not during low-level visual processing. Neural generators of the VEP and AEP are briefly reviewed and results are discussed in relation to current neurobiological models of OCD.

Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants

Objective To examine the association between exposure to newer antidepressants and risk of gastrointestinal (GI) and other bleeding complications among individuals with major depressive disorder (MDD). Design This study uses an incident user cohort design to compare associations between incidence of vascular/bleeding events and the relative affinity (low, moderate or high) of the antidepressant for the serotonin transporter during an exposure risk period for each patient. Setting New England healthcare system electronic medical record database. Participants 36 389 individuals with a diagnosis of MDD and monotherapy with a selective serotonin reuptake inhibitor, serotonin–norepinephrine reuptake inhibitor or other new-generation antidepressant were identified from among 3.1 million patients in a New England healthcare system. Primary and secondary outcome measures Rates of bleeding or other vascular complications, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures. Results 601 GI bleeds were observed in the 21 462 subjects in the high-affinity group versus 333 among the 14 927 subjects in the lower affinity group (adjusted RR: 1.17, 95% CI 1.02 to 1.34). Similarly, 776 strokes were observed in the high-affinity group versus 434 in the lower affinity treatment group (adjusted RR: 1.18, 95% CI 1.06 to 1.32). No significant association with risk for a priori negative control outcomes, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures, was identified. Conclusions Use of antidepressants with high affinity for the serotonin transporter may confer modestly elevated risk for GI and other bleeding complications. While multiple methodologic limitations must be considered, these results suggest that antidepressants with lower serotonin receptor affinity may be preferred in patients at greater risk for such complications.