Mary E. Kelley

Association of Pre-Onset Cannabis, Alcohol, and Tobacco Use With Age at Onset of Prodrome and Age at Onset of Psychosis in First-Episode Patients

OBJECTIVE Several reports suggest that cannabis use is associated with an earlier age at onset of psychosis, although not all studies have operationalized cannabis use as occurring prior to onset of symptoms. This study addressed whether pre-onset cannabis use, alcohol use, and tobacco use are associated with an earlier age at onset of prodromal and psychotic symptoms. Effects of the progression of frequency of use were examined through time-dependent covariates in survival analyses. METHOD First-episode patients (N=109) hospitalized in three public-sector inpatient psychiatric units underwent in-depth cross-sectional retrospective assessments. Prior substance use and ages at onset of prodromal and psychotic symptoms were determined by standardized methods, and analyses were conducted using Cox regression modeling. RESULTS Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with an increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness or prodromal symptoms was the outcome. A gender-by-daily-cannabis-use interaction was observed; progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than in males. CONCLUSIONS Pre-onset cannabis use may hasten the onset of psychotic as well as prodromal symptoms. Age at onset is a key prognostic factor in schizophrenia, and discovering modifiable predictors of age at onset is crucial.

Elevated interleukin-6 in schizophrenia

Interleukin 6 (IL-6) levels have been shown to be increased in a number of autoimmune disorders and have recently been shown to be elevated in the serum of schizophrenic patients. Given the involvement of the CNS in schizophrenia, levels of interleukin-6 in the CSF are also of interest. Thus, we examined levels of both CSF and serum IL-6 concomitantly to determine if these levels were different from control values. In addition, we examined these measures in patients both on and off antipsychotic drugs to determine if any medication or exacerbation effects may account for the difference from controls. CSF IL-6 was measured by ELISA in 61 drug-free male schizophrenic (DSM-IIIR) patients and 25 well-screened healthy male control subjects. Serum IL-6 was measured in 43 of the 61 patients, and in 16 control subjects. Serum IL-6 was significantly higher in the schizophrenic patients compared to control subjects. CSF IL-6 was also higher in the patients, but the difference was not statistically significant. Paired data showed no medication or exacerbation effects on CSF IL-6, but plasma IL-6 significantly decreased in patients that experienced an exacerbation after medication withdrawal. The results indicate that IL-6 levels may be altered in schizophrenia. The relative decrease in exacerbated patients following haloperidol withdrawal may be indicative of a compensatory response of plasma IL-6 levels to relapse.

Racial/Ethnic Variations in Physician Recommendations for Cardiac Revascularization

OBJECTIVES We sought to examine whether physician recommendations for cardiac revascularization vary according to patient race. METHODS We studied patients scheduled for coronary angiography at 2 hospitals, one public and one private, between November 1997 and June 1999. Cardiologists were interviewed regarding their recommendations for cardiac resvacularization. RESULTS African American patients were less likely than Whites to be recommended for revascularization at the public hospital (adjusted odds ratio [OR] = 0.31; 95% confidence interval [CI] = 0.12, 0.77) but not at the private hospital (adjusted OR = 1.69; 95% CI = 0.69, 4.14). CONCLUSIONS Physician recommendations for cardiac revascularization vary by patient race. Further studies are needed to examine physician bias as a factor in racial disparities in cardiac care and outcomes.

Comparison of Consumption Effects of Brief Interventions for Hazardous Drinking Elderly

We sought to determine if Brief Interventions [BIs, Motivational Enhancement (ME), and Brief Advice (BA)] reduced alcohol consumption among hazardous alcohol drinking elderly (65 years or older) and whether the elderly responded similarly to younger populations. In 12 primary care offices from 10 1995 to 12 1997, we screened 13,438 patients of whom 2702 were elderly (180 were hazardous drinkers). Forty-five elderly enrollees were randomized to receive ME (n = 18), BA (n = 12), and Standard Care (SC, n = 12). At baseline, the elderly drank more alcohol and abstained fewer days than the younger cohort (p<0.05). During the year, the elderly in ME, BA, and SC intervention arms increased the number of days abstained, decreased the number of drinks per day, and reduced the number of total days per month drinking. There were trends toward decreases in the alcohol consumption measures in the ME and BA treatment arms compared to SC. The elderlys response to all interventions was similar to that of the younger cohort. This study suggests that hazardous alcohol consumption in the elderly is common and that BIs reduce alcohol consumption in the elderly similar to younger populations.

Pretreatment brain states identify likely nonresponse to standard treatments for depression

BACKGROUND Treatment approaches for major depressive disorder (MDD) result in approximately one third of patients achieving remission after a first treatment. Added treatment generally improves remission rates, but approximately one third of all patients fail to respond after several treatments (sequential monotherapies or combined treatment). A pretreatment biomarker could help identify these patients. Overactivity of the subcallosal cingulate has been associated with failure of response to treatment in MDD, and it is a potential candidate for such a biomarker. METHODS Investigators enrolled 82 patients with MDD currently not receiving treatment in a two-phase treatment study. Patients underwent a fluorodeoxyglucose positron emission tomography scan. After scanning, patients were randomly assigned to 12 weeks of treatment with either escitalopram or cognitive-behavioral therapy (CBT). Patients not achieving remission after 12 weeks of initial treatment were treated with an additional 12 weeks of escitalopram plus CBT. Subcallosal cingulate metabolism was compared between patients who failed to achieve a response and patients who achieved remission as a result of either phase one or phase two treatment. This analysis was followed by a whole-brain analysis making the same comparison. RESULTS After two phases of treatment (24 weeks), 36 patients were identified as remitters, 6 patients were responders, and 9 patients were nonresponders. Subcallosal cingulate metabolism was significantly higher in nonresponders than remitters. In the follow-up whole-brain analysis, increased superior temporal sulcus activity was also associated with nonresponse to two treatments. CONCLUSIONS Patients with MDD who fail to achieve remission as a result of CBT or escitalopram, either alone or in combination, have a distinct brain metabolic pattern compared with patients who achieve remission as a result of CBT, escitalopram, or their combination.

Further Studies of Elevated Cerebrospinal Fluid Neuronal Cell Adhesion Molecule in Schizophrenia

BACKGROUND The purposes of the present study were to attempt to replicate a previous finding of increased cerebrospinal fluid (CSF) neuronal cell adhesion molecule (N-CAM) in schizophrenia, and to assess whether the increases could be related to medication, clinical state effects, or brain structural measures. METHODS CSF N-CAM was measured by the Western blot technique in 45 DSM-III-R diagnosed male schizophrenic patients both on and off haloperidol treatment and in 20 healthy male control subjects. RESULTS CSF N-CAM was significantly increased in schizophrenic patients, with no overlap in the ranges, when compared to controls. There were no significant effects of medication or exacerbation on CSF N-CAM. No associations with measures of brain structure were found. CONCLUSIONS Because N-CAM levels were not shown to be different on and off treatment or in exacerbated versus nonexacerbated patients, the higher levels seen in schizophrenic patients may be inherent to the disorder and possibly related to neurodevelopment.

Tai Chi and perceived health status in older adults who are transitionally frail : A randomized controlled trial

Background and Purpose Tai chi, a Chinese exercise derived from martial arts, while gaining popularity as an intervention for reducing falls in older adults, also may improve health status. The purpose of this study was to determine whether intense tai chi (TC) exercise could improve perceived health status and self-rated health (SRH) more than wellness education (WE) for older adults who are transitionally frail. Subjects Study subjects were 269 women who were ≥70 years of age and who were recruited from 20 congregate independent senior living facilities. Methods Participants took part in a 48-week, single-blind, randomized controlled trial. They were randomly assigned to receive either TC or WE interventions. Participants were interviewed before randomization and at 1 year regarding their perceived health status and SRH. Perceived health status was measured with the Sickness Impact Profile (SIP). Results Compared with WE participants, TC participants reported significant improvements in the physical dimension and ambulation categories and borderline significant improvements in the body care and movement category of the SIP. Self-rated health did not change for either group. Discussion and Conclusion These findings suggest that older women who are transitionally frail and participate in intensive TC exercise demonstrate perceived health status benefits, most notably in ambulation.

Predictors of remission in depression to individual and combined treatments (PReDICT): study protocol for a randomized controlled trial

BackgroundLimited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient’s treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition.Methods/designTreatment-naïve adults aged 18 to 65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: (1) cognitive behavior therapy (CBT, 16 sessions); (2) duloxetine (30–60 mg/d); or (3) escitalopram (10–20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin-releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occurs at an early time-point in treatment, and upon completion of 12-week treatment, when a second Dex/CRH test is also conducted. Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes.DiscussionThe PReDICT study’s evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness.Trial registrationClinicaltrials.gov Identifier: NCT00360399. Registered 02 AUG 2006. First patient randomized 09 FEB 2007.

Elevated cerebrospinal fluid SNAP-25 in schizophrenia

BACKGROUND Research suggests an association between abnormal exocytosis and schizophrenia. We previously demonstrated increased synaptosomal associated protein, 25 kDa (SNAP-25), a member of the exocytotic mechanism, in the cerebrospinal fluid (CSF) of schizophrenia subjects. In this study, we explored SNAP-25 level and clinical variables in a new group of subjects. METHODS Twenty-five haloperidol-treated subjects with chronic schizophrenia and twenty-five healthy control subjects participated in the study. Subjects received haloperidol treatment for at least 3 months and then had a lumbar puncture (n = 19). Medication was replaced by placebo, and the lumbar puncture was repeated (n = 25) after 6 weeks or sooner if limited psychotic symptoms occurred. We measured the level of SNAP-25 in the CSF and symptoms with the Brief Psychiatric Rating Scale (BPRS). RESULTS In both haloperidol (p =.001) and placebo (p =.001) treatment conditions, SNAP-25 was elevated. There was no significant difference in SNAP-25 level between conditions. We identified significant positive correlations among SNAP-25 and the BPRS total score and psychosis and thinking disturbance subscales in subjects on haloperidol. CONCLUSIONS These observations confirm our previous report of elevated CSF SNAP-25 and suggest that synaptic pathology may be linked with the pathophysiology of schizophrenia.

Mood and behavioral symptoms in individuals with chronic solvent exposure

Psychiatric symptoms have been reported for individuals who experience chronic exposure to low levels of organic solvents. However, it is not known what proportion of such individuals experience psychiatric disorder; which specific disorders may be characteristic of this population; or whether bioaccumulation of lead contributes to the relationship between solvent exposure and psychiatric symptoms. Twenty-nine male journeymen painters and 32 male non-painter control subjects were administered semi-structured diagnostic interviews for DSM-III-R Axis I and Axis II disorders. Career solvent exposure and blood lead levels were also measured. Painters and control subjects did not differ significantly with respect to age, intelligence, or demographic characteristics. Results showed that the probability of being diagnosed with a mood disorder differed significantly in painters (41%) and control subjects (16%). Painters (66%) and control subjects (50%) did not differ for substance use diagnoses. Groups also did not differ for personality disorders involving an onset before 25 years of age. In contrast, painters exhibited a sub-clinical pattern of personality dysfunction involving symptomatology that was measured allowing for late onset (after age 25). Finally, a significant dose-response relationship was observed between career solvent exposure, blood lead level, and personality symptoms. In summary, these data showed an increased rate of psychological disturbance in a significant and substantial number of painters. However, not all painters were so characterized. This overall pattern raises a question regarding a potential role for differential vulnerability, which requires empirical validation.