A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder.

OBJECTIVE: The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS: This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Children's Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS: Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001). CONCLUSIONS: Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.

A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder.

OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of cholinergic agents for ADHD. To this end, the authors completed a controlled study of ABT-418, a novel cholinergic activating agent, for the treatment of adults with ADHD. METHOD: This was a double-blind, placebo-controlled, randomized, crossover trial that compared a transdermal patch of ABT-418 (75 mg/day) to placebo in adults who met DSM-IV criteria for ADHD. There were two 3-week treatment periods separated by 1 week of washout. RESULTS: Of the 32 subjects enrolled in the study (88% were men; mean age = 40 years, SD = 9), 29 completed the study. At the endpoint of each active arm (last observation carried forward), a significantly higher proportion of subjects was considered improved while receiving ABT-418 than while receiving placebo (40% versus 13%). Similarly, at endpoint there was a significantly greater reduction in ADHD symptom checklist scores (28% versus 15%). Symptoms reflective of attention, and subjects with less severe ADHD, responded more robustly to ABT-418. Treatment with ABT-418 was relatively well tolerated; dizziness and nausea were the most frequently reported adverse effects. CONCLUSIONS: The results of this investigation indicate that ABT-418, a nicotinic analog, may be a potentially useful agent for the treatment of ADHD.

Controlled trial of high doses of pemoline for adults with attention-deficit/hyperactivity disorder.

Despite the increasing awareness of attention-deficit/hyperactivity disorder (ADHD) in adults, there are a limited number of controlled pharmacologic studies of this disorder. Because the stimulant medication magnesium pemoline (Cylert, Abbott Laboratories, Abbott Park, IL) has been found effective in treating ADHD in pediatric groups, we tested its efficacy in adults with ADHD using higher daily doses than those previously studied. We conducted a 10-week, double-blind, placebo-controlled, crossover design study of pemoline at a target daily dose of 3 mg/kg per day in 35 adult patients with DSM-III-R and -IV ADHD. We used standardized structured psychiatric instruments for diagnosis. To measure improvement, we used separate assessments of ADHD, depressive, and anxiety symptoms at baseline and at each biweekly visit. ADHD outcome was determined using the ADHD symptom checklist and Clinical Global Impression scales of Severity and Improvement. Of the 35 adults with ADHD who were randomized in the trial, 27 (77%) completed the protocol. Treatment with pemoline in the final week of the 4-week active phase was best tolerated at doses substantially lower than the target dose of 3 mg/kg per day (mean dose, 2.2 mg/kg per day; mean+/-SD, 148+/-95 mg). Pemoline was significantly better at reducing ADHD symptoms compared with placebo (z = 2.4,p < 0.02). Using a predefined 30% reduction in symptoms as an indication of improvement, 50% of pemoline-treated subjects and 17% of subjects in the placebo group were considered positive responders (chi2 = 7.1, p = 0.008). These results indicate that pemoline is moderately effective in the treatment of ADHD in adults. Although robust doses were targeted, most adults preferred more moderate dosing (120-160 mg/day). Given the limited efficacy, tolerability, and concerns of hepatic dysfunction, pemoline should be considered as second-line medication for treating ADHD in adults.

Correspondence between DSM-III-R and DSM-IV attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the correspondence between DSM-III-R and DSM-IV definitions of attention-deficit/hyperactivity disorder (ADHD) in clinically referred children. Results of the field trials led to the hypothesis that there would be a strong correspondence between DSM-III-R and DSM-IV subtypes. METHOD: The sample consisted of all children and adolescents consecutively referred to a pediatric psychopharmacology clinic (N = 405). Children were comprehensively evaluated with structured diagnostic interviews assessing both DSM-III-R and DSM-IV ADHD. DSM-III-R symptoms were used to approximate DSM-IV subtypes. Kappa statistics and conditional probabilities were used to examine the correspondence between DSM-III-R and DSM-IV ADHD. RESULTS: Ninety-three percent of children who received a DSM-III-R diagnosis of ADHD also received a DSM-IV ADHD diagnosis. The kappa coefficient assessing the agreement between DSM-III-R and DSM-IV ADHD was .73 (z = 14.6, p < .0001). The kappa coefficient assessing the agreement between the DSM-III-R-approximated subtypes and the actual DSM-IV subtypes was .71 (z = 15, p < .0001). CONCLUSION: These results confirm previous findings and indicate that the change from DSM-III-R to DSM-IV results in minimal changes in case identification and provides support for diagnostic continuity between the two classification systems.

Tracking of dye-labeled lymphocytes in rhesus macaques.

Lymphocytes were isolated from rhesus monkeys and marked with a fluorescent lipophilic dye to monitor their distribution in vivo. Dye-labeled cells were either monitored by blood draws over a three-month period, or identified within peripheral organs upon autopsy. Lymphocyte labeling conditions were optimized. Dye-labeled lymphocytes could be detected in the circulation for at least 100 days by flow cytometry and fluorescence microscopy. Activated lymphocytes were removed from the circulation more rapidly than lymphocytes that had not been activated.

Conditional immortalization of bicarbonate-secreting intercalated cells from rabbit.

We have derived an immortalized cell line from primary cultures of bicarbonate-secreting intercalated cells from rabbit. Cells were transfected with a plasmid encoding a temperature-sensitive large T antigen of SV40 plus the neomycin resistance gene under the control of an SV40 promoter. Transfectants were selected for resistance to G418. One stably transfected clone, designated IC250, was subcloned to ensure clonality, and a subclone (clone C) was characterized in detail. The cells divide continuously at permissive temperature. At restrictive temperature, they cease dividing and assume morphological and transport properties of true bicarbonate-secreting intercalated cells. They express appropriate ultrastructural features, bind peanut lectin in an apical pattern, are rich in carbonic anhydrase, stain for proton-adenosinetriphosphatase in a basolateral pattern, and do not stain with antibodies to erythrocyte band 3. Most monolayers of transformed type B intercalated cells do not achieve a significant transepithelial resistance; those monolayers that are sufficiently electrically tight for electrophysiological studies are capable of chloride-dependent bicarbonate transport.

Isolation and culture of HCO3- -secreting intercalated cells.

Intercalated cells of the distal nephron secrete either H+ or HCO3-. We have succeeded in isolating HCO3- -secreting intercalated cells from the rabbit kidney. When seeded onto collagen-coated permeable supports, these cells form monolayers with a resistance of 595 +/- 75 omega.cm2. The monolayers maintain the characteristics of an epithelium, with apical microvillae and tight junctions. They display the same polarity as do HCO3- -secreting intercalated cells in vivo, namely apical peanut lectin binding and apical Cl- -HCO3- exchange. The monolayers are capable of transepithelial HCO3- transport via this exchanger. The rate of Cl- -dependent transepithelial HCO3- transport is 4 +/- 0.4 nmol.min-1.cm-2. Transepithelial HCO3- transport is completely abolished by 50 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid applied to the apical side of the monolayer. These cultured HCO3- -secreting intercalated cells should prove useful for defining the cellular regulation of HCO3- secretion.