Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.

OBJECTIVE: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. METHOD: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. RESULTS: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. CONCLUSIONS: Paroxetine is generally well tolerated and effective for major depression in adolescents.

School-based behavioral treatment for social anxiety disorder in adolescents: results of a pilot study.

OBJECTIVE: To provide preliminary estimates of feasibility and effectiveness for school-based behavioral treatment in adolescents with social anxiety disorder. METHOD: Six adolescents with social anxiety disorder were treated in a 14-session group treatment program conducted at their school. Assessments were conducted at baseline and after treatment. RESULTS: All participants were classified as treatment responders (markedly or moderately improved). Half of the participants did not meet diagnostic criteria for social phobia after treatment. Clinician severity ratings, as measured by the Anxiety Disorders Interview Schedule for Children for DSM-IV: Child Version and the Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA), decreased significantly after intervention, with effect sizes of 2.5 and 1.8, respectively. All LSAS-CA scale scores decreased significantly after treatment. Self-reported social phobia symptoms on the Social Phobia and Anxiety Inventory for Children were not significantly reduced. Fear and avoidance ratings of the 10 most feared situations significantly decreased after treatment, with effect sizes of 1.5 for anxiety and 2.1 for avoidance. CONCLUSIONS: This study provides preliminary support for the promise of school-based behavioral intervention for treating social phobia in adolescents. The school environment may be a rich and innovative setting for implementation of behavioral treatment because this is the setting where adolescents with social phobia endure the most distress.

Carcinogenicity assays of wood dust and wood additives in rats exposed by long-term inhalation.

OBJECTIVE: This study evaluates whether wood dust and/or wood preservatives develop a carcinogenic potential against the tissues of the airways of rats. METHODS: The formation of tumors of the respiratory tract after exposure to wood dust was studied in six groups of approximately 60 female Fischer 344 rats exposed by long-term inhalation to mean concentrations of (1) 18 mg/m3 of untreated oak wood dust, (2) wood preservatives containing ca. 1 microgram/m3 lindane and 0.2 microgram/m3 of pentachlorophenol (PCP) in the exposure air, or lindane and 18 micrograms/m3 of PCP (group lindane/PCP vapors, and group oak wood treated with lindane/PCP), (3) 21 or 39 micrograms/m3 of sodium dichromate (calculated as CrO3, group chromate aerosol and group oak wood with chromate), and 72 micrograms/m3 of N-nitrosodimethylamine vapors as positive control. The negative control group consisted of 115 animals (sham-exposed). RESULTS: Tumors of the nasal cavity developed in two rats exposed to chromate aerosol or in combination with wood dust (2/102, 2%). Malignant tumors of the lower respiratory tract were induced only in exposed groups of rats (three adenocarcinomas of the lung and four bronchiolar lung carcinomas, 7/254, 2.8%). More respiratory tract tumors were observed in rats exposed to chromate or wood with chromate (5/102, 5%), also in groups exposed to oak wood dust (oak untreated, oak + chromate, oak + lindane/PCP; together 5/155, 3.2%). Analysis of 'unpreserved' oak wood dust revealed up to 5 micrograms/m3 of chromate. When this exposure was taken into account, eight of nine animals with respiratory tract tumors (including nasal cavity) had exposure to chromate, while only one tumor occurred in the group lindane/PCP. Otherwise the incidence of systemic tumors was increased in animals exposed to lindane/PCP, due in particular to a significantly increased incidence of liver tumors (OR = 3.7; 1.24-11.3; P = 0.019). Fatal (mucoepidermoid) tumors were induced by N-nitrosodimethylamine (NDMA) in the positive control (14/46, 30%). No such tumors of the respiratory tract were observed in the negative control. CONCLUSIONS: Tumors in the respiratory tract were found only in exposed animals, predominantly in the groups which inhaled oak wood dust and chromate stain. Chromate may play a decisive role for the etiology of tumors of the nasal cavity in wood workers. This assumption should be supported by further dose-response studies.

Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group.

BACKGROUND: To examine the relationship between respiratory regulation and childhood anxiety disorders, this study considered the relationship between anxiety disorders and symptoms during carbon dioxide (CO(2)) exposure, CO(2) sensitivity in specific childhood anxiety disorders, and the relationship between symptomatic and physiological responses to CO(2). METHODS: Following procedures established in adults, 104 children (aged 9-17 years), including 25 from a previous study, underwent 5% CO(2) inhalation. The sample included 57 probands with an anxiety disorder (social phobia, generalized anxiety disorder, separation anxiety disorder, and panic disorder) and 47 nonill comparison subjects. Symptoms of anxiety were assessed before, during, and after CO(2) inhalation. RESULTS: All children tolerated the procedure well, experiencing transient or no increases in anxiety symptoms. Children with an anxiety disorder, particularly separation anxiety disorder, exhibited greater changes in somatic symptoms during inhalation of CO(2)-enriched air, relative to the comparison group. During CO(2) inhalation, symptom ratings were positively correlated with respiratory rate increases, as well as with levels of tidal volume, minute ventilation, end-tidal CO(2), and irregularity in respiratory rate during room-air breathing. CONCLUSIONS: Childhood anxiety disorders, particularly separation anxiety disorder, are associated with CO(2) hypersensitivity, as defined by symptom reports. Carbon dioxide hypersensitivity is associated with physiological changes similar to those found in panic disorder. These and other data suggest that certain childhood anxiety disorders may share pathophysiological features with adult panic disorder.

Long-term prognosis in attention-deficit/hyperactivity disorder.

The authors have traced the developmental course of ADHD from childhood to adulthood, showing that it is a bumpy road for many. In early and middle adolescence, relative deficits are seen in academic and social functioning, ADHD symptoms remain problematic in two thirds to three quarters of these children, and antisocial behaviors, in some cases amounting to CD, are common. Many of these same difficulties persist into the late teenage years. Deficits continue to be observed in academic and social domains (compared with controls, probands exhibit lower grades, more courses failed, worse performance on standardized tests, have fewer friends, and are rated less adequate in psychosocial adjustment). About two fifths continue to experience ADHD symptoms to a clinically significant degree. One quarter to one third have a diagnosed antisocial disorder, and two thirds of these individuals are arrested. Also, drug abuse is observed in a significant minority of these youths. Importantly, the greatest risk factor for the development of antisocial behavior and substance abuse by the late teenage years is the maintenance of ADD symptoms. When evaluated in their mid-twenties, dysfunctions are apparent in these same areas. Compared with controls, probands complete less schooling, hold lower-ranking occupations, and continue to suffer from poor self-esteem and social skills deficits. In addition, significantly more probands than controls exhibit an antisocial personality and, perhaps, a substance use disorder in adulthood. Furthermore, many do not outgrow all facets of their childhood syndrome. These relative deficits, however, do not tell the whole story of the ADHD child's adult fate. Indeed, nearly all probands were gainfully employed. Furthermore, some had achieved a higher-level education (e.g., completed Master's degree, enrolled in medical school) and occupation (e.g., accountant, stock broker). In addition, a full two thirds of these children showed no evidence of any mental disorder in adulthood. In conclusion, although ADHD children, as a group, fare poorly compared with their non-ADHD counterparts, the childhood syndrome does not preclude attaining high educational and vocational goals, and most children no longer exhibit clinically significant emotional or behavioral problems once they reach their mid-twenties.

Cerebral laterality in adolescent major depression.

This study tests the hypothesis that adolescents with major depression exhibit abnormalities in cerebral asymmetry previously found among adults. Perceptual asymmetry was assessed through tests of verbal and non-verbal dichotic listening in four groups - 48 adolescents with major depression, 22 adolescent comparisons with no history of Axis I disorders, 149 adults with major depression, and 57 comparison adults with no history of Axis I disorders. Data from adults have been previously reported. In both age groups, subjects with major depression were further divided based on the presence or absence of an anxiety disorder. Procedures used to collect perceptual asymmetry data in adolescents and adults were identical. In both age groups, depressed and healthy subjects showed perceptual asymmetry in expected directions for verbal and non-verbal dichotic tasks. Depressed and comparison subjects differed in performance on the Fused-Word Test, though these differences varied as a function of anxiety and developmental level. Relative to comparisons, both adolescents and adults with major depression exhibited an increased right ear/left hemisphere advantage for fused words. Adults but not adolescents with comorbid major depressive and anxiety disorders exhibited a reduced right ear/left hemisphere advantage for fused words. These findings suggest similarities and differences across development in the relationship between cerebral laterality and psychopathology. Further studies using longitudinal and family-based designs, as well as various measures of regional brain activity, are needed to enhance understanding of associations between cerebral laterality and psychopathology across development.

Middle Stone Age stratigraphy and excavations at Die Kelders Cave 1 (Western Cape Province, South Africa): the 1992, 1993, and 1995 field seasons.

Die Kelders Cave 1, first excavated under the direction of Franz Schweitzer in 1969-1973, was re-excavated between 1992 and 1995 by a combined team from the South African Museum, SUNY at Stony Brook, and Stanford University. These renewed excavations enlarged the artefactual and faunal samples from the inadequately sampled and less intensively excavated lower Middle Stone Age (MSA) layers, increased our understanding of the complex site formation processes within the cave, enlarged the hominid sample from the MSA deposits, and generated ESR, TL, and OSL dates for the MSA layers. Importantly, these new excavations dramatically improved our comprehension of the vertical and lateral characteristics of the MSA stratigraphy. Surface plotting of the MSA layers has led to the identification of at least two major zones of subsidence that significantly warped the layers, draping some along the eroding surface contours of major blocks of fallen limestone roof rock. A third zone of subsidence is probably present in the older excavations. Dramatic roof falls of very large limestone blocks occurred at least twice-once in the middle of Layer 4/5 where the roof blocks were only slightly weathered after collapse, and at the top of Layer 6 where the blocks weathered heavily after collapse, producing a zone of decomposed rock around the blocks. Many of the sandy strata are cut by small and localized faults and slippages. All of the strata documented by Schweitzer's excavations are present throughout the exposed area to the west of his excavated area, where many of them thicken and become more complex. Layer 6, the thickest MSA layer, becomes less diagenetically altered and compressed to the west.

Middle and Later Stone Age large mammal and tortoise remains from Die Kelders Cave 1, Western Cape Province, South Africa.

Die Kelders Cave 1, South Africa, has provided more than 150,000 taxonomically identifiable mammal and tortoise bones from Middle Stone Age (MSA) and Later Stone Age (LSA) deposits. Cape dune mole-rats dominate the mammal sample, and they appear to have been accumulated mainly by people during the LSA occupation and mainly by eagle owls in the MSA. In sharp contrast to the LSA fauna, the MSA sample contains extralimital ungulates that imply relatively moist, grassy conditions. The large mean size of the MSA mole-rats also points to greater humidity, while the large size of the gray mongooses implies cooler temperatures. The sum supports luminescence and ESR dates that place the MSA occupation within the early part of the Last Glaciation (global isotope stage 4). The Die Kelders ungulate bones support those from Klasies River Mouth in suggesting that MSA people obtained dangerous terrestrial prey much less frequently than their LSA successors, probably because MSA people lacked the bow and arrow and other projectile weapons. The Die Kelders tortoise bones constrain the extent of climatic change, since their abundance indicates that warm, dry days remained common, at least seasonally. The tortoises tend to be much larger in the MSA layers than in the LSA ones, suggesting that MSA people collected tortoises less intensively, probably because MSA populations were relatively sparse.

Electroencephalographic asymmetries in adolescents with major depression: influence of comorbidity with anxiety disorders.

This study examined whether adolescents with major depressive disorder (MDD) display the abnormal electroencephalographic (EEG) alpha asymmetries found in depressed adults. Resting EEG was recorded in 25 right-handed female outpatients (19 with MDD, 11 of whom also had a current anxiety disorder; 6 with anxiety disorders only) and 10 non-ill controls. In contrast to the non-ill controls, adolescents having MDD but no anxiety disorder showed alpha asymmetry indicative of less activation over right than over left posterior sites. Within the MDD patient group, comorbid anxiety disorders reduced the posterior alpha asymmetry, supporting the potential importance of evaluating anxiety in studies of regional brain activation in adolescent MDD. These preliminary findings are similar to those from adult studies that suggest that MDD is associated with right parietotemporal hypoactivation.

Duinefontein 2: an Acheulean site in the Western Cape Province of South Africa.

Excavations at Duinefontein (DFT) 2 near Cape Town, South Africa have recovered numerous stone artefacts and animal bones on an ancient surface sealed within iron-stained eolian sands. U-series analysis of an overlying calcrete places the sands before 150 ka ago, while the large mammal taxa imply an age between 400 and 200 ka ago. The artefacts include a classic Acheulean handaxe and probable biface shaping flakes that support this age estimate. The principal mammalian species are long-horned buffalo, black wildebeest, greater kudu, Cape zebra, and grysbok/steenbok, which imply a grass-and-bush mosaic instead of the historic small-leafed shrubland. Hippopotamus and reedbuck indicate that water stood nearby, probably in dune swales. The large mammal bones are mostly vertebrae and other axial elements, often in near-anatomical order. Both proximal and distal appendicular elements are rare. Bones with carnivore damage are common, but ones with stone tool marks are scarce. The sum suggests a water-edge attritional death site where people played a minimal role and carcasses were disarticulated mainly by carnivore feeding and by trampling. Stone tool marks tend to be equally rare at other Acheulean attritional death sites, and the implication may be that Acheulean people rarely obtained large mammals, whether by hunting or scavenging. Human scavengers at DFT2 would not have encountered a disproportionate number of distal (versus proximal) limb elements, and it follows that the tendency for distal elements to dominate many archeological assemblages need not reflect scavenging versus hunting. Even if DFT2 was not itself a locus of intense human activity, it provides a useful baseline for evaluating bone damage, skeletal part representation, and other variables at sites where people were deeply involved.

Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.

Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake.

Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue rats and Muta Mouse mice in vivo after inhalation.

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation frequency up to 4. 5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of nickel subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.

Mutagenic activity of carcinogens detected in transgenic rodent mutagenicity assays at dose levels used in chronic rodent cancer bioassays.

Data on transgenic rodent mutagenicity of five human carcinogens were summarised and compared with the results from rodent carcinogenicity studies. Four out of five carcinogens showed mutagenic activity already at daily dose levels which induced cancer in long-term rodent bioassays in at least one target tissue of carcinogenesis. In several of these studies, even single dose applications were sufficient to significantly increase the mutation frequency in vivo. Other genotoxic carcinogens required application of multiple dosing at dose-levels used in rodent cancer bioassays to show their in vivo mutagenicity. A rodent respiratory tract carcinogen, 1,2-dibromoethane (DBE), following inhalation exposure, displayed no mutagenic activity, neither in lung nor in nasal mucosa, at a single 2-h exposure to 30 ppm, which is below the highest concentration used in a NTP cancer bioassay. In contrast, after multiple treatment for 10 days at the same daily doses, a significant increase of the mutation frequency in nasal mucosa was apparent. We conclude, that especially when studying new chemicals in these transgenic rodent mutation assays, a multiple dosing protocol should be preferred. For dose selection, the same criteria could be applied as for chronic rodent bioassays.

Additional human fossils from Klasies River Mouth South Africa.

A fragmentary temporal bone and partial atlas from the Middle Stone Age (MSA) at Klasies River Mouth (KRM) are described and analyzed. The atlas (SAM-AP 6268) is comparable to Levantine "Early Modern", Neandertal and recent human vertebrae. The temporal (SAM-AP 6269) is similar to recent African homologues except that the posteromedial wall of the glenoid fossa is composed entirely of the squamous temporal, a situation that appears to be infrequent among other Pleistocene fossils. The KRM glenoid fossa is also mediolateraly broad and anteroposteriorly short in comparison with many, but not, all recent specimens. Nevertheless, the KRM temporal is decidedly modern, both morphologically and metrically, by comparison with other Pleistocene specimens. The limited evidence provided by this bone is consistent with that of other MSA cranial remains from this site in suggesting an overall, if somewhat ambiguous pattern of morphological modernity.

Adolescent depression: controlled desipramine treatment and atypical features.

The study was designed to test the efficacy of desipramine in adolescents with major depression (MDD). In addition, we assessed the presence of atypical features of MDD, consisting of mood reactivity and two of four associated features (rejection sensitivity, hyperphagia, hypersomnia, and leaden paralysis). Patients were randomized to desipramine (DMI) or placebo for 6 weeks, provided they failed to improve (e.g., meeting MDD criteria and a Hamilton Depression Scale score > or = 18) after 2 weeks on single blind placebo. Of 94 adolescents (ages 13-18) who were diagnosed as having MDD, 64 entered the study and 62 received placebo for 2 weeks. Of these, 45 were randomized to DMI or placebo. Completed analyses did not reveal significant improvement for the active treatment compared to the placebo. A large proportion of adolescents responded to placebo (50%), suggesting the need for very large samples to detect differential treatment efficacy, should it exist. A relatively high rate of atypical depression was observed (47% in the 64 patients entered). In view of the demonstrated specificity of monoamine oxidase inhibitor efficacy in adults with atypical features of MDD, this clinical subtype may have relevance to future investigation of therapeutic interventions in adolescent MDD.

Adult psychiatric status of hyperactive boys grown up.

OBJECTIVE: Numerous studies have examined the adolescent and young adult fate of children with attention deficit hyperactivity disorder (ADHD). In marked contrast, relatively little is known about the adult outcome of these children. There have been only two controlled, prospective studies of psychiatric status into adulthood. The present study was conducted to gain further understanding of the natural course of this common childhood condition. METHOD: This was a prospective follow-up of clinically diagnosed, white boys of average intelligence who were referred by teachers to a child psychiatric research clinic at an average age of 7.3 years. At a mean age of 24.1 years, 85 probands (82% of the childhood cohort) and 73 comparison subjects (94% of adolescent comparison subjects) were directly interviewed by trained clinicians who were blind to group status. RESULTS: Evaluations of the probands and comparison subjects indicated significantly higher prevalences of antisocial personality disorder (12% versus 3%) and nonalcohol substance abuse (12% versus 4%) in the probands, whereas mood disorders (4% versus 4%) and anxiety disorders (2% versus 7%) were not significantly different. At adult follow-up, ADHD was rare, occurring in only 4% of the probands (no comparison subjects). CONCLUSIONS: The results of the present study are consistent with the authors' previously reported major findings. They strongly suggest that children with ADHD are at significantly higher risk for a specific negative course marked by antisocial and substance-related disorders.

Ventilatory physiology of children and adolescents with anxiety disorders.

BACKGROUND: Abnormalities in ventilatory physiology have been noted in adults with panic disorder. We tested the hypothesis that abnormalities in ventilatory physiology differentiate children and adolescents with anxiety disorders from psychiatrically healthy children. METHODS: Ventilatory physiology was monitored with a canopy apparatus during room-air breathing and 15 minutes of carbon dioxide exposure in 33 children and adolescents comprising 18 probands with an anxiety disorder and 15 psychiatrically healthy children. RESULTS: During room-air breathing, probands had significantly larger minute ventilation, larger tidal volumes, and more variable breathing patterns than healthy comparisons, but the groups did not differ in end-tidal carbon dioxide or respiratory rate. During carbon dioxide challenge, probands exhibited larger minute ventilation and respiratory rate responses relative to comparisons. CONCLUSION: These findings on the association between ventilatory physiology and anxiety disorders in children and adolescents are consistent with results from studies of adults with panic disorder.