Empirically tested psychotherapies for youth internalizing and externalizing problems and disorders

This article is a review of specific psychotherapies that have been supported in clinical trials. Treatments that showed significant effects in studies published over a period of 4 decades were identified, with the goal of complementing the overall picture of treatment benefit provided in narrative reviews and meta-analyses with a detailing of the specific interventions that have shown significant effects. The article focuses on treatments for four broad clusters of problems and disorders that account for a very large proportion of youth mental health referrals: anxiety, depression, attention-deficit/hyperactivity, and conduct.     

NBQX or topiramate treatment after perinatal hypoxia-induced seizures prevents later increases in seizure-induced neuronal injury

PURPOSE: To evaluate the efficacy of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline-2,3-dione) and topiramate (TPM) given after hypoxia-induced seizures in preventing the delayed effect of hypoxia on subsequent susceptibility to seizures and neuronal injury. METHODS: We used "two-hit" rodent seizure model to study the long-term effect of perinatal hypoxia on later kainate (KA) seizure-induced neuronal damage and investigated the therapeutic efficacy of a postseizure treatment protocol in reversing the conditioning effect of early-life seizures. RESULTS: Hypoxia at P10 induces seizures without cell death but causes an increase in susceptibility to second seizures induced by KA as early as 96 h after hypoxia, and this lowered seizure threshold persists to adulthood. Furthermore, perinatal hypoxia increases KA-induced neuronal injury at postnatal day (P)21 and 28/30. Repeated doses of NBQX (20 mg/kg) or TPM (30 mg/kg) given for 48 h after hypoxia-induced seizures prevent the increase in susceptibility to KA seizure-induced hippocampal neuronal injury at P28/30. CONCLUSIONS: Our results suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor blockade after hypoxia prevents the priming effect of perinatal hypoxia-induced seizures and that this protection occurs independent of its anticonvulsant action.     

Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice

In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double "Swedish" amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of working memory and learning than single APP mutant mice. In this study we compared performance on spatial memory tests, regional glucose metabolism, Abeta deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age of 2 months no significant morphological and metabolic differences were detected between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed selective impairment of spatial memory, which was significantly worse at 22 months and was accompanied by reduced glucose utilization in the hippocampus and a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4% at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the behavioral and metabolic impairments in APP/PS1 mice and the failure to compensate functionally for PS1-related hippocampal cell loss.     

The ability of three global plasma assays to recognize thrombophilia

Three global assays, the Calibrated Automated Thrombogram (CAT), the ProC Global (PCG), and the Coagulation Inhibitor Potential (CIP) were performed in frozen plasma samples from 24 normal controls and 24 patients with inherited thrombophilia. Six patients had inherited antithrombin (AT) deficiency; 18 patients had abnormalities in the protein C/S anticoagulant system (protein C deficiency (n=3), protein S deficiency (n=10), homozygous FV Leiden mutation (n=5)). Nine of these twenty four patients carried additionally the heterozygous FV Leiden mutation. All three assays separated the thrombophilia group and the control group (P=0.083 for CAT, P<0.0001 for the other two assays) but there was considerable overlap, particularly in the CAT assay. The CAT assay separated all plasma samples with AT deficiency but was less sensitive to abnormalities in the protein C/S system. In contrast, ProC Global was more sensitive to abnormalities in the protein C system than to AT deficiency. The CIP assay was approximately equally sensitive to defects in both systems. Receiver operator characteristic (ROC) curves confirmed that the ProC Global and the CIP assays performed better than the CAT assay (P=0.0179 and P=0.0003, respectively). With the CIP assay ROC analysis showed that with a sensitivity of 100% the specificity was 87.5%. With the PCG assay, optimal threshold resulted in both a sensitivity and a specificity of 79.2%. Although our material is relatively small, the data suggest that at a cut-off value with a specificity of >80%, the CIP assay should be evaluated as a screening test for severe thrombophilia.     

TDM-based imipramine treatment in neuropathic pain

Tricyclic antidepressants (TCA) are the best-documented treatment of neuropathic pain. TCAs have a pronounced interindividual pharmacokinetic variability and a narrow therapeutic index. The aim of this study was to characterize the plasma concentration-effect relationship of imipramine in neuropathic pain and to determine the usefulness of therapeutic drug monitoring (TDM) of TCA treatment in a population with noncancer chronic pain. To do this, 83 patients with chronic noncancer neuropathic pain were included. Information on previous use of TCA was collected, and patients were tested for the presence of hyperalgesia. Pain intensity and pain relief were recorded, and the Short Form McGill Pain Questionnaire and Major Depression Inventory were completed before and during a TDM-based imipramine treatment. Imipramine dose was increased in steps of 25 mg/d every second week, and blood samples were taken at every dose. Endpoints were best possible pain relief, unacceptable side effects, or insufficient pain relief despite plasma drug level > 500 nmol/L. Dose range used was 10-300 mg/d. The study showed that imipramine 75 mg/d caused a 36-fold interindividual variation in steady-state plasma drug concentrations. In 46 responders (global pain relief > 25%) the plasma drug concentration at which an individual maximal analgesic effect was obtained ranged from 50 to 1400 nmol/L, but for the majority it was below 400 nmol/L. The concentration-effect relationship was similar for patients with central versus peripheral neuropathic pain and independent of the presence of hyperalgesia. Previous treatment failure with non-TDM TCA treatment was not a predictor of poor response to TDM-based treatment. In conclusion, there is a pronounced interindividual variability in concentration-effect relationship for imipramine treatment in neuropathic pain, but the majority of patients obtain a maximal analgesic effect at drug levels below 400 nmol/L. The concentration-effect relationship is similar for patients with central and peripheral neuropathic pain. Further studies are needed to document if TDM improves pain relief; however, TDM reduces the risk for toxicity.     

The comparability of estimates of retroilluminated lens opacities as judged from film-based and digital imaging

PURPOSE: Neitz film-based retroillumination cameras, the standard for documenting retroilluminated lens opacities for epidemiologic studies, are no longer produced. A digital imaging system is now available for imaging these opacities. We sought to compare gradings of images from both systems. DESIGN: Comparison of technique. METHODS: One hundred fourteen lenses were imaged with both systems and graded according to protocols. Concordance between the methods was compared using kappa statistics. RESULTS: There was moderate concordance for cortical opacities (kappa = 0.63) and good concordance for posterior subcapsular opacities (kappa = 0.83). Grades from digital images slightly underestimated the frequency and severity of cortical cataract. CONCLUSION: Digital imaging of retroilluminated lens opacities results in similar classification of the severity of opacities. It will be useful for epidemiologic studies of cortical (CC) and posterior subcapsular cataracts (PSC).     

Diameter variations of retinal blood vessels during and after treatment with hyperbaric oxygen

AIMS: To quantify retinal vascular change during and after hyperbaric oxygenation (HO) for 6x5 weekly 90 minute treatments. METHODS: Fundus photographs were taken before, during, and after HO at 2.5 atmospheres absolute pressure (ATA) on days 1, 2, 3, 10, 20, 29, and 30 of treatment on three patients using a specially developed hand held ophthalmoscope with a digital colour camera. Blood vessel diameter was estimated on red free retinal images. The mean of three measurements of arterioles and venoles close to the optic disc was calculated. Consistency and repeatability of the method was verified by estimating the diameter of the vessels by three measurements in each of seven images taken within 70 seconds on the same person. Analysis of variance with Bonferroni correction for multiple comparisons was conducted to ascertain whether significant intergroup differences existed. RESULTS: Breathing 100% oxygen at 2.5 ATA constricts retinal arterioles by 9.6% (standard deviation 0.3%) and venoles by 20.6% (SD 0.3%) of their size in air at ambient pressure. Constriction escalates during treatment. Ten minutes after the HO, arterioles dilate to 94.5% (SD 0.3%) and venoles to 89.0% (SD 0.3%) of their primary size. This pattern is the same for each day of measurement. Heart frequency falls continually during HO. Systolic, diastolic, and mean arterial pressures stay constant. CONCLUSION: Exposure to hyperbaric oxygen causes constriction of the retinal vessels. It is found that this constriction is constant through the series of treatments. This suggests that oxygen or products thereof are responsible for the vascular changes during and after hyperbaric oxygenation probably through autoregulation of the retinal vessels.     

Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: Structural measures

PURPOSE: To determine, using anatomic measurements, whether daily oral dosing with memantine is both safe and effective to reduce the injury associated with experimental glaucoma in primates. METHODS: Argon laser treatment of the anterior chamber angle was used to induce chronic ocular hypertension (COHT) in the right eyes of 18 macaque monkeys. Nine animals were daily orally dosed with 4 mg/kg memantine while the other nine animals received vehicle only. Measurements of intraocular pressure (IOP) from both eyes of all animals were made at regular intervals. Appearance of the optic nerve head, retinal vessels, and surrounding retina was documented with stereo fundus photographs obtained at multiple time points throughout the study. Measurements of optic nerve head topography were obtained from confocal laser scans made from animals with the highest IOPs at approximately 3, 5, and 10 months after elevation of IOP. At approximately 16 months after IOP elevation, animals were killed and histologic counts of cells in the retinal ganglion cell (RGC) layer were made. RESULTS: Histologic measurements showed that, for animals with moderate elevation of IOP, memantine treatment was associated with an enhanced survival of RGCs in the inferior retina. Measurements of optic nerve head topography showed less IOP-induced change in memantine-treated animals. This effect was seen in measurements of both the cup and the neuroretinal rim. A comparison of these same histologic and morphologic measurements in normotensive eyes from the two treatment groups showed that memantine treatment was not associated with any significant effects on these eyes. CONCLUSIONS: Histologic measurements of RGC survival as well as tomographic measurements of nerve head topography show that systemic treatment with memantine, a compound which does not lower intraocular pressure, is both safe and effective to reduce changes associated with experimental glaucoma.     

Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study

PURPOSE: To investigate the age-specific prevalence and causes of visual impairment and blindness in an epidemiologic study of an adult Scandinavian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: The study population was composed of 9980 persons, ages 20 to 84, from the general population of Copenhagen, Denmark. METHODS: This study is based on the third Copenhagen City Heart Study (CCHS III). Participants who reported visual impairment or blindness or had difficulty reading newspaper type and used prescribed eye medications were contacted from 1999 through 2000 and asked to complete a standardized interview concerning their ophthalmologic history. Verification of objective ophthalmologic data was done with a validated questionnaire response method. MAIN OUTCOME MEASURES: Best-corrected visual acuity in the better eye and primary causes of visual impairment and blindness. Visual impairment was defined as visual acuity worse than 20/40 but better than 20/200, and blindness was defined as visual acuity of 20/200 or worse. RESULTS: The age-standardized prevalence rates of visual impairment and blindness were 0.66% and 0.20%, respectively, and rose significantly with age (P<0.001). For persons 20 to 64 years, myopia-related retinal disorders, diabetic retinopathy, optic neuropathy, and retinitis pigmentosa were the most common causes of impaired vision. For persons 65 to 84 years, cataract was the most common cause of visual impairment, whereas age-related macular degeneration was the major cause of blindness. CONCLUSIONS: Visual impairment and blindness are strongly associated with increasing age, and the causes are determined by age. Among persons aged 20 to 64 years, an intervention for the predominating eye diseases might have some effect. Among those aged 65 to 84 years, cataract surgery could reduce visual impairment by one third.     

Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau

Oral polio vaccine (OPV) and diphtheria-tetanus-pertussis (DTP) vaccines are given simultaneously in routine immunisation programmes in developing countries. It is therefore difficult to determine the separate effects of these vaccines on survival. We used the shortage of DTP vaccine in Bissau to examine the impact of OPV on the case fatality at the paediatric ward in Bissau. For 719 children less than 5 years of age whose vaccination card had been seen at admission and who had not yet received measles vaccine, having received OPV only was associated with a case fatality of 6% compared with 15% for children having received combined DTP and OPV vaccinations, the case fatality ratio (CFR) being 0.29 (95% confidence interval (CI) 0.11-0.77). Even if children fleeing the hospital were assumed to have died shortly after leaving the hospital, the case fatality would still be lower for children having received OPV only (CFR = 0.41; (95% CI 0.20-0.81)). The tendency was similar for children hospitalised with pneumonia, diarrhoea, and presumptive malaria. Control for background factors had no impact on the estimate. In areas with high mortality, OPV administered alone may have non-specific beneficial effects or DTP may have a negative effect for children who had received both DTP and OPV.