Calcitriol supplementation attenuates cisplatin-induced behavioral and cognitive impairments through up-regulation of BDNF in male rats.

Chemotherapy-induced cognitive impairment such as memory impairment and concentration problems are now extensively recognized as side effects of chemotherapy. These problems reduce the quality of life in patients. Therefore, the present study aims to examine the effects of calcitriol supplementation (100 ng/kg /day for five weeks) on cognitive impairment, behavioral deficits, and hippocampal brain-derived neurotrophic factor (BDNF) changes following cisplatin treatment (5 mg/kg/ once a week for five weeks). We also determined the impact of cisplatin and calcitriol administration on reaction time against the thermal stimulus and muscle strength. Our findings showed that cisplatin administration resulted in a significant increase in anxiety-like behaviors. Treatment of rats with cisplatin also impaired performance in the passive avoidance and novel object recognition tasks which are indicating cognitive deficits. Co-administration of calcitriol prevented the cisplatin-induced behavioral and cognitive impairments. Cisplatin exposure also resulted in enhanced reaction time to the thermal stimulus and decreased muscle ability. Besides, hippocampal BDNF levels were reduced in cisplatin-treated rats; however, calcitriol alleviated these effects of cisplatin and up-regulated BDNF mRNA in the hippocampus. In addition, calcitriol alone indicated a significant change in BDNF level compared to the control group. We conclude that increased hippocampal BDNF mediates the beneficial effects of calcitriol against neurotoxicity in cisplatin-exposed rats. However, further studies are required to explore the other mechanisms that mediate the beneficial effect of calcitriol.

Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study.

Importance: In light of increasing cannabis use among pregnant women, the US Surgeon General recently issued an advisory against the use of marijuana during pregnancy. Objective: To evaluate whether cannabis use during pregnancy is associated with adverse outcomes among offspring. Design, Setting, and Participants: In this cross-sectional study, data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development Study, which recruited 11 875 children aged 9 to 11 years, as well as a parent or caregiver, from 22 sites across the United States between June 1, 2016, and October 15, 2018. Exposure: Prenatal cannabis exposure prior to and after maternal knowledge of pregnancy. Main Outcomes and Measures: Symptoms of psychopathology in children (ie, psychotic-like experiences [PLEs] and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index, and brain structure (ie, total intracranial volume, white matter volume, and gray matter volume). Covariates included familial (eg, income and familial psychopathology), pregnancy (eg, prenatal exposure to alcohol and tobacco), and child (eg, substance use) variables. Results: Among 11 489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal cannabis exposure data, 655 (5.7%) were exposed to cannabis prenatally. Relative to no exposure, cannabis exposure only before (413 [3.6%]) and after (242 [2.1%]) maternal knowledge of pregnancy were associated with greater offspring psychopathology characteristics (ie, PLEs and internalizing, externalizing, attention, thought and, social problems), sleep problems, and body mass index, as well as lower cognition and gray matter volume (all |ß| > 0.02; all false discovery rate [FDR]-corrected P < .03). Only exposure after knowledge of pregnancy was associated with lower birth weight as well as total intracranial volume and white matter volumes relative to no exposure and exposure only before knowledge (all |ß| > 0.02; all FDR-corrected P < .04). When including potentially confounding covariates, exposure after maternal knowledge of pregnancy remained associated with greater PLEs and externalizing, attention, thought, and social problems (all ß > 0.02; FDR-corrected P < .02). Exposure only prior to maternal knowledge of pregnancy did not differ from no exposure on any outcomes when considering potentially confounding variables (all |ß| < 0.02; FDR-corrected P > .70). Conclusions and Relevance: This study suggests that prenatal cannabis exposure and its correlated factors are associated with greater risk for psychopathology during middle childhood. Cannabis use during pregnancy should be discouraged.

Could Dietary Glutamate Play a Role in Psychiatric Distress?

Glutamate is an amino acid that functions as an excitatory neurotransmitter. It has also been associated with somatic and psychiatric distress and is implicated in the pathophysiology of psychiatric disorders such as schizophrenia. Ingestion of dietary glutamate, such as monosodium glutamate (MSG), has been mechanistically linked with greater distress among patients with chronic pain conditions, though findings have been equivocal. Preliminary research suggests that an MSG-restricted diet confers beneficial effects on somatic symptoms and well-being for some individuals with chronic pain conditions. In addition to associations with somatic distress, glutamate has been associated with the onset and progression of psychiatric symptoms. Thus, the role of dietary glutamate in psychiatric distress represents an underdeveloped and potentially important area for future research aimed at clarifying pathophysiological mechanisms and identifying targets for dietary intervention in psychiatric illnesses.

Neuroprotective Effects of dl-3-n-Butylphthalide against Doxorubicin-Induced Neuroinflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Behavioral Changes.

Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited due to its neurobiological side effects associated with depression. We investigated the neuroprotective efficacy of dl-3-n-butylphthalide (dl-NBP) against DOX-induced anxiety- and depression-like behaviors in rats. dl-NBP was given (30 mg/kg) daily by gavage over three weeks starting seven days before DOX administration. Elevated plus maze (EPM) test, forced swimming test (FST), and sucrose preference test (SPT) were performed to assess anxiety- and depression-like behaviors. Our study showed that the supplementation of dl-NBP significantly mitigated the behavioral changes induced by DOX. To further explore the mechanism of neuroprotection induced by dl-NBP, several biomarkers including oxidative stress markers, endoplasmic reticulum (ER) stress markers, and neuroinflammatory cytokines in the hippocampus were quantified. The results showed that dl-NBP treatment alleviated DOX-induced neural apoptosis. Meanwhile, DOX-induced oxidative stress and ER stress in the hippocampus were significantly ameliorated in dl-NBP pretreatment group. Our study found that dl-NBP alleviated the upregulation of malondialdehyde (MDA), nitric oxide (NO), CHOP, glucose-regulated protein 78 kD (GRP-78), and caspase-12 and increased the levels of reduced glutathione (GSH) and activities of catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in the hippocampus of rats exposed to DOX. Additionally, the gene expression of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-alpha (TNF-α) and protein levels of inducible nitric oxide synthase (iNOS) were significantly increased in DOX-treated group, whereas DOX-induced neuroinflammation was significantly attenuated in dl-NBP supplementation group. In conclusion, dl-NBP could alleviate DOX-induced anxiety- and depression-like behaviors via attenuating oxidative stress, ER stress, inflammatory reaction, and neural apoptosis, providing a basis as a therapeutic potential against DOX-induced neurotoxicity.

Implementation of the 2013 Psychoactive Substances Act and mental health harms from synthetic cannabinoids.

AIMS: Use of synthetic cannabinoids is associated with a range of mental health harms. The 2013 Psychoactive Substances Act (PSA) was intended to limit retail availability of synthetic cannabinoids which had acceptable safety profiles. We evaluated numbers and clinical characteristics of patients presenting with mental health harms associated with use of synthetic cannabinoids for three months before and after implementation of the PSA on 18July 2013. METHODS: Retrospective audit of case notes of patients presenting to an emergency psychiatric service (EPS) in Dunedin. RESULTS: In the three months post-PSA, there was a 42% reduction in EPS contacts and 52% reduction in patient presentations, compared with the three months pre-PSA. Patient demographics (predominantly young males with prior contact with mental health services), presenting symptoms (mood and psychotic symptoms and suicidality), and management and disposition were identical in both periods. CONCLUSIONS: The decrease in mental health harms, as measured by frequency of EPS contacts, appeared to be due to reduced retail availability of synthetic cannabinoids rather that reduced toxicity of available products.

Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice.

Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60-90min; minimal at 72h) with activation of hippocampal pro-apoptotic JNK (+2.5 fold) and increased GFAP (+57%) and nuclear PARP-1 fragmentation (+114%) 72h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72h) reduced Fas ligand (-92%) and Fas receptor aggregates (-24%). KA (72h) also altered the contents of major DISC components: decreased FADD adaptor (-44%), reduced activation of initiator caspase-8 (-47%) and increased survival FLIP-S (+220%). Notably, KA (72h) upregulated the content of anti-apoptotic p-Ser191 FADD (+41%) and consequently the expression of p-FADD/FADD ratio (+1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-κB was also increased (+61%) in the hippocampus after KA (72h). The convergent adaptation of the extrinsic apoptotic machinery 72h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus.

Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice.

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.

Health consequences of exposure to brominated flame retardants: a systematic review.

BACKGROUND: Brominated flame retardants (BFRs), are chemicals widely used in consumer products including electronics, vehicles, plastics and textiles to reduce flammability. Experimental animal studies have confirmed that these compounds may interfere with thyroid hormone homeostasis and neurodevelopment but to date health effects in humans have not been systematically examined. OBJECTIVES: To conduct a systematic review of studies on the health impacts of exposure to BFRs in humans, with a particular focus on children. METHODS: A systematic review was conducted using the MEDLINE and EMBASE electronic databases up to 1 February 2012. Published cohort, cross-sectional, and case-control studies exploring the relationship between BFR exposure and various health outcomes were included. RESULTS: In total, 36 epidemiological studies meeting the pre-determined inclusion criteria were included. Plausible outcomes associated with BFR exposure include diabetes, neurobehavioral and developmental disorders, cancer, reproductive health effects and alteration in thyroid function. Evidence for a causal relationship between exposure to BFRs and health outcomes was evaluated within the Bradford Hill framework. CONCLUSION: Although there is suggestive evidence that exposure to BFRs is harmful to health, further epidemiological investigations particularly among children, and long-term monitoring and surveillance of chemical impacts on humans are required to confirm these relationships.

Urinary metabolites of organophosphate and pyrethroid pesticides and behavioral problems in Canadian children.

BACKGROUND: Exposure to organophosphate pesticides has been associated with neurobehavioral deficits in children, although data on low levels of exposure experienced by the general population are sparse. Pyrethroids are insecticides rapidly gaining popularity, and epidemiological evidence on their potential effects is lacking. OBJECTIVE: We examined the association between exposure to organophosphate and pyrethroid pesticides, indicated by urinary metabolites, and parentally reported behavioral problems in children. METHODS: We used data on children 6-11 years of age from the Canadian Health Measures Survey (2007-2009). We used logistic regressions to estimate odds ratios (ORs) for high scores on the Strengths and Difficulties Questionnaire (SDQ), which may indicate behavioral problems, in association with concentrations of pyrethroid and organophosphate metabolites in the urine of 779 children, adjusting for covariates (sex, age, race/ethnicity, income, parental education, blood lead levels, maternal smoking during pregnancy, and others). RESULTS: At least one urinary metabolite for organophosphates was detected in 91% of children, and for pyrethroids in 97% of children. Organophosphate metabolites were not significantly associated with high SDQ scores. The pyrethroid metabolite cis-DCCA [3-(2,2-dichlorovinyl)-2,2-dimethylycyclopropane carboxylic acid] was significantly associated with high scores for total difficulties on the SDQ (OR for a 10-fold increase = 2.0; 95% CI: 1.1, 3.6), and there was a nonsignificant association with trans-DCCA (OR = 1.6; 95% CI: 0.9, 3.0). CONCLUSION: In contrast with previous studies, we did not observe an association between exposure to organophosphate pesticides and behavioral scores in children. However, some pyrethroid urinary metabolites were associated with a high level of parent-reported behavioral problems. Longitudinal studies should be conducted on the potential risks of pyrethroids.

Prolonged hyperoxia preconditioning attenuates behavioral symptoms of 6-hydroxydopamine-induced Parkinsonism.

OBJECTIVES: Several lines of evidences show that hyperoxia preconditioning provides neuronal protection against central nervous system ischemic damages. Common pathways including mitochondrial dysfunction, apoptosis, and caspase activation are involved in acute neurodegeneration (e.g. after cerebral ischemia) and chronic neurodegeneration (e.g. neuronal death in Parkinson's disease). The aim of the present research was to study the effect of hyperoxia preconditioning on 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. METHODS: Male Wistar rats were first subjected to either air with high oxygen concentration (>90%) or atmospheric air for prolonged (24 hours) or intermittent (six consecutive days, 4 hours each day) periods and then 6-OHDA was injected into their left striatums by stereotaxic surgery. Development and severity of the 6-OHDA-induced Parkinsonism was assessed using apomorphine-induced rotational test, elevated body swing test, and rotarod test within 2-5 weeks after the surgery. RESULTS: Significant data obtained in rats treated with prolonged hyperoxia, but not the intermittent hyperoxia. In these rats, the number of apomorphine-induced rotations was ∼60% lower than that in control and sham groups. Rats belonging to the prolonged hyperoxia group also showed considerably better motor performance and learning pattern in rotarod test. These results were confirmed by the data obtained in the elevated body swing test. DISCUSSION: Our findings show that the prolonged hyperoxia preconditioning attenuates the behavioral symptoms of 6-OHDA-induced Parkinsonism. Considering the well-known correlation between dopaminergic neuronal death in the substantia nigra and the behavioral symptoms of 6-OHDA-induced Parkinsonism, it could be speculated that the prolonged hyperoxia preconditioning induces the mechanisms that provide dopaminergic neuroprotection against Parkinsonism-induced toxins.

Illicit use of androgens and other hormones: recent advances.

PURPOSE OF REVIEW: To summarize recent advances in studies of illicit use of androgens and other hormones. RECENT FINDINGS: Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. SUMMARY: Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

Novel anti-inflammatory compound SEN1176 alleviates behavioral deficits induced following bilateral intrahippocampal injection of aggregated amyloid-ß1₋42.

Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-ß (Aß)1-42-induced macrophage production of nitric oxide, TNF-α, IL-1ß, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated Aß1-42. The rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement, enabling measurement of parameters of operant performance that reflect aspects of learning and memory. Under the ALCR schedule, orally administered SEN1176 at 5, 20, or 30 mg/kg was effective in reducing the behavioral deficit caused by bilateral IH aggregated Aß1-42 injections in a dose-related manner over a 90-day treatment period. SEN1176 at 20 and 30 mg/kg significantly reduced lever switching errors and, at doses of 5, 10, and 30 mg/kg, significantly reduced incorrect lever perseverations, indicating a reduction of the behavioral deficit induced as a result of inflammation following IH Aß1-42 injections. When treatment with SEN1176 was instigated 30 days after IH Aß1-42 injections, it resulted in progressive protection, and withdrawal of SEN1176 treatment 60 days after IH Aß1-42 injections revealed partial retention of the protective effect. SEN1176 also significantly reduced numbers of activated astrocytes adjacent to the aggregated Aß1-42 injection sites. These results indicate the potential of SEN1176 for alleviating chronic neuroinflammatory processes related to brain Aß deposition that affect learning and memory in Alzheimer's disease.

Drug use in a rural secondary school in Kenya.

Alcohol abuse and alcohol-related use problems among adolescents are highly prevalent and are a major concern worldwide. This study estimated the prevalence of drug abuse, knowledge about drug abuse and its effect on psychosocial well-being and induced behavioral problems among students of a public rural secondary school that admitted both girls and boys which offered both boarding and day school facilities. The students filled out a self-reporting substance use tool which measures the prevalence, frequency, and general patterns of substance use. Alcohol, tobacco, khat (catha edulis) and bhang (cannabis) were the most commonly reported substance of use, with user prevalence rates of 5.2%, 3.8%, 3.2%, and 1.7%, respectively. Tobacco use was initiated at 10 years, while cannabis, hard drugs, khat, and alcohol were initiated at 11, 12, 13, and 15 years of age, respectively. Among the students 71% were aware that their schoolmates were on drugs and it was known by 49.8%, 41.7%, 37.6%, 44.3%, and 32.4% of these students that using alcohol, tobacco, khat, cannabis, and hard drugs, respectively was a behavioral problem in the school. Three quarters of the students were aware that use of drugs was harmful to their health, with majority (78.6%) indicating that drug users need help to stop the drug use behavior. However most (73.6%) of the students suggested drug users in school should be punished. The drug use behavioral problems included school dropout, poor scholastic attainment, drunken driving, delinquency, and adolescence pregnancy which threaten the stability of the education system, family as an institution (family difficulties) and society at large. Therefore, teachers have an added burden of playing an active role in guidance and counselling the survivors of drug abuse, a pandemic facing teaching institutions apart from instilling knowledge.

The effects of prenatal cocaine exposure on problem behavior in children 4-10 years.

BACKGROUND: Children prenatally exposed to cocaine may be at increased risk for behavioral problems due to disruptions of monaminergically regulated arousal systems and/or environmental conditions. OBJECTIVE: To assess behavioral outcomes of cocaine (CE) and non-cocaine-exposed (NCE) children, 4 through 10 years old, controlling for other prenatal drug exposures and environmental factors. METHODS: Low socioeconomic status (SES), primarily African American children (n=381 (193 (CE), 188 (NCE)) were recruited from birth. Generalized Estimating Equation (GEE) analyses were used to assess the predictive relationship of prenatal cocaine exposure to odds of caregiver reported clinically elevated behavioral problems at 4, 6, 9 and 10y ears of age, controlling for confounders. RESULTS: Prenatal cocaine exposure was associated with increased rates of caregiver reported delinquency (OR=1.93, CI: 1.09-3.42, p<0.02). A significant prenatal cocaine exposure by sex interaction was found for delinquency indicating that only females were affected (OR=3.57, CI: 1.67-7.60, p<0.001). There was no effect of cocaine on increased odds of other CBCL subscales. Higher prenatal tobacco exposure was associated with increased odds of externalizing symptoms at 4, 9 and 10 years of age. For CE children, those in foster or adoptive care were rated as having more behavior problems than those in biologic mother or relative care. Greater caregiver psychological distress was associated with increased behavioral problems. There were no independent effects of elevated blood lead level on increased behavior problems after control for prenatal drug exposure and other environmental conditions. CONCLUSION: Prenatal cocaine and tobacco exposure were associated with greater externalizing behavior after control for multiple prenatal drug exposures, other environmental and caregiving factors and lead exposure from 4 through 10 years of age. Greater caregiver psychological distress negatively affected caregiver ratings of all CBCL domains. Since cocaine and tobacco use during pregnancy and maternal psychological distress have the potential to be altered through prenatal educational, drug treatment and mental health interventions, they warrant attention in efforts to reduce rates of problem behaviors in children.

Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy.

BACKGROUND: Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine. PURPOSE: Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. METHODS: Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. RESULTS: We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. LIMITATIONS: Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. CONCLUSIONS: This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.

Neurobehavioural effects of pesticides with special focus on organophosphorus compounds: which is the real size of the problem?

The risk of neurobehavioural impairment as a consequence of a prolonged, low dose exposure to neurotoxic pesticides is not clearly demonstrated despite numerous publications addressing the topic. We reviewed the 24 papers published on human neurobehavioural effects of organophosphorus and/or carbamates pesticides up to May 1st 2008. Variables evaluated were compound/s addressed, number of subjects, approach to measure or estimate exposure, characteristics of control groups and presence of confounders, methodological approach, and type of alteration, taking into account cognitive, sensory-motor, psychological, and psychomotor measures. A total of 6 papers considered the whole spectrum of functions, the studies yielding positive or uncertain results were 13 (68%) for cognitive function, 11 (69%) for psychomotor function, 11 (65%) for sensory-motor function, and 11 (65%) for psychological function impairment. In 46% of the positive studies a previous severe acute poisoning was reported. Exposure levels were measured only in 5 studies, and very often there were problems in the selection of controls, and firm conclusions on the risk of neurobehavioural effects cannot be reached yet. The main limits of the available data are: limited number of studies and compounds addressed, significant differences in the approach among studies, poor concordance of the results of different studies, and difficulties in controlling confounding factors. Nevertheless, there are sufficient data to conclude that neurobehavioural impairment might be the consequence of an acute poisoning, and possibly the consequence of relatively high and prolonged exposures.

Predictors of punding in Parkinson's disease: results from a questionnaire survey.

Dopamine replacement therapy (DRT) for Parkinson's disease (PD) has recently been linked to the development of a number of nonmotor behavioral control problems. Punding, one of these nonmotor problems, is a term used to describe complex, purposeless stereotyped behaviors such as the repetitive handling or sorting of objects. A self-report questionnaire was adapted to assess punding in the context of dysfunctional hobby-related activities. We report the results of a survey of PD outpatients from a PD research clinic (n = 141) and non-PD controls (n = 103); conducted to identify clinical and psychological factors predictive of punding behaviors. The PD group reported hobbies and activities, which scored significantly higher on the Punding Scale than controls. Higher impulsivity, poorer disease-related quality of life, younger age of disease onset, and concomitant daily medication dosage from dopamine receptor agonists were independently predictive of higher Punding Scale scores in the PD group. These findings are similar to those seen in dopamine dysregulation syndrome, and provide further evidence for the role of impulsivity and age at disease onset in DRT-related nonmotor behavioral problems in PD.

Interferon-alpha influences tryptophan metabolism without inducing psychiatric side effects.

BACKGROUND: Interferon-alpha (IFN-alpha) treatment is often associated with psychiatric side effects and has been found to lower the amount of tryptophan (TRP) available to the brain. The alterations in tryptophan metabolism might underlie the psychiatric side effects during treatment with IFN-alpha. METHODS: In this study, 43 oncology patients treated with IFN-alpha were included. In order to study de novo depressions, depressed patients at baseline were excluded. Psychiatric evaluation comprising clinical judgment combined with a structured psychiatric interview and observer-based and self-report rating scales was performed at baseline and at 4 weeks, 8 weeks and 6 months after the start of treatment with IFN-alpha, and in the case of emerging psychopathology. Blood samples were drawn at the same evaluation times and assessed for concentrations of TRP, large neutral amino acids, kynurenine, 5-hydroxyindole acetic acid, neopterin and biopterin. RESULTS: During treatment with IFN-alpha, several alterations in laboratory parameters occurred that were consistent with an increased degradation of peripheral TRP. Psychometric ratings revealed hardly any psychiatric changes. No consistent associations were found between changes in the laboratory assessments determined and the diverse psychiatric measures. CONCLUSION: In this study, IFN-alpha was found to alter TRP metabolism without inducing psychiatric side effects. Therefore, a possible relationship between TRP metabolism and depression was not substantiated by this study.

Methylphenidate treated at the test cage--dose-dependent sensitization or tolerance depend on the behavioral assay used.

Methylphenidate is the drug most often used to treat attention deficit/hyperactivity disorder (ADHD), a common behavioral disorder of children and young adults. The objectives of this study are (1) to use two different experimental assays of measuring animal activity--the wheel-running activity and the computerized open field--to establish which is more sensitive to acute and repetitive methylphenidate (MPD) administration and (2) to determine whether repetitive MPD treatment elicits adverse effects such as tolerance and behavioral sensitization. The dose-response protocol of MPD (0.6, 2.5, and 10.0 mg/kg) administration was performed in three groups of animals, with an additional saline control group as follows: single saline injection as the control/baseline followed by 6 consecutive days of MPD injections (0.6, 2.5, or 10.0 mg/kg MPD), 3 days of washout, and a day of MPD rechallenge. In general, the two different activity assays showed similar observations for the acute effect of MPD by eliciting increases in activity in a dose-dependent manner. The groups receiving repetitive 0.6 and 2.5 mg/kg MPD tested in the open-field assay exhibited further increase in activity that can be interpreted as behavioral sensitization, whereas the groups receiving 10 mg/kg MPD exhibited a reduction in activity, suggesting that tolerance was developed to the drug. All the groups (0.6, 2.5, and 10.0 mg/kg MPD) tested following repetitive MPD in the wheel-running assay exhibited a further increase in their activity, for example, all the groups exhibited behavioral sensitization. These different observations were interpreted as potentially measuring different kinds of locomotor activity.