[Addiction from a developmental perspective: the role of conduct disorder and ADHD in the development of problematic substance use disorders]. / Verslaving in ontwikkelingsperspectief: de rol van antisociale gedragsstoornis en ADHD in de ontwikkeling van problematisch middelengebruik.

BACKGROUND: The externalising disorders conduct disorder (CD) and ADHD occur frequently in patients suffering from substance use disorders. These disorders play an important role in the onset and development of addiction. AIM: To examine the influence of CD and ADHD on the current problems and the psychiatric comorbidity of patients with a chronic addiction. METHOD: A group of 193 opiate-addicted patients receiving methadone maintenance treatment were evaluated extensively in the following areas: functioning, quality of life, psychiatric comorbidity (including CD and ADHD) and comorbid addictions. Standardised interviews were used to check for the presence of CD and ADHD. RESULTS: A history of CD was demonstrated in the majority of participants (60.1%). Persistent ADHD was ascertained in 24.9%. Participants with CD and/or ADHD had a more severe addiction, characterised by more psychiatric comorbidity, more serious dysfunctioning and reduced quality of life. A history of CD predisposed patients particularly to antisocial behaviour and personality disorders. ADHD increased the risk of psychiatric comorbidity. CONCLUSION: Psychiatric comorbidity is part and parcel of addiction and reduces the quality of life of addicted patients. Behaviour problems in childhood play a major role in the development of severe addictions. Although CD is the biggest risk factor, the combination of ADHD with CD increases this risk, possibly through increased vulnerability to further psychiatric comorbidity.

[Substance use disorders and ADHD: an overview of recent Dutch research]. / Verslaving en ADHD: een overzicht van recent Nederlands onderzoek.

BACKGROUND: ADHD is an important risk factor for the development of substance use disorders (SUD). AIM: To provide an overview of recent Dutch research into the prevalence of ADHD in SUD populations and the neurobiological substrate of the reduced effect of pharmacological treatment of this patient group. METHOD: We describe three studies: a meta-analysis and meta-regression analysis of the prevalence of ADHD in 6689 SUD patients; a cross-sectional study of the prevalence of ADHD and several other psychiatric disorders in 193 methadon maintenance patients, and finally a study in which the availability and occupation of dopamine transporters before and after methylphenidate treatment were measured using SPECT scans in 24 ADHD patients with and without cocaine addiction. RESULTS: The prevalence of ADHD in SUD patients is estimated to be 23.1% (95% confidence interval 19.4-27.2). This prevalence is influenced by the diagnostic instrument for ADHD and by the substance of abuse: cocaine is associated with a lower ADHD prevalence than other substances. The prevalence found among methadone maintenance patients was similar, namely 24.9%; additional comorbid psychiatric disorders were also frequently present. In the imaging study, lower availability of dopamine transporters and lower occupation by methylphenidate were found in cocaine-dependent ADHD patients than in ADHD patients without SUD. CONCLUSION: These studies confirm the high prevalence of ADHD in SUD patients, and provide a possible explanation for the reduced efficacy of methylphenidate in this patient population.

Influence of attention deficit hyperactivity disorder and conduct disorder on opioid dependence severity and psychiatric comorbidity in chronic methadone-maintained patients.

BACKGROUND: Persistent attention deficit hyperactivity disorder (ADHD) and a history of conduct disorder (CD) are highly prevalent among patients with substance use disorders (SUD). We examined the influence of both diagnoses on problem severity, psychiatric comorbidity, and quality of life in methadone-maintained patients. METHODS: 193 patients in long-term methadone maintenance treatment (MMT) were assessed for ADHD through a semi-structured interview. Psychiatric disorders and SUD were assessed with the MINI, the CIDI-SAM, and the SIDP-IV. RESULTS: Childhood ADHD was diagnosed in 68 (35.2%) patients; 48 (24.9%) had persisting ADHD; a CD history was present in 116 (60.1%). Patients with adult ADHD had significantly higher problem severity scores, lower quality of life scores, more comorbid SUD and more psychiatric comorbidity. Although both ADHD and CD contributed to problem severity, addictive pathology and psychopathology, ADHD was found to substantially increase the risk of psychiatric comorbidity, independent of CD. CONCLUSION: ADHD in MMT patients is characterised by greater addiction severity and more comorbid psychopathology, only partly explained by the influence of a coexisting CD. The presence of ADHD in a substantial minority of patients accentuates the need for early detection and treatment of this complicating disorder.

Updated European Consensus Statement on diagnosis and treatment of adult ADHD.

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

Safety and clinical efficacy of zileuton in patients with chronic asthma.

Zileuton, a leukotriene pathway inhibitor used to treat asthma, improves lung function, relieves symptoms, and is well tolerated. The purpose of this 12-month, parallel-group, open-label study was to assess the efficacy of zileuton and evaluate liver function in patients treated with this drug (approximately 2% of patients treated with zileuton in controlled trials had reversible liver enzyme elevations). A total of 2,947 patients at 233 centers in the United States were randomly assigned in a 5:1 ratio to treatment with zileuton plus usual asthma care or usual asthma care alone. Efficacy variables included asthma exacerbations; need for alternative treatment, steroid rescue, emergency care, and hospitalizations; forced expiratory volume in 1 second (FEV1); and asthma symptom scores. The safety evaluation included measurement of alanine aminotransferase levels. Patients treated with zileuton had significantly fewer corticosteroid rescues (P < 0.001), required less emergency care (P < 0.05), had fewer hospitalizations, and had greater increases in FEV1 (P = 0.048). They also had significantly greater improvements in asthma symptoms. Increases in alanine aminotransferase levels to three times or more the upper limit of normal occurred in 4.6% of patients treated with zileuton and 1.1% of those receiving usual care (P < 0.001); most increases occurred during the first 2 to 3 months. Alanine aminotransferase levels decreased to less than two times the upper limit of normal or to baseline levels during zileuton treatment or after drug cessation. Jaundice or chronic liver disease did not develop in any patient. Adding zileuton to the therapeutic regimens of patients with asthma is likely to improve asthma control and lower utilization of healthcare resources.

Olfactory neuroblastoma with spinal metastasis--a problem in diagnosis.

The olfactory neuroblastoma or esthesioneuroblastoma is a rare neuroectodermal tumor originating from the olfactory neuroepithelium, which can metastasis via cerebrospinal fluid pathways. In the present case of an extensive nasal malignancy with cervical lymph node metastases in a 75-year old woman, its difficult histology alternatively led to a diagnosis of anaplastic carcinoma and non-Hodgkin lymphoma. The patient died from complications following spread of the tumor to the spinal cord and cauda equina. Review of the literature shows that this tumor is notorious for its chameleonic character. In view of its clearly demonstrated malignancy an aggressive therapeutic approach is advocated.

Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: a pilot study of six candidate genes.

The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted.

Transrectal ultrasonography in the followup of prostatic carcinoma patients: a new prognostic parameter?

The use of transrectal ultrasonography has opened new perspectives in the diagnosis and followup of patients with prostatic cancer. Our study has concentrated mainly on measurements of prostatic volume in patients treated by castration or external radiotherapy. Patients who underwent castration had stable disease or progression of the metastases from 3 to 10 months after castration. There is a statistically significant difference between the decreases of volume in the 2 groups at all intervals of the study. To date an increase in prostatic volume after an initial decrease has occurred in only 1 patient, who had no evidence of systemic progression. The initial decrease in volume of the primary tumor seems to be a critical parameter for the prediction of progression or stability in patients treated by endocrine manipulation. Transrectal ultrasonography seems not to be of great value in patients treated by external radiotherapy.

Transrectal ultrasonography in the followup of prostatic carcinoma patients.

Prostatic volume was determined by transrectal ultrasonography before and after castration in 13 patients, and after radiotherapy in 24. Measurements were done after 1, 2 and 3 months, and subsequently at 3-month intervals. Significant volume reductions occurred in the castration and radiation groups within 3 months. The decrease in prostatic volume was significantly more pronounced in the castration group during the entire study (p less than or equal to 0.01). Patients with enlargement of the prostate predominantly owing to benign prostatic hypertrophy also had a decrease in volume. No increase in prostatic volume after initial reduction was encountered for up to 9 months. In several cases progression of metastases occurred with no increase in the volume of the primary tumor. Followup may be too short to encounter local recurrence after radiotherapy or hormone-independent growth after castration. Proctitis after radiotherapy created artifacts that probably led to inaccurate measurements with ultrasonography. The technique provides a new, accurate parameter for followup of conservatively treated prostatic cancer patients. The clinical importance of the technique still remains to be determined.

Prognosis and prostatic volume changes during endocrine management of prostate cancer: a longitudinal study.

A total of 102 patients with histologically proved prostate cancer was followed by transrectal ultrasonography to determine the volume of the prostate during endocrine treatment. The mean volume reduction of the prostate at 3 months after start of treatment was 37.1%, and it was greater in patients treated by orchiectomy (42.1%) compared to those treated by luteinizing hormone-releasing hormone (30.5%). Without consideration of other factors, patients in whom the volume of the prostate had regressed 50% or more at 3 months had a better prognosis (overall survival, intercurrent death corrected survival and survival without distant progression) compared to those with a smaller volume reduction. However, when adjusted for the 2 most important prognostic factors in this study, histological grade and M category, no benefit from a greater prostate reduction as shown by ultrasound could be demonstrated. Similar results applied to the ultrasound findings at month 6. In 24 of the 102 patients an increase of prostatic volume by more than 20% was found after a median interval of 18 months, which was considered local progression. During the observation period systemic progression was encountered in 61 patients. When local progression was observed, the rate of subsequent distant progression was increased by a factor of 2.7, irrespective of grade and M category.

Heterozygous cystinuria and calcium oxalate urolithiasis.

To evaluate the incidence of heterozygous cystinuria in patients with primary and recurrent calcium oxalate stone disease 24-hour urine samples from 140 patients were examined. The frequency of heterozygous cystinuria in this study was only 1.4 per cent (2 patients). The frequency of other metabolic disorders was in accordance with other reports: hypercalciuria (32 per cent), hyperuricosuria (32 per cent) and hyperoxaluria (17 per cent).

Reflux--a retrospective study of 100 ureteric reimplantations by the Politano-Leadbetter method and 100 by the Cohen technique.

The results of 100 consecutive ureteric reimplantations using the Politano-Leadbetter technique were compared with those of 100 cases operated on by the Cohen technique. This retrospective study was concerned only with the effect of the operation on the ureterovesical junction. Cure of reflux was achieved in 88 Politano-Leadbetter reimplantations and in 97 Cohen reimplantations. Both groups and the results are analysed.

Phase 1/2 study of intravesical epirubicin in patients with carcinoma in situ of the bladder.

A total of 34 patients with grade 3 carcinoma in situ of the bladder entered a phase 1/2 study with epirubicin to examine the rate of antitumor activity, the type and frequency of local side effects, and the absorption and recovery rates. The selected doses were 30, 50 and 80 mg. Of the patients 22 were evaluable for report of treatment results. A total of 16 patients had a complete remission proved by biopsy and conversion of urine cytology findings. Mean duration of complete remission was 22.4 months (range 7+ to 50+ months). After a mean followup of 35.3 months (range 14 to 59 months) 8 of 16 patients were still in complete remission, 3 died of a myocardial infarction, 3 had recurrent grade 3 carcinoma in situ, 2 had increase to a higher T category (stages T2 and T4a), and 2 had recurrent papillary stage Ta, grade 2 (1) and stage T1, grade 2 (1) transitional cell carcinoma of the bladder. Six of the 22 patients had no response to 1 or 2 treatment courses with a higher dose. Plasma concentrations of epirubicin after instillation were close to the detection limit of the assay (0.5 to 2.0 ng/ml. plasma).

Effects of a 5-lipoxygenase inhibitor, ABT-761, on exercise-induced bronchoconstriction and urinary LTE4 in asthmatic patients.

The novel 5-lipoxygenase (5-LO) inhibitor, ABT-761, was investigated for its effect on exercise-induced bronchoconstriction in asthmatic subjects. The relationship between 5-LO inhibition and effects on the response of the airways to exercise was examined. In a double-blind, randomized, crossover clinical trial, 10 patients with mild to moderate persistent asthma (who exhibited a fall in forced expiratory volume in one second (FEV1) > or = 20% following standardized exercise challenge) received 200 mg ABT-761 or matched placebo, orally, 5 h prior to exercise on two study days, 7-10 days apart. Lung function, urinary leukotriene E4 (LTE4) and ex vivo calcium ionophore-stimulated LTB4 release in whole blood were measured prior to dosing, prior to exercise and at various time points up to 4 h post-exercise. The mean (SD) maximal percentage fall in FEV1 after exercise was 27.1 (12)% on placebo and 19.9 (10)% on ABT-761 days, respectively (p<0.05). Post-exercise fall in FEV1 was significantly attenuated at 5, 10, 15 and 30 min after exercise and the mean area under curve, representing the overall effect of exercise from 0-45 min post-challenge, was also significantly attenuated by ABT-761 (p<0.001). Ex vivo LTB4 release was inhibited by more than 80% throughout the 4 h post-exercise period, indicating that 5-LO was extensively inhibited at all time points. Urinary LTE4 in the post-exercise period was significantly lower after ABT-761 day than after placebo (40.1 (17.6) versus 89.8 (58.2) pg x mg creatinine(-1); p<0.05). Inhibition of LTB4 release in ABT-761-treated patients correlated positively with the attenuation of post-exercise FEV1 decline (r=0.711; p<0.05). We conclude that ABT-761 is effective in suppressing exercise-induced bronchoconstriction and that this protection is related quantitatively to the degree of 5-lipoxygenase inhibition.

The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects.

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.