Systematic overview of drug interactions with antidepressant medications.

OBJECTIVE: Antidepressants are commonly used drugs with potential for numerous drug interactions. This study aims to systematically review the literature on drug interactions with antidepressants. METHODS: We searched MEDLINE (1966 to November 2003) and EMBASE (1980 to 2003), using the heading drug interactions combined with individual antidepressant names. We restricted searches to English-language articles and human studies. We screened drug interaction texts and review articles for relevant studies. We included articles reporting original human data on drug interactions with antidepressants commonly used in North America. Articles were independently evaluated by 2 reviewers on clinical effect, clinical significance, and quality of evidence. Discrepancies were resolved by consensus. RESULTS: There were 904 eligible interactions, involving 9509 patients, for a total of 598 summary interactions. Of these, 439 (73%) demonstrated an interaction, 148 (25%) had no effect, and 11 (2%) had conflicting evidence. For 510 interactions (85%), the quality of evidence was poor. It was fair for 67 (11%) interactions and good for 10 (2%) interactions. There were no interactions with excellent quality of evidence. There were 145 (24%) interactions of major clinical significance. These were predominantly hypertensive emergencies and serotonin syndrome. Most interacting drugs had central nervous system (CNS) activity. As expected, monoamine oxidase inhibitors (MAOIs) appear to be the most problematic family in terms of potential for serious drug interactions. CONCLUSIONS: Drug interactions with antidepressants are an important cause for concern, but this concern is based primarily on poor evidence. We recommend caution when combining antidepressants with other CNS drugs, particularly when coadministering MAOIs with other substances.     

Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group.

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (less than or equal to ten per ten high-power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log-rank tests (P less than 0.0001 and P = 0.0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [greater than ten per ten high-power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P less than 0.001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades. Age groups (less than or equal to 1 versus greater than 1 year of age), which also emerged as an independent prognostic feature (P less than 0.001), were linked with the grades to define two risk groups as follows: (1) a low-risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high-risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P less than 0.001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.     

Dissociation of item and order spatial memory in rats following medial prefrontal cortex lesions

In order to test whether there is a correspondence in function of prefrontal cortex in rats and humans, rats with medial prefrontal cortex lesions were tested for item and order memory for a list of items (spatial locations in a maze). Results indicate that for order memory rats with medial prefrontal cortex lesions cannot remember the order of presentation of four or eight specific spatial locations. This inability to remember order information can be seen even when animals with lesions have to remember only two spatial locations, can self-order the sequence of four or eight spatial locations, or have been presented with the same study phase on every trial. In contrast, for item memory animals with medial prefrontal cortex lesions retain the first item of the list in the variable study phase situation and remember all the items of the list in a constant study phase situation. However, there are also deficits for the last items within a list in the variable study phase situation for both win-stay and win-shift procedures. This deficit might be a function of an impairment in the utilization of appropriate temporal strategies, which normally would facilitate recognition memory in the win-stay and win-shift tasks. In general, the data suggest a partial, but not complete, dissociation of item-order memory. Furthermore, the data suggest that the medial prefrontal cortex is involved in temporal structuring of information.     

Chronic renal failure presenting as proximal muscle weakness in a child

A 13-year old boy presented with a three-year history of slowly progressive proximal muscle weakness, particularly involving the lower extremities. Chronic renal failure was uncovered in the course of his evaluation. Urologic investigation showed small and poorly functioning kidneys with a BUN of 118 mg/dL and a creatinine of 10.7 mg/dL. There were no anomalies of the proximal or distal collecting systems or history suggestive of recurrent urinary tract infection. The neurologic examination revealed proximal muscle weakness primarily of the lower extremities and especially of the proximal musculature of the pelvic girdle. Nerve conduction studies were normal. The electromyogram (EMG) showed high-voltage polyphasic potentials consistent with neurogenic muscle disease. A biopsy of the right quadriceps muscle demonstrated type II muscle fiber atrophy with histochemical staining. The patient's clinical findings, EMG studies, and muscle biopsy were not specific for either neurogenic or myopathic disease. Following a period of home peritoneal dialysis and renal transplantation, there was significant clinical improvement of the muscle weakness.