Early life stress increases testosterone and corticosterone and alters stress physiology in zebra finches.

Early life stress has enduring effects on behavior and physiology. However, the effects on hormones and stress physiology remain poorly understood. In the present study, parents of zebra finches of both sexes were exposed to an increased foraging paradigm from 3 to 33days post hatching. Plasma and brains were collected from chicks at 3 developmental time points: post hatching days 25, 60 and adulthood. Plasma was assayed for testosterone (T), estradiol (E2), and corticosterone (CORT). The paraventricular nucleus of the hypothalamus was assessed for corticotrophin releasing factor (CRH) and glucocorticoid receptor (GR) expression. As expected, body mass was lower in nutritionally stressed animals compared to controls at multiple ages. Nutritionally stressed animals overall had higher levels of CORT than did control and this was particularly apparent in females at post hatching day 25. Nutritionally stressed animals also had a higher number of cells expressing CRH and GR in the paraventricular nucleus of the hypothalamus than did controls. There was an interaction, such that both measures were higher in control animals at PHD 25, but higher in NS animals by adulthood. Females, regardless of treatment, had higher circulating CORT and a higher number of cells expressing CRH than did males. Nutritionally stressed animals also had higher levels of T than did control animals, and this difference was greatest for males at post hatching day 60. There were no effects of nutritional stress on E2. These findings suggest that nutritional stress during development has long-lasting effects on testosterone and stress physiology.

Antidepressant prescribing practices of outpatient psychiatrists.

BACKGROUND: The authors examined recent changes in the number and proportion of patients prescribed antidepressants by psychiatrists in outpatient private practice and characterized antidepressant prescription patterns by patient age, sex, race, payment source, and clinical diagnosis. METHODS: The authors analyzed physician-reported data from the 1985 and 1993-1994 National Ambulatory Medical Care Survey, focusing on visits to physicians specializing in psychiatry. Logistic regressions were used to examine associations between survey year and antidepressant prescription, adjusting for the presence of other variables. RESULTS: The proportion of outpatient psychiatric visits in which an antidepressant was prescribed increased from 23.1% (95% confidence interval [CI], 19.7%-26.5%) in 1985 to 48.6% (95% CI, 47.5%-49.7%) in 1993-1994. After controlling for several patient variables, psychiatric patients were approximately 2.3 (95% CI, 1.8-2.9) times more likely to receive an antidepressant in 1993-1994 than in 1985. In 1993-1994, selective serotonin reuptake inhibitors accounted for approximately half of the psychiatric visits with an antidepressant prescription. Increases in the rate of antidepressant prescription were particularly evident for children and young adults; whites; new patients; and patients with adjustment disorders, personality disorders, depression not otherwise specified or dysthymia, and some anxiety disorders. CONCLUSIONS: During the late 1980s and early 1990s, there was a significant increase in the prescription of antidepressants by office-based psychiatrists. This increase was greatest for patients with less severe psychiatric disorders.

Services and prevention: pharmacoepidemiology of antidepressant use.

Between 1988 and 1994, data from 3 large sites revealed a 3-5 fold increase in the prevalence of antidepressant (ATD) treatment for U.S. youths aged 2-19 years. In 1994, the ATD prevalence for youths of this age ranged from 13 per 1000 (in the HMO) to 18 per 1000 (in 2 state Medicaid systems). Males predominated in the 10-14-year-olds treated with ATDs, whereas females predominated among 15-19-year-olds. Caucasians were more than twice as likely to receive ATD therapy than their African-American counterparts. Primary care providers were the major source of ATD prescriptions for youths. The leading diagnoses in primary care were ADHD followed by depression, whereas the diagnostic order was reversed for youths who received psychiatric services. This review provides details concerning these patterns and trends in ATD treatment of youths from community-based clinical data sources. In addition, the role of these data in an expanded, comprehensive psychotropic knowledge base is discussed. Finally, the implications of an expanded knowledge base for ATD treatments are discussed in regard to generating research questions on effectiveness and safety and to improve treatment consensus within a public-health perspective.

Hypothesis testing: is clozapine's superior efficacy dependent on moderate D2 receptor occupancy?

BACKGROUND: How clozapine exerts superior antipsychotic efficacy in treatment-resistant schizophrenia is not known. Moderate (rather than "full") occupancy of D2 postsynaptic receptors may be crucial, perhaps by achieving a more effective D1/D2 or serotonin-2a/D2 ratio. The objective of this study was to test the moderate occupancy hypothesis of clozapine's superior efficacy. METHODS: Data from the New York effectiveness of clozapine study were used to compare 6-week clozapine treatment results in patients discontinuing oral neuroleptic medication with similar patients discontinuing long-acting depot neuroleptic. The latter group is assured "full" D2 occupancy during the 6-week clozapine treatment. RESULTS: If moderate occupancy is crucial for superior efficacy, the oral discontinuation group should manifest more improvement. Both groups showed the 6-week improvement expected with clozapine therapeutics [31% and 29% reduction in Brief Psychiatric Rating Scale (BPRS) scores in the depot and oral groups, respectively]. An analysis of covariance (for baseline BPRS) revealed no difference in change scores (df = 1,100; F = 0.17; p = ns). CONCLUSIONS: The reduced D2 occupancy hypothesis is rejected.

New York under the Rivers decision: an epidemiologic study of drug treatment refusal.

OBJECTIVE: To determine the characteristics of cases of drug treatment refusal under the Rivers decision, which mandated court adjudication of such cases, the authors made a retrospective study of all applications for court review during 1 year in New York State inpatient facilities. METHOD: Sociodemographic and clinical characteristics of these 473 cases were compared with those of the 41,535 cases during the same period in which no court review was requested. RESULTS: A 1% prevalence of applications requesting court review for nonemergency administration of medication over objection was found. The patients who refused medication were more likely than the comparison patients to have a crime-associated commitment status, a diagnosis of schizophrenia, and fewer previous hospital days, and they were more likely to be discharged. Medication refusers for whom applications for court review were submitted had relatively longer hospitalizations than the rest of the patients. Almost one-third of the applications submitted were withdrawn before court hearings, yielding a 0.7% prevalence of court-reviewed applications. Ninety-two percent of these applications for medication over objection were approved with virtually no change in the requested orders. CONCLUSIONS: The study findings demonstrate that a front-end judicial determination of competency to refuse medication results in a time-consuming procedure which fails to ensure real due process or provide individualized alternative treatment. A two-tier system with in-house clinical review preceding judicial review is proposed to remedy the deficiencies of the current system.

Pharmaco-epidemiology in 136 hospitalized schizophrenic patients.

The authors surveyed pharmacotherapy in a group of 136 newly admitted patients with a DSM-III diagnosis of schizophrenia. They found that nine antipsychotic agents were used; the median daily dose (in chlorpromazine equivalents) was 1088 mg (mean +/- SD = 1428 +/- 1260 mg; range = 75-6186 mg). Women received greater mean daily doses of antipsychotics than men (1688 versus 1284 mg). Using a Cox model survival analysis, the authors found no statistical association between length of stay and the mean daily dose of antipsychotic medication. The mean daily dose of high-potency agents was 2.7 times greater than the dose of low-potency agents. The excess exposure to haloperidol alone resulted in 16.3% of the overall neuroactive drug costs.

Clinical characteristics of hospitalized psychotic patients who refuse antipsychotic drug therapy.

Thirty psychotic patients who refused antipsychotic medication were compared with 30 patients matched for age, sex, treatment ward, commitment status, and diagnosis who consented to drug treatment. Refusers were no more assaultive or combative than consenters; they were less often diagnosed as having schizophrenia and more often diagnosed as having bipolar or schizoaffective illness. A comparison between 17 of the least symptomatic refusers and 17 of the most persistent refusers showed that persistent refusers were more likely to have a diagnosis of schizophrenia; least symptomatic refusers were more often diagnosed as having affective disorders or schizoaffective disorders.

Increased methylphenidate usage for attention deficit disorder in the 1990s.

OBJECTIVE: To estimate the increased use and the prevalence of methylphenidate (Ritalin) treatment of youth with attention deficit disorder (ADD) during the 1990s. DESIGN: Using time-trend findings from two large population-based data sources, three pharmaceutical databases, and one physician audit, a best-fit estimate of the usage and the usage trends for methylphenidate treatment over the half decade from 1990 through 1995 was sought. SETTING: Five regions in the United States (US) and the nation as a whole. PATIENTS: Youths on record as receiving methylphenidate for ADD. RESULTS: The findings from regional and national databases indicate that on average, there has been a 2.5-fold increase in the prevalence of methylphenidate treatment of youths with ADD between 1990 and 1995. In all, approximately 2.8% (or 1.5 million) of US youths aged 5 to 18 were receiving this medication in mid-1995. The increase in methylphenidate treatment for ADD appears largely related to an increased duration of treatment; more girls, adolescents, and inattentive youths on the medication; and a recently improved public image of this medication treatment. CONCLUSION: The database findings presented serve to correct exaggerated media claims of a 6-fold expansion of methylphenidate treatment, although they do not clarify the issue of the appropriateness of this treatment.

Computerized volume measurement of brain structure.

Morphometric analysis of brain structures recently has become a main focus of interest in studies of some neuropsychiatric diseases. Limitations in imaging and mensuration methodology that is available currently for quantitative measurement of anatomic structures have prompted the development of a computerized system to study brain morphometry. A menudriven semi-automated computer system has been developed to assess in vivo brain morphometry using three-dimensional (3-D) magnetic resonance (MR), gradient echo, contiguous images of the whole brain. Accuracy of the system was tested with phantoms creating white on black contrast to simulate the brain tissue surrounded by subarachnoid cerebrospinal fluid (CSF), and a second set of phantoms creating black on white contrast to simulate the ventricular system in the brain tissue. The first set of phantoms was composed of three water-filled balloons (spherical, elliptical, and multiform) and a fresh postmortem brain. The second set of phantoms consisted of three rods of different diameters from a simple geometric plexiglass rod phantom and a life size cast of a human ventricular phantom. System accuracy was generally within 2.0% of the true volumes. System reliability was evaluated in three patient populations; 12 patients with Alzheimer's disease, nine with schizophrenia and nine healthy controls age-matched to the patients with Alzheimer's disease. Two independent observers measured the ventricular systems of these patients. Reliability of the system was addressed by the correlation between the two sets of measurements. For the sample as a whole, and each of the subgroups, the correlation between the two observers was 0.99. This system compares favorably with other morphometric methods reported.

Questionable value of furosemide in preventing renal failure.

The effects of furosemide on renal function and hemodynamics were evaluated in 54 critically ill surgical patients. Standard clearance techniques were used to measure glomerular filtration rate (GFR), renal plasma flow (RPF), osmolar clearance (COsm), sodium clearance (CNa), and renal blood flow (RBF). RBF distribution to outer cortex, inner cortex-outer medulla, and inner medulla was measured by the radioactive xenon disappearance technique. Furosemide produced a marked rise in urine output, COsm, and CNa; it produced no change in GFR, RPF, RBF, and RBF distribution. Twelve of the 54 patients received furosemide for therapy not related to the study; six patients developed renal failure and five became hypotensive 2 to 10 hours after administration of furosemide. These data demonstrate that furosemide does not protect against renal failure by altering or increasing RBF but may cause renal failure by producing hypovolemia.

Psychotherapeutic medication patterns for youths with attention-deficit/hyperactivity disorder.

OBJECTIVES: (1) To describe temporal patterns of office visits for attention-deficit/hyperactivity disorder (ADHD) and stimulant treatment for 5- to 14-year-old US youths; (2) to compare youth visits for ADHD with and without melication according to patient demographics, physician specialty, reimbursement source, and comorbid diagnoses; and (3) to compare office visits for youths with ADHD in relation to common medication patterns (stimulants alone, stimulants with other psychotherapeutic medication, and nonstimulant psychotherapeutic medications alone). DESIGN: Survey based on a national probability sample of office-based physicians in the United States. SETTING: Physician offices. PARTICIPANTS: A systematically sampled group of office-based physicians. MAIN OUTCOME MEASURES: National estimates of office visits for ADHD and psychotherapeutic drug visits for ADHD for each year and for a combined 8-year period. RESULTS: Youth visits for ADHD as a percentage of total physician visits had a 90% increase, from 1.9% in 1989 to 3.6% in 1996. Stimulant therapy within ADHD youth visits rose from 62.6% in 1989 to 76.6% in 1996. While the majority of non-ADHD youth visits were conducted by primary care physicians, one third of ADHD youth visits were managed by psychiatry and neurology specialists. Health maintenance organization insurance was the reimbursement source for 17.9% of non-ADHD youth visits but only 11.7% of ADHD youth visits. Complex medication therapy was more likely to be prescribed by psychiatrists and less likely to be related to visits with health maintenance organization reimbursement. CONCLUSIONS: National survey estimates in the 1990s confirm the substantial increase in visits for youths diagnosed as having ADHD, with more than three quarters of these visits associated with psychotherapeutic medication treatment. Physician specialty and reimbursement source variables identify distinct patient populations with a gradient in psychotherapeutic medication patterns from single-drug standard (stimulant) therapy to complex multidrug treatment regimens for which evidence-based scientific information is lacking.

Mechanism of inappropriate polyuria in septic patients.

Inappropriate polyuria leading to hypovolemia and hypotension occurs frequently in severely septic patients. It's etiology was studied in three patients with polyuria and systolic hypotension. Glomerular filtration rate and renal blood flow were measured by the standard renal clearance techniques. Renal blood flow distribution to the outer cortex, inner cortex-outer medulla, and the inner medulla were measured by radioactive xenon. The glomerular filtration rate, renal blood flow, and renal blood flow distribution were normal. Polyuria does not result from a maldistribution of renal blood flow. Antidiuretic hormone did not alter the polyuric syndrome. These data suggest that sepsis produces a blockade at either the distal tubule or the collecting duct, thereby preventing salt and water conservation. This blockade may be due to either a toxin or a toxic metabolic breakdown product of sepsis.

Computed tomography of abdominal aortic aneurysm. An in vivo pathological report with a note on dynamic predictors.

A group of computed tomography (CT) descriptors were derived for abdominal aortic aneurysms. Terminology was defined and applied to the interpretation of the CT image in 55 prospective cases. Correlation of geometric parameters of aneurysm and analysis of the relationship of internal aneurysm components such as lumen and thrombus was performed. Predictive growth patterns for aneurysm demonstrated a synchronous increase in the volume of thrombus within the aneurysm in those aneurysms measuring 5 to 7 cm. Aneurysms greater than 7 cm were associated with an expansion of the patent pulsatile lumen, with no appreciable increase in thrombus volume. The thrombus-lumen ratio effectively described the changing internal architecture of aneurysm associated with increase in size. Proper utilization of CT descriptors develops a language that interprets aneurysm stability and potential for rupture and may provide an improved basis for timely surgical planning.

Racial disparity in psychotropic medications prescribed for youths with Medicaid insurance in Maryland.

DESIGN: A retrospective analysis was conducted using state Medicaid prescription drug reimbursement claims for youths aged 5 through 14 years according to the race of the recipients of psychotropic and medical drugs. METHOD: A person-based data set was created from Medicaid administrative data for fiscal year 1991 from the state of Maryland to yield the following: (1) estimates of prevalence of prescription recipients per 100 eligible enrollees; (2) relative prescription use ratios according to race (African-American versus Caucasian); and (3) the interrelation of race and geographic region on prescription prevalence. RESULTS: Five major findings were observed: (1) African-American youths with Medicaid insurance aged 5 through 14 were less than half (39% to 52%) as likely to have been prescribed psychotropic medications as Caucasian youths with Medicaid insurance; (2) the relative difference for nonpsychotropic medication classes was much less pronounced: African-American youths were prescribed nonpsychotropic medications at a rate 60% to 87% of the Caucasian youths' rate; (3) the stimulants (essentially methylphenidate) had the most disparate African-American/Caucasian ratio (1:2.5); (4) the racial disparity for psychotropics was not altered by partial (noncontinuous enrollment) eligibility status; and (5) although geographic variation reduced the racial disparity, the substantial racial difference (1:2.0) remained. CONCLUSION: Compared with Caucasians, African-American youths aged 5 through 14 with Medicaid insurance coverage showed a distinctly lower rate of treatment with psychopharmacological agents.

Pemoline hepatotoxicity and postmarketing surveillance.

OBJECTIVE: To review the numerous reports of hepatotoxic adverse drug reactions (ADRs) ascribed to pemoline that were sent to the U.S. Food and Drug Administration (FDA) between 1975 and 1996 and to describe the medical community's lack of awareness of these reports. METHOD: All ADR reports from 1975 through 1996 wherein pemoline was the suspect agent were obtained from the FDA MedWatch Internet site, and some details of nine pemoline-related deaths in youths were obtained directly from the FDA. The published literature on this subject was fully reviewed. RESULTS: (1) In premarketing clinical trials with pemoline in the early 1970s, hepatic abnormalities were noted in enzyme levels (1%-3% of youths receiving maintenance treatment), during rechallenges (6 of 6), and in biopsies (2 of 2). (2) Between 1975 and 1989, 12 cases of jaundice and 6 deaths in youths ascribed to pemoline hepatotoxicity were reported to the FDA. (3) The first medical literature report of a serious ADR ascribed to pemoline was in a 1989 letter to the editor. (4) Physicians generally only became aware of serious pemoline hepatotoxicity in December 1996. (5) Pemoline use increased until 1997. CONCLUSION: Limitations in postmarketing surveillance and public reporting in the United States, particularly in the 1980s, largely accounted for delays in an appropriate response to pemoline hepatotoxicity.

Clinical and treatment characteristics of children with attention-deficit/hyperactivity disorder in psychiatric practice.

OBJECTIVE: To capture information about the clinical characteristics of, and treatments for, children with attention-deficit/hyperactivity disorder (ADHD) in psychiatric practice. METHOD: A mailed, self-administered questionnaire was sent to 81 practicing psychiatrists for them to complete on the next three consecutive patients aged 14 years and younger with ADHD seen during the 12-day study period. Information collected included the sociodemographic, clinical, and treatment characteristics of sampled patients. RESULTS: Patients in the study were predominantly white (85%), male (78%), and between 10 and 14 years old (58%). The most common ADHD subtype was combined/predominantly hyperactive (86%); 31% had no other comorbidity. Ninety-seven percent were receiving medications, with 49% receiving two or more. The single most common medication reported was methylphenidate (51% of patients) followed by clonidine (20%). Psychotropics other than psychostimulants were used in a majority of patients (55%). CONCLUSIONS: Psychiatrists, and child and adolescent psychiatrists in particular, see a more severely impaired and complex group of patients than would be expected of primary care providers. The treatment patterns of psychiatrists for these patients do not reflect the simpler treatments usually studied in clinical trials.

Fenestration of the internal carotid artery: a rare mass of the hypotympanum associated with persistence of the stapedial artery.

A 61-year-old woman was examined because of unilateral nonpulsatile tinnitus involving the right ear. CT scanning showed a soft-tissue mass in the hypotypanum. Angiographically, the mass was identified as a fenestrated or duplicated internal carotid artery associated with persistence of the stapedial artery. Embryologic considerations are discussed.

Pharmacoeconomics of the new antipsychotics for the treatment of schizophrenia.

Inevitably, the greater availability of more costly antipsychotic medications has resulted in attempts to regulate the use of these agents. Early objections over the cost of treatment with clozapine or risperidone have in part been mollified by preliminary statistics on the cost effectiveness of these agents. However, this issue is complex and requires careful consideration of pharmacoeconomic principles in the development and clinical distribution of novel antipsychotics. Future cost-effectiveness studies need to consider a balance of public and private perspectives. These studies should be conducted in several settings, preferably also within the context of broader, multimodal treatment intervention strategies.

Acute cerebrospinal fluid hydrothorax: a delayed complication of subdural-pleural shunting.

A 31/2-year-old child with a bilateral chronic subdural hematoma due to battering suffered a recurrence on one side. She was treated successfully with a subdural-pleural shunt. Two months later, she returned with severe respiratory embarrassment due to what we think was a cerebrospinal fluid hydrothorax. The maintenance of her earlier neurological recovery was confirmed, and her hydrothorax was cured by removing the shunt. No hydrocephalus ensued.

Neurosyphilis presenting as a focal mass lesion: a case report.

A patient with subacute aphasia and hemiparesis was found to have a low density white matter lesion with mass effect on the computed tomographic (CT) scan. Serological examination and biopsy established the diagnosis of paretic neurosyphilis. This CT appearance has not previously been described in cases of neurosyphilis. Neurosyphilis should be considered as a potentially treatable cause of a cerebral mass lesion.