Long-term effects of maternal separation on chronic stress response suppressed by amitriptyline treatment.

Abstract The early-life environment has many long-term effects on mammals. Maternal interaction and early stressful events may affect regulation of the HPA axis during adulthood, leading to differential glucocorticoid secretion in response to stressful situations. These adverse experiences during postnatal development may even sensitize specific neurocircuits to subsequent stressors. Later in life, the overreaction of the HPA axis to stress can constitute a risk factor for metabolic and mental diseases. As tricyclic antidepressants are known to correct glucocorticoid hypersecretion during depression, we treated maternally separated animals with amitriptyline, at a lower dose than habitually used in depression models, to prevent the response to chronic stress during adulthood. Male Wistar rats were separated from the mother for 4.5 h every day for the first 3 weeks of life. From postnatal day 50, animals were subjected to chronic variable stress during 24 d (five types of stressors at different times of day). During the stress, protocol rats were orally administered amitriptyline (5 mg/kg) daily. We observed that maternal separation caused a reduction in plasma ACTH levels (p < 0.05), but evoked hypersecretion of corticosterone (p < 0.05) when it was combined with stress in adulthood. This rise was completely prevented by antidepressant treatment with amitriptyline.

Venlafaxine induces P-glycoprotein in human Caco-2 cells.

PURPOSE: The objective of this study was to evaluate the effect of a treatment with venlafaxine on the expression of multidrug resistance-associated protein (MRP) gene and multidrug resistance-related proteins (MDR) in human colon carcinoma cells (Caco-2) compared to a known P-glycoprotein (PGY1) inducer, rifampine. METHODS: Caco-2 cells were treated with venlafaxine (50 microM, 100 microM, 250 microM, and 500 microM) and rifampin (25 microM and 50 microM) to test the possible induction of MRP and MDR expression. The treatment times used were 1.5, 3, 6, 12, 24, 48, and 72 h. RNA was isolated from the cells, and MDR and MRP genes were amplified using PCR. RESULTS: Both venlafaxine and rifampine had the most dramatic effect at the 50 microM concentration. There was an increase in MDR and MRP expression in Caco-2 cells after the acute treatment (1.5, 3, and 6 h) with venlafaxine. These results were similar to those with rifampine. CONCLUSIONS: PGY1 contributes to renal and biliary elimination of drugs by transporting the drug out of the cell and back into the intestinal lumen, where drugs may be further metabolized by intestinal enzymes such as Cytochrome P (CYP)-450 3A4. Its function is to limit the bioavailability of orally administered compounds. Due to the increase in MDR and MRP gene expression seen after the acute treatment with venlafaxine, there could be a potential drug-drug interaction with other medications that are metabolized via CYP450-3A4 when coadministered with venlafaxine.

Sex differences in rats: effects of chronic stress on sympathetic system and anxiety.

In this study we tested whether periodic maternal deprivation (MD) (4.5 h daily during the first 3 weeks of life) caused chronic changes in anxiety and medullo-adrenal responses to chronic stress in either male or female adult (2.5 months of age) rats, or both. Repeated maternal deprivation had a sex-specific effect on epinephrine (E) and norepinephrine (NE) levels: an increase in both measures was observed only in females. Unpredictable stress did not produce changes on plasma catecholamine levels either in males or females. However, when the females were maternally deprived as well as stressed they showed an increase in plasma NE p < 0.05. On the other hand, non-maternally deprived (NMD), maternally-deprived and stressed males showed high levels of catecholamines compared to females p < 0.001. In the elevated plus maze test, MD-treated males displayed a slight increase in anxiety-related behavior compared with NMD rats. This was indicated by a reduction in the time spent on the open arms, whereas females showed less anxiety, indicated by an increase in the number of entries, and in the time spent on the open arms. After exposure to chronic stress only the females displayed decreased anxiety-related behavior. These results suggest that there are sex-induced effects in emotional reactivity, perception of the stressor and in the evaluation of novel situations. Thus, maternal deprivation and chronic variable stress caused both long-term alterations in sympathetic response and gender-dependent changes in the anxiety index of adult rats.

The role of the anterodorsal thalami nuclei in the regulation of adrenal medullary function, beta-adrenergic cardiac receptors and anxiety responses in maternally deprived rats under stressful conditions.

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac beta-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac beta-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac beta-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial beta-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.

Periodic maternal deprivation and lesion of anterodorsal thalami nuclei induce alteration on hypophyso adrenal system activity in adult rats.

The hypothalamic-pituitary-adrenal (HPA) axis is normally regulated by extrahypothalamic limbic structures, among these, the anterodorsal thalami nuclei (ADTN), which exert an inhibitory influence on HPA, in basal and acute stress conditions in rats. In the present work we have investigated whether neonatal maternal deprivation (MD) produces long-term changes in the ADTN regulation of HPA activity. Maternal deprivation, in female rats, for 4.5 hs daily, during the first 3 weeks of life, produced at 3 months old, a significant decrease in plasma ACTH concentration (p<0.001) and an increase in plasma corticosterone (C) (p<0.001), compared to control non-deprived rats (NMD). Also MD showed higher plasma epinephrine (E) and norepinephrine (NE) levels than NMD rats. The increase of NE (66.6% p<0.001) was higher than that observed in E (19%). After 30 days of ADTN lesion, plasma ACTH values were higher than in sham lesioned rats, in both NMD and MD animals. ACTH response was greater in MD rats. Plasma C, in NMD, was higher, whereas in MD lesioned animals, it was significantly lower than in sham lesioned. In MD rats, lesion produced a significant increase in plasma E and NE (p<0.001), and again, NE increase was higher than E increase. The more accentuated increase of NE than E, suggests sympathetic nervous system hyperactivity. In summary, neonatal maternal deprivation induces long-term alterations on HPA axis sensitivity and medullo adrenal secretion; enhanced sympathetic nervous system activity and, therefore affected the ADTN inhibitory influence on ACTH and adrenal glands secretion.

A pharmacokinetic drug-drug interaction study of venlafaxine and indinavir.

Depression is a common occurrence in the human immunodeficiency virus (HIV)-infected population. Complications in treating depressed HIV-infected individuals include the use of multiple medications, additive side effects, and potentially significant drug-drug interactions. Based on the pharmacologic characteristics of venlafaxine and indinavir, we hypothesized that significant pharmacokinetic drug-drug interactions would not occur when these drugs where taken concurrently. Nine healthy adult subjects were given a single 800 mg oral dose of indinavir and serial blood samples were collected for measurement of plasma drug concentrations. Over the next 9 days, venlafaxine was administered at a dosage of 50 mg every 8 hours following a brief titration. A venlafaxine trough plasma concentration and serial concentrations following venlafaxine administration were obtained on day 10. On day 11, venlafaxine and indinavir were administered together and serial blood sampling was repeated. Indinavir had no effect on venlafaxine plasma concentrations but resulted in a 7% decrease in plasma concentrations of O-desmethyl-venlafaxine (ODV)(P = 0.028). This effect is unlikely to be clinically significant. Venlafaxine coadministration resulted in a 28% decrease in the area under the concentration time curve (AUC) of plasma indinavir (P = 0.016) and a 36% decrease in its maximum plasma concentration (Cmax; P = 0.038). As the plasma concentration of protease inhibitors is a critical factor in maintaining efficacy and minimizing the potential for viral resistance, the decrease in both AUC and Cmax of indinavir from coadministration of venlafaxine is of concern. The clinical significance of these results obtained from a small number of healthy volunteers is unknown. Further studies are needed to substantiate or refute this apparent drug-drug interaction. Until such time, venlafaxine should be used cautiously in patients receiving indinavir.

Engineering challenges to the long term operation of the International Space Station.

The U.S. Congress has maintained an intense interest in the ISS program since its inception. In the Appropriations Act of 1997, the Senate of the United States included language directing National Aeronautics and Space Administration (NASA) to have the National Research Council (NRC) under take a study that evaluates the engineering challenges posed by extravehicular activity (EVA) requirements, United States and non-United States space launch requirements, the potential need to upgrade or replace equipment and components after Assembly Complete, and the requirement to decommission and disassemble the facility. NASA and the NRC decided the focus should be on the anticipated challenges in the continuous operation and maintenance of the ISS after assembly of the on-orbit facility has been completed. This would encompass the operational years, from late 2004 (if the current schedule holds) to 2020-2025. This executive summary overviews the results of this NRC study. It focuses on the U.S. operation of the ISS after Assembly Complete, including cooperative efforts by the United States and Russia. The paper summarizes the primary findings and recommendations in each of the areas considered during this two-year NRC study.

Selective serotonin reuptake inhibitors in the treatment of paediatric anxiety disorders: a review.

Anxiety disorders (obsessive-compulsive disorder, social phobia/selective mutism, panic disorder, separation anxiety, generalized anxiety disorder, simple phobia and post-traumatic stress disorder) are the most prevalent psychiatric disorders in children and adolescents. The selective serotonin reuptake inhibitors (SSRIs)--citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline--have demonstrated efficacy in treating anxiety disorders in adults. Although less information is available on the use of these agents in the paediatric population, research into the SSRIs for childhood anxiety disorders is increasing. This article reviews current literature, including case reports as well as open and controlled trials, on the effectiveness and tolerability of the SSRIs in the paediatric population. It also discusses developmental differences in children that should be considered in the utilisation of the SSRIs in paediatric patients.

Mania with bupropion: a dose-related phenomenon?

OBJECTIVE: To report a case in which bipolar depression was resistant to usual therapies, requiring dosages of bupropion >450 mg/d and to review the literature on mania associated with bupropion and propose a potential theory of a dose-related threshold associated with bupropion and mania. CASE SUMMARY: A 44-year-old white man with a 25-year history of bipolar affective disorder presented with depression resistant to usual therapies. Bupropion therapy was initiated and the dosage was titrated to 600 mg/d. After exceeding the maximum recommended daily dose (450 mg/d), he experienced a manic episode attributed to high-dose bupropion. DISCUSSION: Due to increased risk of seizures, current prescribing guidelines state that the total daily dose of bupropion is not to exceed 450 mg/d. Since bupropion is the agent least likely to cause a manic switch in bipolar disorder, this agent seemed a logical choice to treat the patient's depression. Due to a lack of response, the bupropion dosage was titrated to a maximum of 600 mg/d. Since the patient did not switch into mania until the dosage exceeded 450 mg/d, we speculate that this adverse reaction is a dose-related phenomenon. Scientific literature supports this theory. CONCLUSIONS: A switch into mania is a potential risk associated with antidepressant drug use in bipolar affective disorder. Bupropion is believed to be associated with a decreased risk compared with other antidepressant therapies. However, our case report as well as others support the theory that this decreased risk may be due to dosages not exceeding the recommended daily dose (450 mg/d). Doses of bupropion >450 mg/d should be used with caution in depressed patients with bipolar affective disorder.

Factors affecting prescribing of the newer antidepressants.

OBJECTIVE: To survey various prescriber types and specialties to determine whether differences exist in prescribing patterns for the newer antidepressants. DESIGN, SETTING, AND PARTICIPANTS: A survey about prescribing of the newer antidepressants was mailed to 1,500 New York state licensed prescribers who were randomly selected from membership rosters. Nurse practitioners; physician assistants and physicians in family medicine, primary care, general practice, and internal medicine; and psychiatrists were included. MAIN OUTCOME MEASURES: Prescriber responses regarding factors involved with choosing among the newer antidepressants. RESULTS: A total of 508 surveys (36%) were returned, of which 398 (29%) were acceptable for analysis. In choosing among the newer antidepressants, most prescribers ranked patient diagnosis and past success as a high priority, and free drug samples and drug-representative detailing as a low priority. The majority of each prescriber type preferred fluoxetine for major depression and depression associated with fatigue; paroxetine for concomitant anxiety and depression, as well as for panic disorder; and sertraline for geriatric patients and patients with suicidal ideation. Differences existed between the prescriber groups when asked whether prescribing habits for the newer antidepressants were based on familiarity with a particular agent (p = 0.0009) and on labeled indications (p = 0.002). CONCLUSIONS: This is the first study to demonstrate prescribing preferences for the newer antidepressants among different prescriber groups. Additional studies are needed to determine predictors of patient response to newer antidepressants and clinical guidelines for their use.

Increased plasma atrial natriuretic factor in catecholamine-producing tumor patients.

The aim of this study was to evaluate plasma levels of ANF in patients with catecholamine-secreting tumors with and without hypertension and to relate ANF secretion to levels of plasma and urinary catecholamines and blood pressure. Twenty-one pheochromocytoma (15 with sustained, 6 with paroxysmal hypertension), 6 neuroblastoma (1 hypertensive) patients and 28 aged-matched controls were studied in basal conditions. Plasma and urinary norepinephrine (NE),epinephrine (E), dopamine (DA) and DOPA were determined by HPLC-ED and plasma ANF by RIA. Both neuroblastoma and pheochromocytoma patients had significantly higher plasma ANF levels than controls. Neuroblastomas showed higher ANF concentration than pheochromocytomas. No differences were found in plasma ANF between hypertensive and normotensive patients. Pheochromocytomas with ANF levels within the normal range had plasma and urinary NE and urinary DA and DOPA levels significantly higher than patients with high ANF. Plasma ANF levels were unrelated to systolic or diastolic blood pressure or heart rate. A negative correlation between plasma ANF and urinary DA was found only in the patients groups. In conclusion, plasma ANF was increased in pheochromocytoma and neuroblastoma patients. Our data suggest that the excessive catecholamine secretion is not responsible for the increased ANF secretion in these patients. The significance of the relationships among plasma ANF and urinary and plasma catecholamines requires further investigation.

Citalopram in the treatment of depression and other potential uses in psychiatry.

During the past decade, treatment options for depression have increased with the introduction of new agents. Older agents, such as tricyclic antidepressants and monoamine oxidase inhibitors, increase noradrenergic and serotonergic neurotransmission. Attempts to separate antidepressant effects from adverse effects led to the development of selective serotonin reuptake inhibitors (SSRIs). Citalopram is the newest SSRI to be marketed in the United States. Of all SSRIs on the market, it is the most selective for serotonin reuptake pump. Its efficacy in treating depression was evident in both placebo-controlled and comparator trials. In addition, citalopram was studied in the treatment of other psychiatric disorders. The agent has less inhibition of cytochrome P450 enzymes than other SSRIs, possibly giving it a lower potential for drug interactions.

Quetiapine, an atypical antipsychotic.

The discovery of antipsychotic agents in the 1950s revolutionized the treatment of schizophrenia. A large body of evidence supports the dopamine D2 receptor antagonist's efficacy in the treatment of psychotic symptoms. However, the advent of newer agents seems to point to a more complex interaction of neurotransmission in the pathophysiology of schizophrenia. In fact, a defining characteristic of atypical agents is a higher ratio of serotonin (5HT2) receptor blockade to D2 receptor blockade. Clozapine was the first atypical agent to be introduced; it was followed by risperidone, olanzapine, and now quetiapine, which is a dibenzothiazepine derivative structurally related to clozapine and olanzapine.

Role of propofol in refractory status epilepticus.

OBJECTIVE: To provide a review of the proposed mechanism of action, clinical efficacy, adverse effects, and therapeutic considerations associated with the use of propofol in the management of patients with refractory status epilepticus. DATA SOURCES: A MEDLINE database (January 1966-April 1998) was searched for literature pertaining to status epilepticus and propofol. Additional literature was obtained from the references of selected articles identified in the search. Information from all articles published in English was considered for inclusion in the article. DATA SYNTHESIS: Propofol is a unique, nonbarbiturate, anesthetic agent possessing anticonvulsant properties, although the exact anticonvulsant mechanism is unknown. Several case reports and two small, open, uncontrolled studies have described the efficacy of propofol in refractory status epilepticus. Most of these clinical reports discuss the utility of propofol after traditional treatment regimens have failed or are not tolerated. Initiation of propofol usually resulted in termination of seizure activity and/or electroencephalographic burst suppression within seconds that was sustained during the drug's use. Additionally, propofol was well tolerated. Advantages of propofol compared with traditional barbiturate anesthetic agents include better cardiovascular tolerability and a more favorable pharmacokinetic profile, allowing for rapid assessment of efficacy and neurologic assessment upon drug withdrawal. Propofol has been associated with a variety of neuroexcitatory adverse events such as opisthotonos, muscle rigidity, and choreoathetoid movements. Additionally, although the data are inconclusive, propofol has also been reported to cause seizures. CONCLUSIONS: Propofol has shown promising results in the management of refractory status epilepticus when traditional therapies have failed or were not tolerated; however, controlled clinical trials are needed to better assess the comparative efficacy, neurologic adverse effects, and clinical outcome to better define its role in refractory status epilepticus.

Compliance with depot antipsychotic medication by patients attending outpatient clinics.

Outpatients with schizophrenia often have problems complying with a regimen of oral antipsychotic medications. Use of depot medications improves compliance, but patients' geographic location and access to transportation may affect compliance with a depot regimen. The authors used retrospective chart review to examine whether patients' geographic location and sociodemographic characteristics and characteristics of their medication use were related to compliance with a depot regimen. The subjects were 75 patients attending an urban clinic and 23 patients attending a rural clinic in New York State. Median rates of compliance were 94.7 percent for the urban patients and 96.4 percent for the rural patients, not a significant difference. The only characteristic associated with a decreased compliance rate was a history of substance abuse.

Effect of over-the-counter dosages of naproxen sodium and acetaminophen on plasma lithium concentrations in normal volunteers.

Prescription doses of nonsteroidal antiinflammatory agents have been shown to decrease clearance and increase plasma concentrations of lithium. This study was designed to evaluate whether over-the-counter (OTC) doses of naproxen sodium or acetaminophen have the same potential to affect lithium concentration. This was a prospective, crossover, 3-phase study conducted at the Clinical Pharmacology Studies Unit of the Albany Medical Center Hospital during July and August of 1995. The 3-phase study comprised the following: phase 1, lithium carbonate (300 mg every 12 hours) alone for 7 days; phase 2, lithium and either naproxen sodium (220 mg every 8 hours) or acetaminophen (650 mg every 6 hours) for 5 days; and phase 3, a 2-day washout period followed by a crossover to lithium with the alternate drug (acetaminophen or naproxen sodium) for 5 days. Twelve healthy male volunteers were recruited, nine of whom completed the study and were included in the statistical analysis. Mean (+/-SD) plasma lithium concentrations for subjects in treatment group 1 (lithium in phase 1, lithium and naproxen sodium in phase 2, lithium and acetaminophen in phase 3) were 0.38 (+/-0.11), 0.40 (+/-0.07), and 0.36 (+/-0.11) mEq/L, respectively. Mean plasma lithium concentrations for subjects in treatment group 2 (lithium in phase 1, lithium and acetaminophen in phase 2, lithium and naproxen sodium in phase 3) were 0.43 (+/-0.05), 0.48 (+/-0.10), and 0.48 (+/-0.05) mEq/L, respectively. One-way repeated-measures analysis of variance and paired t-test showed no statistically significant differences (p>0.05) in plasma lithium concentrations during any phase of the study. The results of this study demonstrated that OTC doses of naproxen sodium and acetaminophen did not increase plasma lithium concentrations in these volunteers when taken for short periods of time.

Sertindole, a new atypical antipsychotic for the treatment of schizophrenia.

The introduction of antipsychotics for the management of schizophrenia greatly improved the quality of life of many patients suffering from this debilitating disease. Although typical antipsychotic drugs represent a significant advancement in psychopharmacology, they carry a heavy side effect burden, have little efficacy in the management of negative symptoms, and are ineffective in about one-third of patients with schizophrenia. Atypical antipsychotic agents characterized the next major advancement in pharmacotherapy. They differ from typical antipsychotics in their mechanism of action, side effect profiles, and clinical efficacy. Sertindole is a new atypical antipsychotic.

Seizure resulting from a venlafaxine overdose.

OBJECTIVE: To report a case of venlafaxine overdose. CASE SUMMARY: A 40-year-old woman with major depression took an overdose of venlafaxine in an apparent suicide attempt. After the ingestion of 26 venlafaxine 50-mg tablets, the patient experienced a witnessed generalized seizure. She was admitted to the medical intensive care unit, venlafaxine was discontinued, and no further sequelae were seen. DISCUSSION: To our knowledge, this is the first reported case of venlafaxine overdose that resulted in a generalized seizure. Based on nonoverdose pharmacokinetics and pharmacodynamics of venlafaxine and the potential risks of available interventions, no emergent therapy was instituted. CONCLUSIONS: The venlafaxine overdose in our patient resulted in a single episode of generalized seizure but elicited no further sequelae.

A comparison of patient-rated burden and incidence of side-effects: lithium versus valproate.

The purpose of the study was to determine if patients receiving valproate perceived a lesser burden than patients receiving lithium, and to determine the incidence of side-effects. Psychiatric inpatients with an affective component to their illness, receiving either lithium or valproate, were asked to complete several questionnaires, one of which was a newly developed visual-analogue scale to assess patient-rated level of burden. The scores were analyzed by Student's t-test, and were also used to determine if any correlations existed. Twenty-nine patients were analyzed, and the patient-rated level of burden was found to be 1.4± 1.3 for lithium and 1.2± 1.6 for valproate; (P=0.1, not significant). The mean numbers of side-effects reported were 12.3 ± 6.7 for lithium and 18.7 ± 13.4 for valproate; (P=0.1). No correlation relationships were detected. We concluded that there was no difference in level of burden, and that burden scores could not be correlated with any variables. Similar studies should be conducted to assess patient preferences, with the hopes of increasing compliance and minimizing rehospitalizations.