bluuebunny/crossref_metadata_2025 huggingface dataset:
Appearance of Eosinophilic Granule Cells as Pathological Changes in the Uteri of Two Aged Virgin Donryu Rats
Authors: Yoshida Midori , Sasahara Kenji , Ando-Lu Jin , Takahashi Masakazu , Maekawa Akihiko
Published: April 2009

The morphological features of cells containing eosinophilic granules (EG cells) present as pathological changes in the uteri of 2 aged virgin Donryu rats were described and compared with granulated metrial gland (GMG) cells of a pregnant rat. Microscopically, EG cells distributed diffusely from the mesometrial triangle to the subendometrium with partly focal accumulation in Case 1 and infiltrated diffusely from the endometrium to the serosa without any clumping in Case 2. They were large cells with eosinophilic and hyaline intracytoplasmic granules, positive for the periodic acid-Schiff reaction. Both EG and GMG cells reacted positively to concanavalin A, wheat germ agglutinin, and phytohemagglutinin on lectin histochemical investigation, although common results were not always obtained for immunohistochemistry. These results show that EG cells are morphologically similar to GMG cells, suggesting a possibility that EG cells are GMG cells. EG cells were without neoplastic properties or pronounced cell-proliferative activity. In Case 1, histological changes of the ovaries and vagina were indicative of a pseudopregnant status. In Case 2, the rat had been maintained under abnormal hormonal conditions, and no evidence of any pseudopregnant-like status was found. These results suggest, thus, that the appearance of EG cells is evidence of a reactive pathological condition in the uteri of aged virgin rats, although the precise pathogenesis and biological significance of EG cells remain to be determined.
Experimental Model of Renal Tumors in Polycystic Kidneys: Effects of Long-Term 2-Amino-4,5-Diphenylthiazole Administration in Rats Treated with N-Ethyl-N-Hydroxyethylnitrosamine
Authors: Tsumatani Kenichi , Nakagawa Yoshinori , Kitahori Yoshiteru , Konishi Noboru , Uemura Hirotsugu , Ozono Sechiro , Hirao Yoshihiko , Okajima Eigoro , Hirao Kazuya , Hiasa Yoshio
Published: April 2009

We previously reported that treatment of Fischer-344 rats with 2-amino-4,5-diphenylthiazole (DPT) results in renal cystic changes. The present study was undertaken to examine the effects of long-term DPT treatment after initiation of kidney carcinogenesis with N-ethyl- N-hydroxyethylnitrosoamine (EHEN) in Wistar rats. One hundred forty-four 6-wk-old male Wistar rats were divided into 6 equal receiving groups: 1000 ppm EHEN or normal tap water for 2 wk followed by 1.06% DPT or basal diet for the subsequent 14 or 30 wk. Controls were maintained without treatment throughout. Subgroups of 6 animals from each group were sacrificed after 8, 16, 24, and 32 wk for histopathological assessment of lesion development in the kidneys and liver. Animals treated with DPT first developed cystic changes of the kidneys (primarily at the corticomedullary border) after 8 wk of treatment, and these changes progressed with time thereafter. In the groups in which DPT treatment was discontinued after 14 wk, cysts then gradually decreased in size. All tumors detected in the kidneys were histopathologically diagnosed as renal cell adenomas. The tumor multiplicity after 32 wk of treatment was significantly higher in Group I, receiving EHEN + DPT for 30 wk (6.33 ± 4.46), and Group III, receiving EHEN + DPT for 14 wk (3.83 ± 1.57), than in Group V, EHEN alone (1.00 ± 0.58) (p < 0.05). Renal cell tumors within cysts were only seen in Groups I and III. The general bromodeoxyuridine labeling indices for the kidneys at week 32 were significantly higher in Group I (55.94 ± 21.08 cells/mm2) and Group III (53.75 ± 12.38 cells/mm2) than in Group V (22.38 ± 6.98 cells/mm2) (p < 0.05). In conclusion, DPT caused cystic changes in rat kidneys, which, however, gradually decreased in size after the treatment was discontinued, suggesting a reversible nature. DPT clearly also promotes renal tumor development after EHEN initiation, and this effect persists, to a certain extent, even after the insult is removed.
Apoptotic Cell Death of Erythrocytes in Xenopus Larvae Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
Authors: Sakamoto Michiko K. , Mima Shin , Takahashi Kenichi P. , Tanimura Takashi
Published: April 2009

Xenopus embryos were exposed to 200 ppb 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 5 days from the 2- to 8-cell stage of cleavage to the early larval stage. Larvae that developed generalized edema were collected at 7 days after the end of TCDD exposure for light and electron microscopic studies. Erythrocytes in the peripheral blood of the edematous larvae were examined. Between 0.3 and 33.9% of identifiable erythrocytes of exposed larvae had dilated perinuclear cisternae. Furthermore, some had extremely condensed nuclear chromatin usually coalesced against 1 pole of the nuclear membrane and overall compacted cytoplasm. The erythrocytes showing nuclear condensation were phagocytosed by macrophages. These features are typical of cells undergoing apoptosis. Anemia is 1 symptom of TCDD toxicity in various animal species, including mammals. In this study, we demonstrate that TCDD induces apoptotic cell death in circulating erythrocytes of Xenopus larvae, which may be 1 cause of anemia in this species.
Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin
Authors: Burkhardt John E. , Förster Christian , Lozo Edith , Hill Michael A. , Stahlmann Ralf
Published: April 2009

Effects of the fluoroquinolone difloxacin on articular-epiphyseal cartilage in growing beagle dogs have been described by light microscopic, electron microscopic, and biochemical methods. Here we present data from an immunohistochemistry study with humeral head cartilage from 3-mo-old beagle dogs after treatment with 1 or 2 oral doses of 300 mg difloxacin/kg body weight. Dogs were euthanatized either 24 hr (single dose) or 48 hr (2 doses) after onset of dosing, and cartilage tissue was stored at -90°C until it was studied by immunohistochemistry. Antibodies against matrix components (collagen II, fibronectin) as well as antibodies against cellular structures (integrins) were used. After single-dose treatment (24-hr group), cartilage lesions such as clefts were not observed, but increased staining for fibronectin was found in cartilage samples from 5 of 6 animals. Markedly increased staining for fibronectin was also demonstrated in the vicinity of clefts within cartilage of all animals of the 48-hr group. Collagen II staining was homogeneously distributed in cartilage from controls and was slightly reduced in territorial matrix in 2 of 6 dogs of the 48-hr group. Integrin staining on chondrocytes was not significantly affected by difloxacin under the given conditions with the exception of a slight reduction of the α v integrin chain in 1 of 5 dogs of the 48-hr group. Overall, the most important result is the finding that fibronectin was a sensitive immunohistochemical marker for change in cartilage samples due to difloxacin treatment in dogs.
Spontaneous Skin Neoplasms in Long-Evans Rats
Authors: Sommer Mary M.
Published: April 2009

Two hundred sixty-one neoplasms involving the skin and its appendages were observed in a total of 980 (490 of each sex) Long-Evans (LE) control rats of 7 carcinogenicity studies. All studies were 2 yr in duration and were conducted in the years 1983 through 1994. Skin neoplasms were reevaluated and classified according to current criteria and nomenclature. The various neoplasm incidences were compared to those published for Sprague-Dawley (SD), Fischer-344 (F-344), and Wistar rats. The most common neoplasms involved the mammary glands, affecting 28% of LE females. This incidence is comparable to the 31% incidence reported for SD females. Mammary gland fibroadenomas were observed in 22% of LE females compared to 19-31% of SD, 7-29% of F-344, and 4-25% of Wistar females. Mammary gland adenocarcinomas occurred in 7% of LE females in our laboratory, while incidences of 9-17% of SD, 0-2% of F-344, and 1-13% of Wistar females are reported. In LE males, the incidences of mammary gland fibroadenomas (1%) and adenocarcinomas (0.6%) were comparable to the 0-3% reported recently in other strains. As is observed in other strains, the incidence of nonmammary gland skin neoplasms in LE males (11.4%) was greater than the incidence in females (2.7%). Fibromas were the most common nonmammary gland skin neoplasm and affected 3.3% of males and 0.6% of females. The incidences of fibromas in SD, F-344, and Wistar rats range from 0-7%, 0-3.2%, and 0-12%, respectively, in males and from 0-3.3%, 0-1.1%, and 0-4%, respectively, in females. Of the 4 strains, only SD males have more nonmammary gland epithelial than mesenchymal skin neoplasms. The difference between the LE and SD males can be attributed to the criteria used to classify keratoacanthomas. Only one keratoacanthoma was observed in LE rats in this review. Reevaluation of skin neoplasms found in 980 LE control rats and comparison of the resulting incidences with those of other strains demonstrated that most skin neoplasms in LE rats have comparable incidences to those reported for SD, F-344, and Wistar rats.
Review Article: Pathology of Minamata Disease
Authors: Eto Komyo
Published: April 2009

Minamata disease, or methylmercury poisoning, was first discovered in 1956 around Minamata Bay, Kumamoto Prefecture, Japan. A similar epidemic occurred in 1965 along the Agano River, Niigata Prefecture, Japan. The neuropathology of Minamata disease has been well studied; this review focuses on human cases of Minamata disease in Kumamoto Prefecture. Nervous system lesions associated with Minamata disease have a characteristic distribution. In the cerebral cortex, the calcarine cortex was found to be involved in all cases of Minamata disease, particularly along the calcarine fissure. The destruction of nerve tissue was prominent in the anterior portions of the calcarine cortex. Occasionally, the centrifugal route from the visual and visual association areas (internal sagittal stratum) showed secondary degeneration in prolonged cases after acute onset. Postcentral, precentral, and temporal transverse cortices showed similar changes, though they were less severe. Intense lesions in the precentral cortex caused the development of secondary bilateral degeneration of the pyramidal tracts. In the cerebellum, the lesions occurred deeper in the hemisphere. The granule cell population was most affected. In the peripheral nerves, sensory nerves were more affected than motor nerves. Secondary degeneration of Goll's tracts was occasionally seen in prolonged or chronic cases.
Nasal Toxicity of CI-959, A Novel Anti-inflammatory Drug, in Wistar Rats and Beagle Dogs
Authors: Walsh Kathleen M. , Courtney Cynthia L.
Published: April 2009

CI-959, 5-methoxy-3-(1-methylethoxy)- N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide, an anti-inflammatory agent, was considered for development as a treatment for rhinitis. Two-week topical nasal studies in Wistar rats and Beagle dogs were performed to assess nasal toxicity of CI-959. Rats were given daily doses in the right nostril of 0.05 ml of solutions of varying concentrations (0.5, 2, 10, 20, 30, 60, and 90 mg/ml; doses of 0.08, 0.3, 1.6, 3.2, 4.8, 9.6, and 14.6 mg/kg) of CI-959. Beagle dogs were given daily doses in the right nostril of 0.5 ml of 10, 20, 30, 60, and 90 mg/ml solutions (doses of 0.5, 0.8, 1.2, 2.8, and 3.7 mg/kg) of CI-959. Rats given ≥60 mg/ml either lost weight or had decreased weight gain. Salivation at dosing was seen in both species. Four sections of nasal cavity were examined from each animal. In rats, 0.5 mg/ml was the "no effect" dose; minimal changes were seen at 2 mg/ ml, and significant changes were dose related in severity at ≥10 mg/ml in all 4 nasal levels. Degeneration and necrosis of respiratory and olfactory epithelia were minimal to moderate in severity. Adhesions and fibro-osseous proliferation of ethmoturbinates, epithelial hyperplasia, squamous metaplasia, and exudate were also seen. In dogs, 10 mg/ml was the no effect dose; respiratory epithelium was affected at ≥20 mg/ml. Respiratory epithelial degeneration was minimal to mild, with loss of ciliated and goblet cells and thinning of mucosa. Distribution of degeneration increased with increased concentrations. In both species, in accordance with the suggested action of CI-959, infiltration with neutrophils was not significant. CI-959 was locally toxic to nasal cavity respiratory and olfactory epithelia in rats and respiratory epithelium in dogs.
Systemic and Histopathologic Changes in Beagle Dogs After Chronic Daily Oral Administration of Synthetic (Ethinyl Estradiol) or Natural (Estradiol) Estrogens, with Special Reference to the Kidney and Thyroid
Authors: Zayed Ibrahim , Van Esch Eric , Mcconnell Robert F.
Published: April 2009

Four groups of 3 male and 3 female sexually mature Beagle dogs were treated daily po with either ethinyl estradiol (EE) or estradiol (E2). A fifth group of 4 males and 4 females acted as a control group. Three groups of dogs were treated with EE: One group was treated at dose levels of 2.0, 1.5, and 1.0 mg/kg for 6 mo; the other 2 groups received either 0.5 mg/kg or 1.0 mg/kg for 1 yr. The fourth group was treated with 5.0 mg/kg E2for 1 yr. Results obtained for the clinical, hematological, and biochemical parameters and the histopathologic findings of most organs and tissues in EE- and E2-treated dogs were essentially comparable to those documented in the literature for dogs treated with synthetic or natural estrogens. Chronic treatment with EE or E2induced similar effects, with the exception of mesothelial proliferation of the genital serosa, which was observed in EE-treated dogs only. Additional new estrogen-related findings were observed in the kidneys and thyroid glands of EE- and E2-treated dogs. Increased interstitial fibrous tissue occurred at the corticomedullary junction and in the outer cortex of the kidney. It appeared to originate primarily from the perivascular fibrous tissue of branches of the renal arteries and veins. Extension of this lesion into the renal parenchyma resulted in secondary atrophic changes of tubules and glomeruli. The treatment relationship and specific characteristics of this renal alteration differentiated it from other chronic renal interstitial and vascular diseases. Squamous metaplasia of urogenital tract epithelia, including renal cortical tubule epithelium, occurred as expected in both EE- and E2-treated dogs. Unexpectedly, squamous metaplasia of thyroid follicular epithelium also occurred. It was present in scattered follicles of both EE- and E2-treated dogs. The renal and thyroid changes did not alter clinicopathological function tests for either of these organs. These 2 new findings extend the list of estrogen-related effects in the dog.
Antisaccade eye movement abnormalities in Tourette syndrome: evidence for cortico-striatal network dysfunction?
Authors: Dursun Serdar M. , Burke John G. , Reveley Michael A.
Published: April 2009

Saccadic eye movements are rapid eye movements which act to redirect the eyes from one object of interest to another. Accurately and objectively measurable, their underlying neuroanatomical mechanisms have been extensively studied. The antisaccade task allows the study of the frontocortico-striatal network involved in the voluntary control of saccadic eye movements. In this task, the subject is instructed to inhibit a reflex eye movement towards a peripheral target light and, instead, to generate a movement in the equal and opposite direction. An error occurs when the subject fails to suppress reflexive saccades towards the target. Significantly high error rates and increased latencies in the antisaccade task have been reported in disorders associated with dysfunction of the frontocortico-striatal network. Increased saccadic eye movement latencies and error rates have been reported in Tourette syndrome patients (n = 4) who were receiving antipsychotic medication. To investigate this further, we tested the antisaccade task on six male Tourette syndrome patients. The results were compared with 18 age- and sex-matched mentally and physically healthy, medication/alcohol-free controls. Antisaccade latencies were (mean ± SD; ms) 751.2 ± 186.7 for the Tourette syndrome group and 417 ± 75.3 for controls, and error rates were 59 ± 14.3 for the Tourette syndrome group and 11.9 ± 6.4 for controls, repectively. These significant results may further support dysfunction of the frontocortico-striatal network in Tourette syndrome.
Psychostimulants and psychiatrists: the Trent Adult Psychiatry Psychostimulant Survey
Authors: Bramble David
Published: April 2009

This study reports upon the results of a postal questionnaire survey of 107 adult psychiatrists which investigated their current use of psychostimulant pharmacotherapy and their attitudes towards the diagnostic status of attention-deficit hyperactivity disorder (ADHD) in adulthood. Of the 88 respondents, only a minority of 11 (12.5%) used psychostimulants in their usual practice, albeit very infrequently (one or two prescriptions per year on average). Methylphenidate hydrochloride (‘Ritalin’) was the prescribers’ most popular agent and ‘narcolepsy’ was the most frequently cited clinical indication for psychostimulants. ADHD appeared to represent only a very small area of current clinical activity and a minority of clinicians expressed the view that it did not exist in adults. It is concluded that psychostimulant therapy is relatively undeveloped in British adult psychiatry and that the clinical speciality generally appears to be unprepared for the growing numbers of adolescents with ADHD who are currently managed by child psychiatrists and who may require ongoing psychiatric care, including psychostimulant therapy.
Evidence-based psychopharmacology 3. Assessing evidence of harm: what are the teratogenic effects of lithium carbonate?
Authors: Warner James P.
Published: April 2009

Critical appraisal techniques are not only useful in evaluating evidence of therapeutic trials. In this final article of the series of evidence-based psychopharmacology, the evidence about the teratogenic effects of lithium carbonate is considered. This exercise highlights the importance of assessing the evidence oneself and not relying on the interpretation others put on it.
Serotonin, stress and corticoids
Authors: Chaouloff Francis
Published: April 2009

There is evidence for stressor- and brain region-specific selectivity in serotonergic transmission responses to aversive stimuli. The aim of the present review is to provide an overview of the effects of different acute and repeated/chronic stressors on serotonin (5-HT) release and reuptake, extracellular 5-HT levels, and 5-HT pre- and postsynaptic receptors in areas tightly linked to the control of fear and anxiety, namely the dorsal and median raphe nuclei, the frontal cortex, the amygdala and the hippocampus. In addition, our knowledge of the impacts of corticoids on serotonergic systems in these brain areas is also briefly provided to examine whether the hypothalamo-pituitary-adrenal axis may play a role in stress-induced alterations in 5-HT neurotransmission. Taken together, the data presented reinforce the hypothesis that stress affects such a transmission, partly through the actions of corticoids. However, we are still left with unanswered, albeit crucial questions. First, the question of the specificity of the serotonergic responses to stress, with regard to the site of action and the nature of the stressor still remains open due to the heterogeneity of the results obtained so far. This could indicate that environmental factors, other than the stressor itself, may have enduring consequences on 5-HT sensitivity to stress. Second, the question regarding the role of stresselicited changes in 5-HT transmission within coping processes finds in most cases no clearcut answer. In keeping with human symptomatology, the need to consider the environment (including the early one) and the genetic status when assessing the effects of stress on 5-HT neurotransmission is underlined. Such a consideration could help to answer the questions raised.
Behavioural effects of acute tryptophan depletion in healthy male volunteers
Authors: Shansis Flávio M. , Busnello João V. , Quevedo João , Forster Letícia , Young Simon , Izquierdo Ivan , Kapczinski Flávio
Published: April 2009

Acute tryptophan depletion (ATD) studies have been used to assess the role of the serotonergic system in various aspects of human behaviour. Changes in mood have already been described in selected groups of individuals submitted to ATD. The present study was a randomized, double-blind, cross-over trial designed to evaluate the effects of ATD on mood, memory, attention and induced anxiety in normal male volunteers. Twelve healthy male volunteers were submitted to two separate sessions of ATD, 1 week apart. Drinks containing either a balanced mixture of amino acids (B) or a similar mixture devoid of tryptophan (T–) were administered in each session. Mood was assessed using self-rating scales. Attention and memory were assessed using a battery of psychological tests. Anxiety induction was carried out using a simulation of public speaking. Blood levels of tryptophan were assessed before and after the B and T– drinks. Results showed that ATD markedly decreased plasma tryptophan (p< 0.0001). Mood ratings, memory and attention were not changed by the T– drink. There was no difference among the anxiety levels measured under T– or B mixtures. These data supports the notion that ATD does not change mood and cognitive function in healthy subjects.
Pharmacokinetics of mirtazapine and lithium in healthy male subjects
Authors: Sitsen J. M. A. , Voortman G. , Timmer C. J.
Published: April 2009

A substantial proportion of patients diagnosed with depression and treated with antidepressants show no or insufficient response. In such patients, lithium is often added to the antidepressant for augmentation. The present study investigated the possible drug–drug interaction between mirtazapine and lithium in 12 healthy male subjects in a randomized, double-blind, placebo-controlled two-period cross-over design. Subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups. After an overnight fast, they received either a single oral dose of 600 mg lithium carbonate (16 meq Li+) for 10 days at 08.00 h and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9 or the same number (n= 4) of placebo capsules and and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9. At pre-defined times, blood samples were drawn for the measurement of mirtazapine plasma concentrations and lithium serum concentrations. In addition, psychometric tests were performed and the safety and tolerability of the drugs were assessed. The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively.
Chronic administration of the cholesterol reducing drug gemfibrozil fails to alter 5-HT1A and 5-HT2A mediated receptor behaviours in rats
Authors: McCreary Andrew C. , Handley Sheila L.
Published: April 2009

Some studies have suggested that reductions in plasma cholesterol might be associated with suicidal behaviour. Serotonergic systems are thought to be involved in suicidal ideation and behaviour and links with altered 5-HT1A and 5-HT2A receptors have been proposed. We have therefore examined the effects of cholesterol reduction using gemfibrozil, upon 5-HT2A and 5-HT1A receptor-related behaviours in rats. Rats were treated chronically (57 days) with gemfibrozil (50 mg/kg p.o.) or gum acacia vehicle and challenged sequentially with the 5-HT1A agonist 8-hydroxy-d-n-aminopropyl tetralin, to elicit 5-HT1A syndrome behaviours, and the 5-HT2 receptor agonist 1-(2, 5-dimethoxy-4-iodophenyl)2-amino-propane to establish their head-shake frequency. Significant cholesterol reduction, within the clinical range, failed to induce any changes in either 5-HT1A or 5-HT2A mediated behaviours. These data suggest that cholesterol reduction fails to induce changes in 5-HT1A and 5-HT2A receptor tone suggesting that the reduction of plasma cholesterol, within the human clinical range, does not result in neuroplasticity of the 5-HT1A and 5-HT2A receptors in rats.
Hypnopompic hallucinations with donepezil
Authors: Yorston G. A. , Gray R.
Published: April 2009

A case of hypnopompic hallucinations associated with donepezil is described. Electroencephalogram (EEG) and sleep EEG changes are common in Alzheimers Disease and acetylcholinesterase inhibitor drugs can affect rapid eye movement sleep and alertness. The importance of assessing sleep in patients treated with these drugs is discussed.
Residual effects of hypnotics on disengagement of spatial attention
Authors: Bocca Marie-Laure , Denise Pierre
Published: April 2009

In an earlier study, we postulated that the residual effects of hypnotics could induce a spatial attention disengagement deficit independent of any decrease in alertness. To test this hypothesis, we compared the residual effects of zolpidem, zopiclone and flunitrazepam in two ocular saccade tests, gap and overlap. In the gap paradigm, the lateral target is illuminated 200 ms after the extinguishing of the central target. In the overlap paradigm, the central target stayed on when the lateral target was illuminated. Zopiclone increases latency in the overlap, but not in the gap test, which appears to be specific to a deficit of disengagement of spatial attention. Zopiclone impairs the saccadic precision in gap, but not in overlap, which may be interpreted as an impairment of visuospatial memory. The effects of zolpidem are limited to visuospatial impairment. The effects of flunitrazepam are massive and probably the results of a decrease in alertness.
Adverse effects associated with the use of donepezil in general practice in England
Authors: Dunn N. R. , Pearce G. L. , Shakir S. A. W.
Published: April 2009

Donepezil is an acetylcholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is reported to have a relatively favourable side-effect profile. We report here on a pharmacovigilance study carried out post-marketing in England. An observational cohort study using the technique of Prescription-Event Monitoring was carried out. Some 1762 patients (mean age 72.9 years; 42% male) were followed up for 6 months minimum. The commonest adverse events were nausea, diarrhoea, malaise, dizziness and insomnia. Aggression, agitation and abnormal dreams were uncommonly associated with the drug. There were no cardiac rhythm disturbances or liver disorders causally associated. The commonest adverse drug reactions are already reported in the product information. Given the relatively small size of this cohort, the signals of abnormal dreams and psychiatric disturbance as possible adverse drug reactions need further investigation in carefully planned studies.
A dose-finding and discontinuation study of clomipramine in panic disorder
Authors: Lotufo-Neto Francisco , Bernik Márcio , Ramos Renato T. , Andrade Laura , Gorenstein Clarice , Cordás Taki , Melo Márcio , Gentil Valentim
Published: April 2009

Eighty-one panic disorder patients with or without agoraphobia were treated with flexible doses of clomipramine under single-blind conditions. Fifty-seven (70.3%) reached operational criteria for full remission in 16.2 ± 6.5 weeks, with a mean dose of 89.1 ± 8.2 mg/day. Fifty-four (81%) of them received a continuous post-remission maintenance treatment at full doses of clomipramine for 4–6 months. No patient relapsed during the clomipramine maintenance phase. Their medication was then tappered and discontinued with placebo substitution under double-blind conditions. Fifty-one (63%) patients were followed-up until relapse or recurrence for up to 3 years, with periodic assessments. Three different outcome groups were identified: the first (n = 19, 19; 37.2%) experienced an early/immediate relapse (5.2 ± 4.9 weeks after drug discontinuation); the second group (n= 22, 22; 43.1%) experienced recurrence after 42.9 ± 35 weeks following discontinuation; and the third group (n = 10, 10; 19.6%) remained assymptomatic and functionally well throughout the follow-up. Predictors of early relapse were: (1) higher baseline score in the Beck Depression Inventory; (2) higher global score on the phobic avoidance scale after the full remission criteria; and (3) the need for higher clomipramine doses to reach full remission. The need for long-term or intermittent maintenance for most patients is emphasized.
Treatment of bipolar affective disorder in clinical practice
Authors: Ahmed Z. , Anderson I. M.
Published: April 2009

A case note survey of 100 outpatients with a clinical diagnosis of bipolar affective disorder in a UK inner city teaching hospital revealed monotherapy with a mood stabilizer in only 23% of patients, mostly lithium (15%). Overall, 51% of patients were prescribed lithium, 19% carbamazepine and 5% valproate with only 8% receiving a combination of two mood stabilizers. Treatment appeared to be inadequate in 13/51 of patients on lithium, 9/19 of those on carbamazepine and 1/5 of those on valproate. Antipsychotics were used as monotherapy in 20% of patients and combined with a mood stabilizer in 43% of patients. Only 6% of patients were on atypical antipsychotics. These findings suggest that the treatment for many patients does not match recommendations. Clearer evidence on the place of combination mood stabilizers and adjunctive antipsychotics, particularly atypicals is needed in the treatment of bipolar affective disorder.
Intermittent, luteal phase nefazodone treatment of premenstrual dysphoric disorder
Authors: Kodesh A. , Katz S. , Lerner A. G. , Finkel B. , Sigal M.
Published: April 2009

Three outpatients who fulfilled full DSM-IV diagnostic criteria for premenstrual dysphoric disorder (PDD) were successfully treated with intermittent (luteal phase) nefazodone. They received the medication at low doses of up to 100 mg/day (50 mg b.i.d.), for 2 weeks through the luteal phase of the menstrual cycle only. All the patients reported a marked symptomatic improvement, including full remission of their emotional symptoms, and two achieved in addition full remission of their somatic symptoms. Side-effects reported during the treatment were mild. The use of luteal phase nefazodone seems to be a promising treatment strategy for the management of PDD. It offers advantages over daily dosing throughout the menstrual cycle, such as reduced incidence and severity of side-effects, and avoids the stigma that may accompany the continuous use of psychopharmacological treatment, with the advantage that compliance may be improved.
Antidepressant discontinuation (withdrawal) symptoms presenting as ‘stroke’
Authors: Haddad Peter M. , Devarajan Sivakumaran , Dursun Serdar M.
Published: April 2009

We report two patients who developed a severe discontinuation (withdrawal) reaction following stoppage of paroxetine and venlafaxine, respectively. Neurological symptoms were prominent and neither patient could walk unaided. Both patients feared they had suffered a ‘stroke’ and arranged an emergency medical consultation. One patient was correctly diagnosed, the antidepressant was recommenced and symptoms resolved within 24 h. Failure to recognize the reaction resulted in the other patient being referred to a neurologist, undergoing a computed tomography brain scan and an electroencephalogram and remaining symptomatic for over 8 weeks. Relevant pharmacological issues are discussed. The cases illustrate the importance of patients and clinicians being familiar with antidepressant discontinuation symptoms.
The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers
Authors: McCartan Denise , Bell Robert , Green Jonathan F. , Campbell Clarke , Trimble Karen , Pickering Alan , King David J.
Published: April 2009

Latent inhibition (LI) is a measure of reduced learning about a stimulus to which there has been prior exposure without any consequence. It therefore requires a comparison between a pre-exposed (PE) and a non-pre-exposed (NPE) condition. Since, in animals, LI is disrupted by amphetamines and enhanced by antipsychotics, LI disruption has been proposed as a measure of the characteristic attentional deficit in schizophrenia: the inability to ignore irrelevant stimuli. The findings in humans are, however, inconsistent. In particular, a recent investigation suggested that since haloperidol disrupted LI in healthy volunteers, and LI was normal in non-medicated patients with schizophrenia, the previous findings in schizophrenic patients were entirely due to the negative effects of their medication on LI (Williams et al., 1998). We conducted two studies of antipsychotic drug effects on auditory LI using a within-subject, parallel group design in healthy volunteers. In the first of these, single doses of haloperidol (1 mg. i.v.) were compared with paroxetine (20 mg p.o.) and placebo, and in the second, chlorpromazine (100 mg p.o.) was compared with lorazepam (2 mg. p.o.) and placebo. Eye movements, neuropsychological test performance (spatial working memory (SWM), Tower of London and intra/extra dimensional shift, from the CANTAB test battery) and visual analogue rating scales, were also included as other measures of attention and frontal lobe function. Haloperidol was associated with a non-significant reduction in LI scores, and dysphoria/akathisia (Barnes Akathisia Rating Scale) in three-quarters of the subjects. The LI finding may be explained by increased distractibility which was indicated by an increase in antisaccade directional errors in this group. In contrast, LI was significantly increased by chlorpromazine but not by an equally sedative dose of lorazepam (both drugs causing marked decreases in peak saccadic velocity). Paroxetine had no effect on LI, eye movements or CANTAB neuropsychological test performance. Haloperidol was associated with impaired SWM, which correlated with the degree of dysphoria/akathisia, but no other drug effects on CANTAB measures were detected. We conclude that the effect of antipsychotics on LI is both modality and pharmacologically dependent and that further research using a wider range of antipsychotic compounds is necessary to clarify the cognitive effects of these drugs, and to determine whether there are important differences between them.
Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function
Authors: Hopwood Sarah E. , Owesson Catarina A. , Callado Luis F. , McLaughlin Daniel P. , Stamford Jonathan A.
Published: April 2009

The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150–200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H]dihydroalprenolol and [3H]ketanserin binding was lower in the chronic tramadol group than controls (β: 37 ± 8 and 217 ± 56 fmol/mg; 5-HT2A: 23 ± 3 and 44 ± 7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164 ± 7%) than tramadol-treated rats (144 ± 6%; p< 0.05). Chronic tramadol had no effect on dorsal raphé (DRN) or median raphé (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p= 0.055) in DRN. The selective 5-HT1Aagonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54 ± 2 versus 32 ± 6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology.
Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors
Authors: Schmitt Jeroen A. J. , Kruizinga Monique J. , Riedel Wim J.
Published: April 2009

The current study was carried out to investigate the cognitive effects of two serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, with special reference to differences in their affinity for other neurotransmitter systems, i.e. anticholinergic activity of paroxetine and putative dopamine reuptake activity of sertraline. The study was conducted according to a double-blind, three-way cross-over design. During three treatment periods of 2 weeks, 24 healthy middle-aged (aged 30–50 years) subjects of both sexes received sertraline (50 mg on days 1–7, 100 mg on days 8–14), paroxetine (20 mg on days 1–7, 40 mg on days 8–14) and placebo. Paroxetine specifically impaired delayed recall in a word learning test at a dose of 20 and 40 mg. Sertraline did not affect word learning but improved performance on a verbal fluency task at a dose of 50 and 100 mg. Neither drug affected performance on a short-term memory scanning task. These subtle but significant changes in cognitive performance can be explained by subtle differences in pharmacological profiles of these SSRIs. The additional anticholinergic effects of paroxetine could account for its induction of long-term memory impairment. Similarly, the additional dopaminergic effects of sertraline could account for its induction of slightly improved verbal fluency. The impairing and facilitating cognitive effects of paroxetine and sertraline, respectively, may be more pronounced in the elderly depressed patient.
The placebo response in social phobia
Authors: Oosterbaan Désirée B. , van Balkom Anton J. L. M. , Spinhoven Philip , van Dyck Richard
Published: April 2009

The placebo response forms a growing problem in randomized, placebo-controlled clinical trials in psychiatry. Research into the placebo response is on the increase, but remains very limited in relation to social phobia. Together with the dropout rate, the placebo effect is an important factor limiting the discriminative properties of any study. In this study, we reviewed 15 placebo-controlled studies in social phobia, focussing on patients and study characteristics. In social phobia, the placebo effect has turned out to be moderately large and has shown no increase over the past decade. Placebo response was highest in large, multicentred trials and was independent of study duration. No validation for a placebo run-in was found. Taking into account both response to placebo and active drug, as well as dropout rate, the most discriminative results are probably to be expected in a sample of patients who are moderately to severely impaired. More research in the field of the placebo response is needed.
Cocaine-primed craving and its relationship to depressive symptomatology in individuals with cocaine dependence
Authors: Elman Igor , Karlsgodt Katherine H. , Gastfriend David R. , Chabris Christopher F. , Breiter Hans C.
Published: April 2009

Several lines of evidence suggest a link between cocaine-primed craving and depressive symptomatology. The purpose of this study was to directly relate these two clinical phenomena. Thirty-three cocainedependent subjects were rated on the Hamilton Rating Scale for Depression (HRSD) at baseline and then administered an i.v. bolus of cocaine (0.2 mg/kg). Multiple regression analysis revealed that only the HRSD score was an independent predictor of cocaine-primed craving (F= 4.09; d.f. = 10,22; r=0.81, p< 0.003) when baseline spontaneous craving during early withdrawal, age, gender, frequency of use, time since last use, monetary expenditure on cocaine and the Addiction Severity Index Drug Composite Scores were considered. These data support the hypothesis that depressive symptomatology affects cocaine-primed craving and that this relationship is relatively specific to symptoms defined by the HRSD and is not seen with a number of other clinical and demographic variables.
Side-effects of risperidone therapy mimicking cerebrospinal fluid shunt malfunction: implications for clinical monitoring and management
Authors: Edwards Richard J. , Pople Ian K.
Published: April 2009

Risperidone is an atypical antipsychotic used in the treatment of several psychiatric disorders in both children and adults. We present two patients with hydrocephalus and learning difficulties who were admitted to the neurosurgical unit with a suspected cerebrospinal fluid shunt malfunction and raised intracranial pressure. They had both been commenced on risperidone for the treatment of aggressive outbursts. Twelve days after commencing risperidone, the first patient developed symptoms of headache, nausea, vomiting, drowsiness, lethargy and two episodes of collapse. The second patient presented with similar symptoms 4 days after his risperidone dose was increased. An unnecessary shunt exploration was averted in both cases when it was noted that the side-effect profile of risperidone mimicked exactly those of shunt malfunction. Discontinuation of the drug resulted in complete resolution of all symptoms within 72 h. Many patients with shunted hydrocephalus have associated developmental disorders that may warrant treatment with risperidone. Clinicians should be aware of the potential symptom overlap between shunt malfunction and risperidone side-effects in these patients.
Moclobemide discontinuation syndrome predominantly presenting with influenza-like symptoms
Authors: Curtin Francois , Berney Patricia , Kaufmann Christophe
Published: April 2009

A case of moclobemide discontinuation syndrome who predominantly presented with influenza-like symptoms is presented. Sertraline treatment did not modify the symptoms, which may suggest different mechanisms with regard to different antidepressant drug discontinuation syndromes. Implications for clinical care are reviewed.
The development of a clinical syndrome of asymptomatic pancreatitis and eosinophilia after treatment with clozapine in schizophrenia: implications for clinical care, recognition and management
Authors: Garlipp P. , Rosenthal O. , Haltenhof H. , Machleidt W.
Published: April 2009

Clozapine, the first atypical antipsychotic, is indicated for the treatment of therapy-resistant schizophrenia. It needs to be monitored closely because of its well-known potential side-effects, especially agranulocytosis. We present a case of a middle-aged woman with chronic schizophrenia, who was treated with clozapine and developed a clinical syndrome of asymptomatic pancreatitis and eosinophilia within the fifth week of treatment. Asymptomatic pancreatitis has rarely been reported up to now and is not recognized as a typical side-effect of clozapine. In our opinion, pancreatic enzymes should be monitored especially in the first 6 weeks of clozapine treatment.
Effects of bromocriptine and haloperidol on prepulse inhibition: comparison of the acoustic startle eyeblink response and the N1/P2 auditory-evoked response in man
Authors: Abduljawad K. A. J. , Langley R. W. , Bradshaw C. M. , Szabadi E.
Published: April 2009

Experiments with animals have shown that D2 dopamine receptors are involved in regulating prepulse inhibition (PPI) of the acoustic startle reflex (suppression of the reflex response evoked by a loud sound by prior presentation of a low-intensity stimulus). Recently we found that PPI of the human eyeblink startle response could be suppressed by a D2 receptor agonist, bromocriptine, and that this suppression could be reversed by a D2 receptor-blocking neuroleptic, haloperidol.The present work attempted to replicate this finding and to extend it to PPI of the N1/P2 component of the auditory-evoked potential. Elevenhealthy males (18–30 years) participated in four sessions in which they received oral doses of placebo, bromocriptine 1.25 mg, haloperidol 3 mg and combined treatment with bromocriptine 1.25 mg + haloperidol 3 mg, according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory-evoked potentials took place 120 min after ingestion of haloperidol and/or 90 min after ingestion of bromocriptine. Sound stimuli (1-kHz) were presented in 60 trials separated by variable intervals (mean 25 sec): (i) 40 msec 115 dB (‘pulse alone’: 20 trials); (ii) 40 msec 85 dB (20 trials); (iii) 40 msec 85 dB, followed after 120 msec by 40 msec 115 dB (‘prepulse/pulse’: 20 trials). The amplitudes of the EMG and N1/P2 responses were not altered significantly by any of the treatments. Bromocriptine attenuated PPI of the EMG response significantly, this attenuation being absent following combined haloperidol/bromocriptine treatment. Neither bromocriptine nor haloperidol significantly altered PPI of the N1/P2 complex. Bromocriptine suppressed and haloperidol elevated serum prolactin levels, these changes being absent when the two drugs were given in combination. The results suggest that different mechanisms may be involved in regulating PPI of the eyeblink and the N1/P2 component of the auditory-evoked potential, and that D2 receptors may be involved in the former case, but not the latter.
Effects of smoking status and schizotypy on latent inhibition
Authors: Casa V. Della , Höfer I. , Weiner I. , Feldon J.
Published: April 2009

Two experiments investigated the effects of smoking status and schizotypy on the ability to gate out irrelevant information as assessed in auditory and visual latent inhibition (LI), Stroop effect and negative priming.The two experiments used 10 or 30 pre-exposures for auditory LI and a long or short interstimulus interval for the Stroop task, respectively, which included negative priming and served as masking task for the visual LI. Smoking status did not affect performance on any of the tasks, except for auditory LI after 30 pre-exposures, which was enhanced. The relationship between schizotypy and cognitive performance was complex. In Experiment 1, high schizotypals had smaller visual LI and negative priming than low schizotypals, whereas in Experiment 2 the reverse was observed, namely, larger LI and negative priming in high schizotypals.