bluuebunny/crossref_metadata_2025 huggingface dataset:
Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients
Authors: Delieu J. M. , Badawoud M. , Williams M. A. , Horobin R. W. , Duguid J. K.
Published: April 2009

Subclinical abnormality of neutrophil populations of patients suffering from schizophrenia and medicated with antipsychotic drugs was evaluated using cellular immaturity as a criterion. Neutrophil maturity of patients and controls was compared by determining mean nuclear lobularity in peripheral blood smears. White blood cell and neutrophil counts were made. Subjects were patients medicated with chlorpromazine (n = 17) or clozapine (n = 48). Controls (n = 58) were healthy, non-medicated clinical and academic staff. Determination of mean lobe number involved assessment of 300 neutrophils per individual. For subject and control groups, means and medians of mean lobe numbers and mean white cell and neutrophil counts were determined. Means for each group were compared using the Mann–Whitney U-test; variances using Fratios. Means of lobe numbers of both patient populations were significantly different (p < 0.0001) compared to controls. Two-thirds of patients had mean lobe numbers outside the control range. Dose–response (mean lobe number) plots were significant for patients medicated with both chlorpromazine and clozapine. White cell and neutrophil counts in patients and controls did not differ significantly. For six patients, mean lobe numbers were obtained before and after medication commenced and all showed lowering of mean lobe number. The mean lobe number of the one patient who subsequently suffered from agranulocytosis was at the low end of the patient range. Thus, patients medicated with antipsychotic drugs typically have immature neutrophils, but normal white cell and neutrophil numbers. This effect is probably drug-induced. Mean lobe number may predict patients at risk from agranulocytosis.
Serotonergic involvement in the psychosocial dimension of personality
Authors: Tse Wai S. , Bond Alyson J.
Published: April 2009

Neurotransmitter systems have been associated with aspects of personality and changes in various dimensions have been shown after antidepressant treatment. A reduction in harm avoidance and an increase in self-directedness and cooperativeness, as measured by the Cloninger's Temperament and Character Inventory (TCI), have been reported in psychiatric patients receiving treatment with serotonergic antidepressants. However, some of these changes have been associated with clinical improvement. The present study therefore used a randomized, double-blind, placebo-controlled design to examine the role of the serotonergic system on these personality factors in the normal population. Twenty healthy male volunteers were randomly allocated to either placebo (n = 9) or citalopram treatment (n = 11) for 2 weeks. Baseline depression and anxiety scores were low and did not differ between groups. The TCI was administered pre-and post-treatment. There were no baseline differences on any TCI factor between groups. Citalopram induced a significant increase in self-directedness (p< 0.05) but not cooperativeness or harm avoidance ratings after treatment. Thus, citalopram has effects on personality aspects which appear to be separate from its antidepressant properties.
Effects of clonidine and diazepam on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man
Authors: Abduljawad K. A. J. , Langley R. W. , Bradshaw C. M. , Szabadi E.
Published: April 2009

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30–500 ms before the ‘startle-eliciting’ stimulus (prepulse inhibition). We examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on prepulse inhibition of these two responses in healthy volunteers. Fifteen males (aged 18–35 years) participated in three sessions in which they received oral doses of placebo, diazepam 10 mg and clonidine 0.2 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 clonidine and 60 min after ingestion of diazepam. Sound stimuli (1 kHz) were presented in 60 trials separated by variable intervals (mean 25 s): (i) 40-ms 115-dB (‘pulse alone’, 20 trials); (ii) 40-ms 85-dB (20 trials); (iii) 40-ms 85-dB, followed after 120 ms by 40-ms 115-dB (‘prepulse/pulse’, 20 trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. The amplitude of the EMG response was significantly reduced both by diazepam and by clonidine; neither drug significantly altered prepulse inhibition of the EMG response. Diazepam, but not clonidine, significantly reduced the amplitude of the N1/P2 potential; neither drug significantly affected prepulse inhibition of the N1/P2 potential. Both drugs reduced self-rated alertness and anxiety, and systolic blood pressure; clonidine, but not diazepam reduced diastolic blood pressure and salivation. The results confirm previous findings that sedative drugs can suppress the startle response without affecting prepulse inhibition of this response, and provide new information on the effects of these drugs on the N1/P2 potential and its inhibition by prepulses.
The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England
Authors: Biswas Pipasha N. , Wilton Lynda V. , Pearce Gillian L. , Freemantle Shayne , Shakir Saad A. W.
Published: April 2009

Olanzapine is an ‘atypical’ antipsychotic indicated for the treatment of schizophrenia. We analysed adverse events (AEs) reported in primary practice in England. Dispensed prescriptions issued between December 1996 and May 1998 provided exposure data. Questionnaires sent to general practitioners provided outcomes. Frequently reported AEs were: drowsiness/sedation (n = 19), extrapyramidal disorder (n = 13) and unspecified side-effects (n = 33). Events with highest incidence density in first month and reason for stopping were: drowsiness/sedation [n = 153, incidence density (ID)1 18.9], weight gain (n = 117, ID1 8.9) and malaise/lassitude (n = 65, ID1 5.2). Extrapyramidal disorders were more common in elderly population (> 70 years, ID1 3.6, risk 26.0 per 1000 patients) compared to < 70 years (ID1 1.1, risk 8.4 per 1000 patients). Serious suspected adverse reactions were neuroleptic malignant syndrome (n = 1) and angioneurotic ooedema (n = 2). There were eight reports of diabetes mellitus assessed as possibly due to olanzapine. Diabetes mellitus was an unlabelled AE and possible signal generated by prescription-event monitoring.
Antipsychotic induced hyperprolactinaemia: a series of illustrative case reports
Authors: Haddad Peter M. , Hellewell Jonathan S. E. , Wieck Angelika
Published: April 2009

Hyperprolactinaemia is a common side-effect of many antipsychotic drugs but, in comparison to extrapyramidal side-effects, it has received little attention. Four case reports are presented which illustrate important clinical and pharmacological aspects of the syndrome. Two of the cases were caused by conventional antipsychotic drugs and two by risperidone, an atypical antipsychotic. Symptoms included gynaecomastia, galactorrhoea, amenorrhoea and sexual dysfunction. Three patients were switched to a prolactin sparing antipsychotic leading to normalization of serum prolactin and resolution of the symptoms. Patients prescribed prolactin elevating antipsychotics should, where possible, have this issue explained to them prior to commencing treatment and be screened for symptoms suggestive of hyperprolactinaemia before starting treatment and regularly thereafter.
Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans
Authors: Simpson Cathy A. , Rush Craig R.
Published: April 2009

The acute behavioural effects of triazolam (0.125 and 0.25 mg), temazepam (15 and 30 mg), and placebo, alone and in combination with ethanol (0 and 0.5 g/kg), were assessed in 10 volunteers. Ethanol alone did not impair performance and produced only a few subject-rated drug effects. Triazolam and temazepam alone produced some performance impairment and a few subject-rated drug effects. These effects tended to be dose-dependent and were comparable for the two drugs across the range of doses tested. The triazolam–ethanol and temazepam–ethanol combinations produced robust performance impairment and sedative-like subject-rated drug effects that were similar in magnitude. The findings of the present study suggest that even a moderate amount of ethanol in combination with a clinical dose of triazolam or temazepam can cause performance impairment that might diminish an individual's ability to respond adequately to unexpected demands (e.g. smoke alarms or middle-of-the-night child care).
Behavioural effects of acute phenylalanine and tyrosine depletion in healthy male volunteers
Authors: Grevet Eugenio H. , Tietzmann Marcos R. , Shansis Flávio M. , Hastenpflug Caroline , Santana Luiz C. , Forster Letícia , Kapczinski Flávio , Izquierdo Ivan
Published: April 2009

Acute phenylalanine and tyrosine depletion (APTD) studies have been used to assess the role of the cathecholaminergic system in various aspects of human behaviour. In this study we conducted a randomized, double-blind, controlled and cross-over comparison to evaluate the effects of APTD on memory, attention and mood in normal subjects. Twelve healthy male volunteers were included in this study. The subjects ingested a nutritionally balanced mixture (B) or a similar mixture deficient in phenylalanine and tyrosine (PT–). Before and 5 h after ingestion of the drink, volunteers underwent tests on mood, memory and attention. Results of the memory tests showed that PT– mixture impaired word recall as measured in Rey's test (p = 0.016). The assessment of changes in mood showed that the balanced mixture improved scores of as alertness (VAMS factor I, p = 0.037) and the PT– mixture induces an opposite effect, increased scores of anxiety (Profiles of Mental State composed-anxious dimension, p= 0.022). These results suggest that tyrosine plasma levels and cathecholamines may be important factors in regulating mood and memory.
Tolerance and sensitization to the hypnotic effects of alcohol induced by chronic voluntary alcohol intake in rats
Authors: Darbra Sònia , Prat Gemma , Pallarés Marc , Ferré Nuria
Published: April 2009

The effect of a chronic alcohol exposure on the development of tolerance to the depressive effects of alcohol were examined in male Wistar rats that voluntary self-administered alcohol. A free-choice drinking procedure based on the limited access paradigm and the addition of glucose that implies an early availability of the alcoholic solution was used (Alcoholism Primary Praecox procedure). Alcohol induced sleep time (3.5 g alcohol per kg i.p.) was measured at 90 days (after 2 months of alcohol consumption) or at 60 + 90 days old (1 or 2 months of alcohol consumption). The psychomotor performance was also evaluated by means of an 80° inclined screen test. Subjects that had been tested for the hypnotic effects at both 60 and 90 days showed a higher intake of alcoholic solution than the animals only tested at 90 days. The same consumption increase was observed in the glucose group. No significant differences between groups were observed in the inclined screen test. Tolerance to the hypnotic effects of alcohol was observed at 90 days. On the other hand, no significant differences between alcohol and control groups (glucose or water) were observed in the sleep time at 60 days. In the alcohol-drinking rats tested for two trials (60 and 90 days), sensitization instead of tolerance to the second hypnotic alcohol injection was seen. Tolerance to the hypnotic effects of alcohol observed after chronic voluntary alcohol consumption may provide animal models of alcoholism based on limited access to sweetened alcoholic solutions with construct validity.
The atypical antipsychotic olanzapine enhances ingestive behaviour in the rat: a preliminary study
Authors: Thornton-Jones Zoe , Neill Joanna C. , Reynolds Gavin P.
Published: April 2009

The weight gain associated with several antipsychotic drugs, most notably the newer ‘atypical’ compounds olanzapine and clozapine, introduces problems of compliance and morbidity in the treatment of schizophrenia. The mechanisms underlying this process have been little studied due to the lack of models of the effects of antipsychotic drugs on weight gain and/or feeding behaviour in vivo. Here, we report how the effects of olanzapine (0.5 mg/kg, i.p.) on ingestive behaviour were investigated in the food-deprived rat using a runway to food goal paradigm. Compared with vehicle-treated animals, olanzapine delayed the reductions in food intake and in running speed that occurred after the first trial blocks, without effects on starting speed. These results indicate that olanzapine can increase feeding behaviour through a suppression of satiety, suggesting a mechanism for its effects on weight gain and also providing an acute model for further assessment of the underlying pharmacology.
Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine
Authors: Bell Caroline , Forshall Sam , Adrover Mariona , Nash Jon , Hood Sean , Argyropoulos Spilios , Rich Ann , Nutt David J.
Published: April 2009

The neurobiological basis of panic disorder has not been clearly established, although a role for serotonin (5-HT) has been postulated. It is clear that drugs which increase 5-HT neurotransmission are effective in treating the condition but how they do so remains a point of debate. The aim of this study was to determine if lowering brain serotonin activity using the technique of tryptophan depletion provoked a short-term relapse of panic symptoms in patients with panic disorder who had responded to drug treatment. Fourteen patients with panic disorder who had responded to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received an infusion of flumazenil (used as a pharmacological challenge) and placebo on each day. The tryptophan depleted drink produced an 87% reduction in plasma tryptophan concentration. Flumazenil produced a panic attack (defined by changes in the panic inventory) in seven out of 14 patients when tryptophan depleted and one out of 14 on the control day (p < 0.02). Three patients also experienced temporary depressive symptoms when tryptophan depleted, with no mood changes being seen on the control days. We conclude that rapid lowering of brain serotonin function can allow the precipitation of panic symptoms in response to flumazenil in panic disorder patients who have responded to treatment with an SSRI. This implies that in panic disorder increased 5-HT availability is important in maintaining the response to SSRIs.
Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine
Authors: Harkin Andrew , Houlihan Diarmaid D. , Kelly John P.
Published: April 2009

The present study set out to establish the chronic mild stress (CMS) animal model of depression in male CD-1 mice, a commonly used mouse strain. Mice were exposed to a series of mild stressors (e.g. soiled bedding, paired housing, cage tilt, white noise) presented in a continuous unpredictable fashion. Intermittently, CMS was discontinued and the mice were presented with both water and a palatable saccharin solution (0.1% w/v) in a two-bottle choice test overnight (15 h). Repeated exposure of these mice to the stressors led to a reduction in preference for the saccharin solution. This change in preference was attributed to an increase in the consumption of water rather than a decrease in the consumption of saccharin solution. Over time and with extensive testing, CMS no longer affected performance in the two-bottle saccharin preference test. Treatment with the tricyclic antidepressant imipramine (20 mg/kg i.p., once daily) had a varied effect on the CMS-induced change in preference for saccharin, dependent on the timing of initiation of imipramine treatment. In the first instance, following 5 weeks of CMS where a reduction in saccharin preference was established, treatment with imipramine for a further 5 weeks maintained the stress-induced deficit in saccharin preference. However, using a different approach, pre-treatment with imipramine once daily for 2 weeks, prior to onset of CMS, and co-treatment thereafter, attenuated CMS-induced changes in saccharin preference. Finally, when imipramine treatment was scheduled to begin with the CMS procedure, imipramine failed to prevent the CMS-induced reductions in saccharin preference. Changes in behaviour observed after exposure to CMS may be linked to a stress-induced deterioration of the sensitivity of the mice to a rewarding stimulus. Treatment with imipramine can reduce these behavioural changes but is only effective when given repeatedly prior to onset of CMS.
Inhibition by venlafaxine of the increase in norepinephrine output in rat prefrontal cortex elicited by acute stress or by the anxiogenic drug FG 7142
Authors: Dazzi Laura , Vignone Vincenzo , Seu Emanuele , Ladu Stefania , Vacca Giada , Biggio Giovanni
Published: April 2009

Venlafaxine is an antidepressant drug that inhibits the reuptake of serotonin and norepinephrine with different efficacies. The effects of repeated administration of this drug on the increase in the extracellular concentration of norepinephrine in the prefrontal cortex, induced by stress or by the anxiogenic drug FG 7142, were studied in freely moving rats. Exposure to foot-shock stress induced a marked increase (+120%) in the extracellular norepinephrine concentration in the prefrontal cortex of control rats. Long-term administration of venlafaxine (10 mg/kg i.p., once a day for 21 days) reduced the effect of stress on norepinephrine output by 75%. This effect of venlafaxine persisted for at least 5 days after discontinuation of drug treatment. Acute administration of FG 7142 (20 mg/kg i.p.), a benzodiazepine receptor inverse agonist, increased norepinephrine output (+90%) in control rats. Chronic treatment with venlafaxine prevented the effect of FG 7142. In contrast, the acute administration of this antidepressant had no effect on the stressor FG 7142-induced increase in norepinephrine output. These plastic changes in the sensitivity of norepinephrine neurones to foot-shock stress and to an anxiogenic drug may reveal an important neuronal mechanism for the physiological regulation of emotional state. Furthermore, this mechanism might be relevant to the anxiolytic and antidepressant effects of venlafaxine.
Prevention of the stress-induced increase in the concentration of neuroactive steroids in rat brain by long-term administration of mirtazapine but not of fluoxetine
Authors: Serra Mariangela , Pisu M. Giuseppina , Dazzi Laura , Purdy Robert H. , Biggio Giovanni
Published: April 2009

The effects of acute and chronic administration of fluoxetine on the basal and stress-induced increases in cerebrocortical and plasma concentrations of allopregnanolone (3α,5α-tetrahydroprogesterone; 3α, 5α-THPROG) and tetrahydrodeoxycorticosterone (3α,5α-TH DOC) were compared with those of mirtazapine, an antidepressant that (unlike fluoxetine) is not a selective serotonin reuptake inhibitor. A single injection (20 mg/kg i.p.) of fluoxetine or mirtazapine resulted in significant increases in the cerebrocortical and plasma concentrations of 3α,5α-TH PROG and 3α,5α-TH DOC. In contrast, long-term administration (10 mg/kg i.p., once daily for 2 weeks) of fluoxetine, but not that of mirtazapine, induced marked decreases in the cortical and plasma concentrations of these neuroactive steroids. Chronic treatment with fluoxetine, however, did not inhibit the increases in the cortical and plasma concentrations of 3α,5α-TH PROG and 3α,5α-TH DOC induced by acute foot-shock stress. In contrast, chronic treatment with mirtazapine prevented or significantly reduced the stress-inoduced increases in neurosteroid concentrations in the cerebral cortex and plasma, respectively. These results show that mirtazapine, similar to fluoxetine, initially increases the cortical concentration of neuroactive steroids; however, chronic administration of this drug modulates the plasma and brain availability of these hormones in a manner distinct from that of fluoxetine.
Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251
Authors: Vinklerová Jana , Nováková Jana , Šulcová Alexandra
Published: April 2009

Cannabinoids are drugs that are frequently abused not only alone, but also in combination with other drugs. The present study investigated possible functional interactions between the psychostimulant methamphetamine and the cannabinoid receptor agonists anandamide, or R-(+)-methanandamide and cannabinoid antagonist AM 251 in the rat model of i.v. drug self-administration. In rats trained to self-administer methamphetamine, the intake was significantly decreased by the cannabinoid antagonist and tended to be dose-dependently increased by pre-treatment with cannabinoid receptor agonists. Possible mechanisms for these drug interactions are discussed and the use of the cannabinoid antagonist for the treatment of drug abuse is considered.
Effect of chronic fluoxetine and WAY-100635 treatment on serotonergic neurotransmission in the frontal cortex
Authors: Dawson L. A. , Nguyen H. Q. , Smith D. L. , Schechter L. E.
Published: April 2009

Clinical augmentation strategies have shown that some improvement in antidepressant efficacy can be achieved by combining the β-adrenergic/serotonin (5-HT)1A/1B receptor antagonist (±)pindolol with a selective serotonin reuptake inhibitor (SSRI). This has lead to the hypothesis that a combination of a 5-HT1Areceptor antagonist with an SSRI will lead to a faster onset of antidepressant action. Although there is a significant accumulation of acute preclinical data supporting this rationale, until recently, there have been no investigations examining the chronic effects of combining an SSRI with a 5-HT1Areceptor antagonist. Here, we determined the chronic effects of fluoxetine (10 mg/kg o.d.), administered in combination with the selective 5-HT1Areceptor antagonist WAY-100635 (1 mg/kg b.i.d.), on serotonergic neurotransmission in the frontal cortex using in-vivo microdialysis. Following chronic administration of fluoxetine ± WAY-100635, functional changes in serotonergic neurotransmission, as well as 5-HT1Aautoreceptors, were assessed by administering fluoxetine or (±) 8-hydroxy-2-(di-n-propylamino)tetralin [(±) 8-OH-DPAT] 24 h after the last chronic dose. Chronic administration of WAY-100635 alone produced no detectable change in the functional status of the 5-HT1Areceptor. However, fluoxetine alone produced a time-dependent adaptation in serotonergic transmission such that fluoxetine (acutely administered on day 15) was able to produce a two fold increase in extracellular 5-HT levels but the decrease in response to 8-OH-DPAT was completely attenuated. These data indicate that the fluoxetine-induced adaptation was mediated by desensitization of the 5-HT1Areceptor. WAY-100635 given chronically in combination with fluoxetine blocked the SSRI-induced desensitization of the 5-HT1Areceptor. Furthermore, chronic treatment with this combination produced no tolerance in terms of its ability to acutely increase forebrain 5-HT levels. These data suggest that augmentation of an SSRI by combined pharmacotherapy with a 5-HT1Aantagonist would be effective upon prolonged exposure.
Striatal dopamine D2 receptor binding of risperidone in schizophrenic patients as assessed by 123I-iodobenzamide SPECT: a comparative study with olanzapine
Authors: Schmitt G. J. E. , Meisenzahl E. M. , Dresel S. , Tatsch K. , Rossmüller B. , Frodl T. , Preuss U. W. , Hahn K. , Möller H.-j.
Published: April 2009

The aim of this investigation was to compare the degree of striatal dopamine-(D2) receptor blockade by two atypical antipsychotic drugs, risperidone and olanzapine. The percentage of D2 receptor occupancy during treatment was calculated by comparing the results of 123I-iodobenzamide SPECT with those from healthy control subjects. Twenty inpatients suffering from schizophrenia or schizoaffective psychosis according to DSM IV/ICD-10 criteria were treated with clinically recommended doses of risperidone and compared with 13 inpatients treated with up to 20 mg olanzapine. Neuroleptic dose and D2 receptor blockade correlated strongly for both risperidone (Pearson r = –0.86, p = 0.0001) and olanzapine (Pearson r = –0.77, p = 0.002). There was no significant difference between the D2 receptor occupancy of the two substances when given in the clinically recommended dose range (unpaired t-test, t= –0.112, p=0.911).
Fluoxetine treatment of depressed patients with comorbid anxiety disorders
Authors: Sonawalla Shamsah B. , Farabaugh Amy , Johnson Mary W. , Morray Meridith , Delgado Margarita L. , Pingol Mark G. , Rosenbaum Jerrold F. , Fava Maurizio
Published: April 2009

Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared to major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in severity of both depressive and anxiety symptoms in outpatients with major depression with comorbid anxiety disorder following fluoxetine treatment. We enrolled 123 outpatients (mean age 38.9 ± 10.8 years; 49% women) with major depressive disorder accompanied by one or more current comorbid anxiety disorders in our study. Patients were treated openly with fluoxetine 20 mg/day for 8 weeks. Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D) and the patient-rated Symptom Questionnaire (SQ) Scales for Depression and Anxiety. The mood and anxiety disorder modules of the Structured Clinical Interview for DSM-III-R were administered at screen and endpoint. We used ‘intent to-treat’ analysis in examining all patients assigned to treatment and completing the baseline visit. The mean number of comorbid anxiety disorders per patient was 1.5 ± 0.68. The mean HAM-D-17 score and mean Clinical Global Impressions-Severity scores decreased significantly from baseline to endpoint (week 8) following fluoxetine treatment (p < 0.0001). There were significant decreases in all four SQ scale scores, from baseline to endpoint: depression, anxiety, somatic symptoms and anger-hostility (p < 0.0001). Fifty-three percent of patients (n = 65) were depression responders (i.e. ≥ 50% decrease in HAM-D-17 score at endpoint) and 46% (n = 57) were remitters (HAM-D-17 ≤ 7 at endpoint). Patients with panic disorder had significantly higher baseline HAM-D-17 scores compared to those without panic disorder (p< 0.01). Patients with comorbid obsessive–compulsive disorder (OCD) were significantly less likely to be responders to fluoxetine at endpoint (≥ 50% decrease in HAM-D-17) and to be remitters (HAM-D-17 score of ≤ 7 at endpoint) compared to patients without comorbid OCD (p < 0.01). Of the 41 patients on whom endpoint Structured Clinical Interview for DSM-III-R modules for anxiety disorders were available, 49% (n = 20) no longer met criteria for one or more of their anxiety disorder diagnoses at endpoint. Our preliminary findings suggest that fluoxetine is effective in treating outpatients with major depression with comorbid anxiety disorders, with a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are required in larger samples to confirm our findings.
Repeated administration of milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors but not postsynaptic 5-HT1A receptors
Authors: Mochizuki Daisuke , Hokonohara Tadami , Kawasaki Koh , Miki Naomasa
Published: April 2009

The effects of the repeated administration of milnacipran, a serotonin (5-HT)-noradrenaline reuptake inhibitor (SNRI), on the functional status of somatodendritic 5-HT1Areceptors, and postsynaptic 5-HT1Areceptors were explored using electrophysiological approaches in rats. In-vitro electrophysiological recordings in the dorsal raphe nucleus showed that 5-HT inhibited the firing of serotonergic neurones, and the selective 5-HT1Areceptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), reversed the inhibitory effect of 5-HT. The potency of 5-HT to inhibit the firing of serotonergic neurones was slightly attenuated after 3 days of treatment with milnacipran (30 mg/kg, p.o., twice daily), and significantly attenuated after 7 or 14 days treatment at the same dose. The tricyclic antidepressant, imipramine, did not significantly modify the inhibitory effect of 5-HT. After 7 days treatment at 30 mg/kg, p.o., once daily, milnacipran reduced the potency of 5-HT to inhibit the firing of serotonergic neurones, whereas the selective serotonin reuptake inhibitors, fluvoxamine and fluoxetine (60 and 30 mg/kg, p.o., once daily, respectively), did not modify it under these conditions. Treatment with milnacipran (30 mg/kg, p.o., twice daily) for 14 days did not change the inhibition of the CA1 field potential in rat hippocampal slices by 5-HT. These data suggest that somatodendritic 5-HT1Areceptors, but not postsynaptic 5-HT1Areceptors, rapidly desensitize in response to the repeated administration of milnacipran.
Dopamine receptor mechanism(s) and morphine tolerance in mice
Authors: Zarrindast Mohammad-Reza , Dinkoub Zahra , Homayoun Houman , Bakhtiarian Azam , Khavandgar Simin
Published: April 2009

Based on our previous demonstration of the involvement of dopamine-2 (D2) dopamine receptors in morphine antinociception, we examined the role of D2 dopamine receptors in the expression and development of tolerance to morphine antinociception in mice. Tolerance to morphine antinociception was assessed by the tail-flick response after the administration of morphine (50 mg/kg) once daily for 3 days. The D2 dopamine receptor agonist, quinpirole (0.01, 0.02 and 0.03 mg/kg), but not the D2 dopamine receptor antagonist, sulpiride (12.5, 25 and 50 mg/kg), increased morphine antinociception in morphine non pre exposed mice. The response of quinpirole was decreased by the lower doses of sulpiride. Both quinpirole and sulpiride decreased the expression and development of tolerance to antinociception induced by morphine (1.5, 3 and 6 mg/kg). The effect of quinpirole on the expression and development of tolerance, was reduced by a lower and per se non-effective dose of sulpiride. It was concluded that D2 dopaminergic receptors may play a part in the expression and development of tolerance to the antinociceptive effect of morphine.
Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats
Authors: Zarrindast M. R. , Bakhsha A. , Rostami P. , Shafaghi B.
Published: April 2009

The effect of post-training intrahippocampal injection of γ-aminobutyric acid (GABA) receptor agonists and antagonists, immediately after a training session on memory retention of passive avoidance learning in rats, was measured in the presence and absence of physostigmine. Post-training treatments were carried out in all the experiments. The different doses of the GABAA receptor agonist muscimol (2, 4 and 6 μg/rat) decreased memory retention in rats dose-dependently. The higher response was obtained with 6 μg/rat of the drug. When the GABAA receptor antagonist bicuculline (0.5, 1, 2 and 4 μg/rat) was administered, only one dose of the drug (1 μg/rat) increased memory retention; however, the antagonist reduced the effect of muscimol. The GABAB receptor agonist, baclofen (0.25, 0.5, 1 and 2 μg/rat) also reduced memory retention in the animals. Intrahippocampal injection of lower doses of the GABAB receptor antagonist CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid) (2.5, 5, 10 μg/rat) did not effect memory retention, although the higher doses of the drug (25 and 50 μg/rat) decreased memory retention. The doses of antagonist (2.5, 5 and 10 μg/rat), which did not elicit any response alone, reduced the effect of baclofen. The inhibitory response of CGP35348 was also decreased by bicuculline. In another series of experiments, physostigmine improved memory retention. The GABA receptor agonists, muscimol and baclofen, as well as the GABA receptor antagonists bicuculline and CGP35348, decreased the effect of physostigmine. Atropine decreased memory retention by itself and potentiated the response of muscimol and baclofen. It is concluded that GABAA and GABAB receptor activation may be involved in the impairment of memory retention.
The effects of single-dose lorazepam on memory and behavioural learning
Authors: Matthews Allison , Kirkby Kenneth C. , Martin Frances
Published: April 2009

To assess the influence of lorazepam on memory and behavioural learning, a non-clinical sample of undergraduate psychology students (n= 24), received lorazepam (2.5 mg) or placebo orally. Pre-drug and post-drug neuropsychological assessment comprised the Rey auditory verbal learning test, verbal fluency test, digit span and word stem completion. Relative to placebo, lorazepam induced a marked deficit in delayed free-recall, perceptual priming, and written word fluency, with preservation of digit span. Behavioural learning was assessed on a computer-aided vicarious exposure treatment for obsessive–compulsive disorder, administered post-drug, and repeated 1 week later, drug free. Compared to placebo, lorazepam treated participants enacted 51% less exposure activity on the behavioural learning task post-drug. Whilst both groups enacted increased exposure at the drug-free session, exposure activity was 49% less in the lorazepam group, indicating a carryover effect of the impaired learning under drug 1 week before. There were no significant differences between lorazepam and placebo on indices of overall activity on the program. These results suggest lorazepam-induced impairment in the ability to learn behavioural strategies, possibly due to impaired acquisition of information into long-term episodic memory. These findings suggest caution in the co-prescribing of benzodiazepines in people undergoing behavioural therapies in clinical populations.
The potential cardiotoxicity of antipsychotic drugs as assessed by heart rate variability
Authors: Silke B. , Campbell C. , King D.
Published: April 2009

Most antipsychotic drugs have cardiac effects as a consequence of their pharmacological actions. Recently, thioridazine has been subjected to a restricted indications notice and sertindole had its license withdrawn because of concerns about their potential cardiotoxicity. In the development of new atypical agents, heart-rate corrected QT effects are evaluated but it is unclear how predictive these are of clinically significant cardiotoxicity or sudden death. Heart rate variability (HRV) is a potential index of cardiotoxicity which has been found to be decreased following antidepressants and clozapine. We studied acute HRV changes following antipsychotic agents. Sixteen healthy male volunteers received risperidone (4 mg), olanzapine (10 mg), thioridazine (50 mg) or placebo in a randomized cross-over design. Subjective effects and psychomotor function were assayed at 2 h and both linear (summary statistics) and non-linear (scatterplot) measures of HRV were evaluated by continuous electrocardiogram recording over 10 h. Differential effects of single doses of the three antipsychotic drugs on HRV were found, and these were independent of their sedative effects. Olanzapine increased, and thioridazine decreased HRV, while risperidone had no effect. HRV is sensitive to the acute effects of antipsychotics. It may prove to be a reliable index of their potential for cardiotoxicity. Further studies in both healthy volunteers and patients on antipsychotic medication will be valuable.
Acute dystonic reaction in an elderly patient with mood disorder after titration of paroxetine: possible mechanisms and implications for clinical care
Authors: Arnone D. , Hansen L. , Kerr J. S.
Published: April 2009

The administration of a serotonin reuptake inhibitor may lead to extra pyramidal signs, as reported in the literature. The risk seems to be increased in elderly people. We describe a case of acute dystonic reaction to paroxetine treatment in an elderly patient, who presented with a bipolar affective disorder. The underlying mechanism, possibly generated in the subcortical motor areas, is linked to changes that occur in the pharmacokinetic variables, the decreased neuroplasticity of ageing neurones and to previous exposure to neuroleptic medications.
The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation
Authors: van Steveninck A. L. , van Berckel B. N. M. , Schoemaker R. C. , Breimer D. D. , van Gerven J. M. A. , Cohen A. F.
Published: April 2009

Various methods are used to quantify sedative drug effects, but it is unknown how these surrogate measures relate to clinically relevant sleepiness. This study assessed the sensivity of different surrogates of sedation to clinically relevant sleepiness induced by sleep deprivation. Nine healthy volunteers completed a balanced three-way cross-over study with 1-week wash-out periods. Adaptive tracking, smooth-pursuit and saccadic eye movements, body sway, digit symbol substitution (DSST), visual analogue scales (VAS) and electroencephalograms (EEG) were evaluated on three occasions: (1) during the day after normal sleep, (2) during wakefulness at night; and (3) during the day after a night of sleep deprivation.VAS of alertness showed a gradual decline at night and a constant average reduction of 38 percent [95% Confidence intervals (CI), 28–47%] during the day after sleep deprivation. Average mood scores diminished by 14 percent (95%, CI 2–24%) during the day after sleep deprivation. Adaptive tracking, saccadic eye movements and body sway tended to deteriorate at night, but overall this was not statistically significant. After a night of sleep deprivation, adaptive tracking decreased by 21 percent (95% CI, 11–30%), saccadic eye movements decreased by 9–10 percent (95% CI, 5–13%/6–15%) and body sway increased by 37 percent (95% CI, 5–79%). In contrast, EEG b2-amplitudes declined significantly at night by 18 percent (95% CI, 6–29%), without changes during the day after sleep deprivation. Smooth pursuit, DSST and other EEG-amplitudes remained unchanged. These resultsemphasize that reductions in adaptive tracking, saccadic peak velocity and body sway caused by sedative drugs really reflect sedation. They also provide a level of clinical significance for these surrogates of sedation. EEG parameters and smooth pursuit were unaffected by sleep deprivation, so drug-induced changes in these measures may notreflect sedation in a stricter sense. The motivation and alertnessnecessary for DSST may overcome mild sedation.
Longitudinal patterns of antidepressant prescribing in primary care in the UK: comparison with treatment guidelines
Authors: Dunn Rodney L. , Donoghue John M. , Ozminkowski Ronald J. , Stephenson Deborah , Hylan Timothy R.
Published: April 2009

The objective of this study was to determine whether patients beginning therapy on the most common tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) differed in their likelihood of having antidepressant treatment that was consistent with recommended treatment guidelines in the UK. An analytical file constructed from a large general practitioner medical records database (DIN-LINK) from the UK for the years 1992-97 was constructed. A total of 16 204 patients with a new episode of antidepressant therapy who initiated therapy on one of the most often prescribed TCAs (amitriptyline, dothiepin, imipramine and lofepramine) or SSRIs (fluoxetine, paroxetine and sertraline) were analysed. A dichotomous measure was defined to indicate whether subjects were prescribed at least 120 days of antidepressant therapy at an adequate average daily dose within the first 6 months after initiation of therapy. Only 6.0% of patients initiating therapy on aTCA and 32.9% of patients initiating therapy on a SSRI were prescribed antidepressant treatment that was consistent with treatment guidelines. After controlling for observable characteristics, patients who initiated therapy on a SSRI were much more likely (odds ratio=7.473, p<0.001) to have a prescribed average daily dose and duration consistent with recommended treatment guidelines within the first 6 months of initiating therapy than were patients who initiated therapy on a TCA. These findings suggest that initial antidepressant selection is an important determinant of whether the subsequent course of treatment is consistent with current national guidelines for the treatment of depression in the UK.
Attenuation of some subjective effects of amphetamine following tyrosine depletion
Authors: McTavish S. F. B. , McPherson M. H. , Sharp T. , Cowen P. J.
Published: April 2009

Fifteen healthy volunteers received d-amphetamine (20mg orally) 2 h after ingesting either a nutritionally balanced amino acid mixture or one lacking the catecholamine precursors, tyrosine and phenylalanine (TYRfree). Plasma tyrosine levels were significantly lowered in subjects who received the TYR-free mixture but mean plasma amphetamine levels were higher. Despite this, the TYR-free mixture appeared to decrease the subjective psychostimulant effects of amphetamine, as determined by visual analogue scales. In contrast, the TYR-free mixture failed to lower the subjective anorectic effect of amphetamine. These findings are consistent with animal experimental studies indicating that tyrosine depletion attenuates the release of dopamine produced by amphetamine but not the release of noradrenaline.
Effects of D-cycloserine, a positive modulator of N-methyl-D-aspartate receptors, and ST 587, a putative alpha-1 adrenergic agonist, individually and in combination, on the non-delayed and delayed foraging behaviour of rats assessed in the radial arm maze
Authors: Pussinen Raimo , Sirviö Jouni
Published: April 2009

The present study investigated whether alpha-1 adrenergic and glutamatergic N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms interact in memory processes, by examining the effects of individual and combined systemic administration of ST 587, a putative alpha-1 agonist, and D-cycloserine (DCS), a partial agonist at the glycine-B binding site of the NMDA receptor, on the performance of rats in non-delayed and delayed (4-6h) foraging behaviour in the radial arm maze task, using the delayed non-matching to sample (DNMTS) version. The results indicated that DCS (5.0mg/kg) decreased working memory errors, i.e. the number of re-entries into the previously visited arms during the sampling phase. In addition, both ST 587 (100 jig/kg) and DCS (10 mg/kg), when administered alone 30 min before a sampling phase, improved retention of this task as reflected by the increased number of correct choices before the first error during the retention phase. The combined administration of ST 587 and DCS, however, did not lead to better retention in the DNMTS task compared with the administration of each of the drugs alone. Combinations of sub-threshold doses of ST 587 (50 or 75 jig/kg) and DCS (5.0 or 7.5 mg/kg) also did not improve retention in this task. DCS (5.0 or 7.5 mg/kg) increased activity as indicated by the increased number of arm entries in a given time during the sampling phase. These findings suggest that the systemic administration of a positive modulator of the NMDA receptor facilitates hippocampal-dependent memory functions, but that these effects are not enhanced by combined administration with an alpha-1 agonist, even though the alpha-1 agonist is effective when given alone. The results support the idea that NMDA receptors modulate both mnemonic and non-mnemonic functions in the brain.
Brain uptake of iomazenil in cirrhotic patients: a single photon emission tomography study
Authors: Kapczinski Flávio , Quevedo João , Curran H. Valerie , Fleminger Simon , Toone Brian , Cluckie Alice , Lader Malcolm
Published: April 2009

Brain uptake of123I-iomazenil was studied in seven cirrhotic patients and eight normal controls using single photon emission computerized tomography. The highest concentration of the ligand was found in the occipital cortex, which corresponds to the brain region with the highest concentration of benzodiazepine receptors.The peak uptake was delayed in patients across all brain regions. The uptake in occipital cortex was higher in low albumin cirrhotics. Patients with low albumin also presented a more delayed peak uptake in occipital cortex and a higher volume of distribution of iomazenil in plasma, compared to patients with normal albumin levels and controls. The changes in brain uptake (delayed peak uptake and increased maximal uptake in occipital cortex) appears to reflect changes in the pharmacokinetics of the ligand, particularly in cirrhotics with low levels of plasma albumin. The curve of brain uptake of the tracer was modelled into a two compartments equation, which seems to provide a practical and reliable method to calculate the slopes of acquisition and decay, time to peak and maximal acquisition.
Comparison of the effects of diazepam on the fear-potentiated startle reflex and the fear-inhibited light reflex in man
Authors: Bitsios P. , Philpott A. , Langley R. W. , Bradshaw C. M. , Szabadi E.
Published: April 2009

It has been shown previously that the amplitude of the acoustic startle reflex is enhanced, and the amplitude of the light reflex reduced, when subjects anticipate an aversive event, compared to periods when subjects are resting (`fear-potentiated startle reflex' and `fear-inhibited light reflex'). We examined whether the anxiolytic diazepam would reverse the effects of threat on the startle and pupillary reflexes. Twelve male volunteers participated in three weekly sessions in which they received oral treatment with placebo, diazepam 5 mg and diazepam 10 mg, according to a balanced crossover double-blind design. One hour after ingestion of the treatments, miotic responses to light pulses and electromyographic responses of the orbicularis oculi muscle to sound pulses were elicited during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with a signicant increase in the amplitude of the electromyographic (EMG) response, a signicant reduction of the miotic response amplitude, and an increase in self-rated anxiety. Diazepam attenuated all these effects of THREAT. Diazepam did not affect the amplitude of the miotic response under the SAFE condition, but did suppress the EMG response under this condition.These results confirm the validity of the fear-potentiated startle reflex and fear-inhibited light reflex as laboratory models of human anxiety, and reveal some differences between the effects of diazepam on the two reflexes.