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Psychopharmacology (2002) 163:106–110DOI 10.1007/s00213-002-1151-x O R I G I N A L I N V E S T I G A T I O N Catherine J. Harmer · Zubin Bhagwagar ·Phillip J. Cowen · Guy M. Goodwin Acute administration of citalopram facilitates memory consolidationin healthy volunteers Received: 8 February 2002 / Accepted: 8 May 2002 / Published online: 29 June 2002 Springer-Verlag 2002 Abstract Objectives: Decreasing serotonergic neurotrans- mission in humans has been found to impair memoryconsolidation. Such effects may be relevant to the Serotonergic circuits have long been held to play a role in memory deficits seen in major depression and the learning and memory processes. However, results from cognitive actions of antidepressant drugs used to treat animal studies have yielded inconsistent findings con- them. However, the improvement in cognitive function cerning the direction of its effect (Altman and Normile often found following successful pharmacological treat- 1988). While there is evidence that stimulation of ment in depression may be confounded by symptom serotonin activity impairs, whereas blockade of its improvement. Rationale: The present study assessed the activity enhances, learning and memory (see McEntee effects of an acute challenge with the selective seroto- and Crook 1991), the opposite findings have also been nergic re-uptake inhibitor citalopram in healthy (non- reported (e.g. Bammer 1982; Flood and Cherkin 1987).
depressed) females. Methods: Immediate and delayed These inconsistencies may relate to interactions between recall/recognition was assessed using the auditory verbal the type of memory assessed, dose and specificity of learning test following 10 mg (intravenous) citalopram or agents used and the timing of the serotonergic manipu- placebo in a double-blind between groups design.
Results: Immediate recall on the verbal memory test In humans, decreasing serotonergic neurotransmission, was unaffected by citalopram administration. However, using the method of tryptophan depletion, has been volunteers receiving citalopram showed enhanced long- reported to decrease memory and learning (Park et al.
term memory performance in terms of delayed recall and 1994; Riedel et al. 1999; Schmitt et al. 2000). In recognition relative to those receiving placebo. Sustained particular, long-term, as opposed to short-term, memory attention performance was also comparable in the two appears to be primarily affected. In the study by Riedel et groups of subjects suggesting that non-specific increases al. (1999), immediate recall of verbal items was unaf- in information processing are not responsible for this fected by tryptophan depletion, but delayed recall and effect. Conclusions: These results indicate that augmen- recognition of these same items was significantly im- tation of serotonergic neurotransmission is associated paired. In a subsequent investigation, only tryptophan with increased memory consolidation, which may be depletion given prior to learning affected delayed recall.
relevant to its therapeutic and cognitive actions in acutely Administration of the tryptophan-free drink 1 h after presentation of a word list did not affect the storage orretrieval of this verbal material (Schmitt et al. 2000). The Keywords SSRI · Citalopram · Memory consolidation · involvement of serotonin in memory does not appear to be restricted to verbal material, as tryptophan depletionhas also been reported to impair performance in non-verbal memory tasks, such as paired associate learningand pattern recognition memory (Park et al. 1994;Rubinsztein et al. 2001).
A role for serotonin in learning and memory may be relevant to clinical conditions such as depression, Alz- )) · Z. Bhagwagar · P.J. Cowen · G.M. Goodwin Neurosciences Building, University Department of Psychiatry, heimer’s disease and the symptoms associated with prior ecstasy (MDMA) use. Major depressive disorder has been associated with impaired recall both on immediate and delayed measures (Austin et al. 1992; Brown et al. 1994), and memory deficits are usually seen to improve follow- final learning trial), and recognition. Signal detection theory was ing recovery from the disorder with antidepressant applied to the data from the recognition test to derive a measure ofaccuracy corrected for the subject’s response tendency. The treatment (Peselow et al. 1991), particularly selective proportion of correctly recognized words (cr) and the proportion serotonergic reuptake inhibitors (SSRIs) (Keegan et al.
of falsely recognized (fr) constitute the non-parametric sensitivity 1991; Bondareff et al. 2000). This improvement may be measure: A’=1–1/4(fr/cr+(1–cr)/(1–fr)).
related to direct actions of the antidepressant on memoryor may be a non-specific effect of symptom improvement.
Similarly, deficits in immediate and delayed memoryhave been reported to occur in individuals with past A measure of sustained attention was also given, adapted from a history of ecstasy use with associated abnormalities of test by Wesnes and Warburton (1984) and Sahakian et al. (1989). In serotonergic functioning (e.g. Reneman et al. 2000, this task, digits between 1 and 9 were presented in the centre of thescreen at a rate of 200 per minute (pseudo-random order) for 7 min.
Subjects were asked to monitor the digits for any one of three The effects of increased, as opposed to decreased, specified digit sequences (3–5–7, 2–4–6 or 4–6–8), which they serotonin levels have not been investigated to the same should respond to by pressing a button on a key pad. A practice degree in humans. Such results may help confirm the role session was given initially, with target sequences appearing in red,to familarise volunteers with the nature of the task. In the testing of serotonin in memory processes and also provide a phase all digits were given in black on a white screen. This task possible mechanism for the cognitive effects of antide- yields three measures: speed of correct detections, number of pressant treatment in major depression. The present study correct detections and responses made in the absence of appropriate therefore investigated the effects of an acute challenge stimuli (false alarms). Signal detection analysis can also be applied with the SSRI, citalopram, on verbal short and long-term to these results, giving two independent measures of performance:response sensitivity and response bias.
memory in non-depressed female subjects. Sustainedattention was also examined to assess whether moreglobal changes in information processing were found following SSRI treatment. Based on the effects of Subjective state was recorded using visual analogue scales for the tryptophan depletion in humans, it was postulated that following variables: happiness, sadness, fear, disgust, anger, citalopram would specifically facilitate long-term mem- alertness and anxiety. The Befindlichkeits scale (BFS: von Zerrsen ory recall and recognition, without affecting immediate et al. 1974) was also given to provide an additional measure of Subjects attended the laboratory at midday, having fasted frombreakfast, and an IV cannula was inserted. After a 30-min rest period subjects received infusion of either citalopram (10 mg, IV)or placebo given over 30 min. The immediate recall part of the Twenty-four healthy female volunteers between the ages of 21 and AVLT was given 45 min after the end of the infusion, by which 59 years took part in this study. Participants were screened to time effects of citalopram on serotonin function have been reported exclude those with a current or previous history of psychiatric (Attenburrow et al. 2001). In between the distraction and delayed disorder (assessed using semi-structured interview for DSM IV), recall, subjects were given the sustained attention task. Subjective current medication (apart from the contraceptive pill), current or state was assessed at baseline and prior to the psychological testing.
previous substance use, or significant physical illness. All gavetheir written consent to participate in this study, which wasapproved by the local ethical committee. Volunteers were randomly allocated to receive citalopram (10 mg, IV) or placebo in a double-blind between groups design. These two groups were matched in Performance in these tasks was analysed using two-way split-plot terms of age (mean age: 40.1€3.6 and 37.3€3.7 years, respectively) analysis of variance (ANOVA), with group and learning trial as and years of education (mean: 13.4€0.7; 14.6€0.7). All volunteers factors (for immediate and delayed recall). Significant main effects were tested within the follicular phase of their menstrual cycle.
were completed using simple main effect analyses. Recognitionmemory was analysed using one-way ANOVA.
The auditory verbal learning test assesses a number of different components of learning, recall, and recognition (Rey 1964). In theimmediate recall phase, a 15-item word list was read to the subject five times, and after each trial the subject was asked to repeat backas many items as they could remember in any order. Immediaterecall on a distracter list was then assessed, providing a short delay Recall of the 15-item word list improved over the five after which free recall of the original list was tested. Fifteen repetitions in both groups of subjects [Fig. 1: main effect minutes later, subjects were tested for long delay free recall, of trial: F(4,88)=108.7, P<0.001]. However, there was no followed by a recognition test, where they were asked to respond effect of group or group by trial interaction in this with a “Yes” or “No” to each item on a list comprising the 15targets plus 35 distractors. Data were analysed with respect to four analysis (F<1, NS), suggesting that citalopram adminis- dependent variables: learning over trials 1–5, short-delay and long- tration had no effect on acquisition and short term recall.
delay free recall (expressed as a percentage of performance on the Mean performance in the delayed recall and recognitioncomponent of the AVLT is given in Fig. 2. Recallfollowing the distracter [F(1,22)=6.6, P<0.05] and the 15-min delay [F(1,22)=5.1, P<0.05] was significantly facil-itated by citalopram administration. A facilitatory effectof citalopram on long-term memory was also seen in therecognition Fig. 1 Immediate recall over the five learning trials following There was no effect of citalopram on target sensitivity, citalopram (black) or placebo (white). Values represent mean response bias or reaction time on this measure of The changes in memory occurred in the absence of anysubjective alterations in mood and anxiety, as judged bystandard visual analogue rating scales and the BFS scaleof mood changes (all comparisons, P>0.08).
Acute administration of citalopram was found to facilitatelong-term recall and recognition of verbal material in theabsence of effect on immediate recall in healthy females.
These results are consistent with previous findings, whichsuggest decreased memory consolidation following re-duction of serotonin activity with tryptophan depletion inhealthy volunteers (Riedel et al 1999). These datatherefore indicate reciprocal effects of serotonin in long-term memory processes in humans. Citalopram adminis-tration did not affect sustained attention performance orsubjective ratings of mood and energy, suggesting that thememory effects are unlikely to represent a non-specificaction.
Results from animal studies have revealed inconsistent Fig. 2 Delayed recall and recognition following citalopram (blackbars findings concerning the role of serotonin in learning and ) or placebo (grey bars). Top graph: following distracter list and 15-min delay. Values represent mean number of items recalled, memory. However, in humans, tryptophan depletion, expressed as a percentage of each subjects’ final score on the acting to decrease serotonin neurotransmission, has immediate recall component of the AVLT. Lower graph: recogni- deleterious effects on memory consolidation. Using a tion memory. Values represent signal detection score, A’ €1 SEM.
slightly different procedure from the one used here, Asterisks represent statistical comparison of the two groups:*P<0.05 administration of a tryptophan free mixture prior tolearning was found to impair delayed recall and recog-nition at both 30 min and 18 h after list presentation,whilst leaving short-term memory intact (Riedel et al.
(with SD in brackets) in thesustained attention task follow- 1999). The present data directly mirror this pattern of results: enhanced long-term, but not short-term, memoryperformance following citalopram. The present results Altman HJ, Normile HJ (1988) What is the nature of the role of the therefore provide additional evidence for the role of serotonergic nervous system in learning and memory: prospects serotonin in memory, and further suggest that increasing for development of an effective treatment strategy for seniledementia. Neurobiol Aging 9:627–638 serotonin levels can lead to enhancements in memory Attenburrow MJ, Mitter PR, Whale R, Terao T, Cowen PJ (2001) Low-dose citalopram as a 5-HT neuroendocrine probe. Psy- These findings may have implications for our under- standing of the effects of SSRIs on memory processes in Austin MP, Ross M, Murray C, O’Carroll RE, Ebmeier KP, Goodwin GM (1992) Cognitive function in major depression.
depression. Depression is associated with impaired memory performance, which is ameliorated after suc- Bammer G(1982) Pharmacological investigations of neurotrans- cessful pharmacological treatment (Keegan et al. 1991; mitter involved in passive avoidance responding: a review and Bondareff et al. 2000). The present data suggest that some new results. Neurosci Biobehav Rev 6:247–296 Bondareff W, Alpert M, Friedhoff AJ, Richter EM, Clary CM, SSRIs are capable of facilitating memory performance, Batzar E (2000) Comparison of sertraline and nortriptyline in independently from symptom improvement. The volun- the treatment of major depressive disorder in late life. Am teers in the current study were free from current or previous depression and reported no changes in mood Brown RG, Scott LC, Bench CJ, Dolan RJ (1994) Cognitive following citalopram administration. The impaired mem- function in depression: its relationship to the presence andseverity of intellectual decline. Psychol Med 24:829–847 ory seen in depressed patients may, over time, contribute Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) to the feelings of inadequacy and low self-esteem Clonidine and diazepam have differential effects on tests of associated with this disorder. Hence, it is possible that attention and learning. Psychopharmacology 120:322–332 antidepressant drug treatment effects on memory form a Flood JF, Cherkin A (1987) Fluoxetine enhances memory process- ing in mice. Psychopharmacology 93:36–43 valuable process in the response to such treatment.
Keegan D, Bowen RC, Blackshaw S, Saleh S, Dayal N, Remil- However, while the effects seen here were restricted to lard F, Shrikhande S, Cebrian Perez S, Boulton A (1991) A delayed recall, depression is associated with more global comparison of fluoxetine and amitriptyline in the treatment of cognitive deficits including impaired immediate recall major depression. Int Clin Psychopharmacol 6:117–124 McEntee WJ, Crook TH (1991) Serotonin, memory and the aging and attention (Austin et al 1992; Brown et al 1994). It remains to be assessed whether this acute SSRI admin- McTavish SF, McPherson MH, Harmer CJ, Clark L, Sharp T, istration would have more global effects in volunteers Goodwin GM, Cowen PJ (2001) Antidopaminergic effects of with pre-existing deficits in memory performance. It dietary tyrosine depletion in healthy subjects and patients with would also be useful to characterise the effects of these manic illness. Br J Psychiatry 179:356–360 O’Hanlon JF, Robbe HW, Vermeeren A, van Leeuwen C, agents on tests tapping into different memory components Danjou PE (1998) Venlafaxine’s effects on healthy volunteers’ or subdivisions, such as working memory, autobiograph- driving, psychomotor, and vigilance performance during 15- day fixed and incremental dosing regimens. J Clin Psycho- Vigilance performance was not affected by citalopram Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, administration in the current study. Previous studies have Robbins TW, Cowen PJ (1994) Tryptophan depletion in normal reported decreased vigilance performance following oral volunteers produces selective impairments in learning and treatment with SSRIs in tasks demanding more sustained processes of attention than the task used here (such as the Peselow ED, Corwin J, Fieve RR, Rotrosen J, Cooper TB (1991) Disappearance of memory deficits in outpatient depressives 45-min version of the Mackworth clock; Ramaekers et al.
responding to imipramine. J Affect Disord 21:173–183 1995; O’Hanlon et al 1998). However, the 7-min task Ramaekers JG, Muntjewerff ND, O’Hanlon JF (1995) A compar- does show a characteristic vigilance decrement over ative study of acute and subchronic effects of dothiepin, testing and has been shown to be sensitive to other fluoxetine and placebo on psychomotor and actual driving pharmacological manipulations such as clonidine (Coull performance. Br J Clin Pharmacol 39:397–404 Reneman L, Booij J, Schmand B, van den Brink W, Gunning B et al. 1995) and amphetamine (McTavish et al. 2001).
(2000) Memory disturbances in “Ecstasy” users are correlated This short task was used as a control for the level of with an altered brain serotonin neurotransmission. Psychophar- sustained attention required by the memory task and the absence of an effect with IV citalopram therefore suggests Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ, Booij J (2001) Cortical serotonin that alterations in this ability cannot explain the improved transporter density and verbal memory in individuals who memory performance seen in the current sample.
stopped using 3,4-methylenedioxymethamphetamine (MDMA In summary, the current results suggest that adminis- or “ecstasy”): preliminary findings. Arch Gen Psychiatry tration of a serotonergic agent enhances long-term Rey A (1964) L’examen de Clinique en Psychologie. Presses memory, in the absence of changes in sustained attention or mood. These effects therefore confirm the facilitatory Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM role of serotonin in memory consolidation, as previously (1999) Tryptophan depletion in normal volunteers produces suggested by studies investigating the effects of decreased selective impairment in memory consolidation. Psychopharma- Rubinsztein JS, Rogers RD, Riedel WJ, Mehta MA, Robbins TW, Sahakian BJ (2001) Acute dietary tryptophan depletion impairs maintenance of “affective set” and delayed visual recognition von Zerrsen D, Strian F, Schwarz D (1974) Evaluation of in healthy volunteers. Psychopharmacology 154:319–326 depressive states, especially in longitudinal studies. In: Pichit P Sahakian B, Jones G, Levy R, Gray J, Warburton D (1989) The (ed) Psychological measurements in psychopharmacology.
effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer Wesnes K, Warburton DM (1984) The effects of cigarettes of varying yield on rapid information processing performance.
Schmitt JAJ, Jorissen BL, Sobczak S, van Boxtel MPJ, Hoger- vorst E, Deutz EP, Riedel WJ (2000) Tryptophan depletionimpairs memory consolidation but improves focussed attentionin healthy young volunteers. J Psychopharmacol 14:21–29

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