Posted by Quintal on August 9, 2007, at 10:33:56
In reply to Re: beta carbolines to reverse benzo cognitive pro » Quintal, posted by linkadge on August 9, 2007, at 8:42:19
Benzodiazepines can cause depression with long-term use. This is a well known fact and proven by many studies as well as clinical experience. Heather Ashton has done some excellent work on the subject, have you read it?
Benzodiazepines seem to cause a *progressive* deterioration in mental performance and mood over time, usually several years. So somebody could be relatively unaffected at the beginning, yet over time their cognitive functioning declines and their mood darkens. This happens gradually so it may be attributed to other factors in a person's life. Benzos also lose their anxiolytic efficacy as tolerance develops and after a while fear creeps in from every corner until it's everywhere (agoraphobia/GAD). This too is a well known and documented phenomenon. Interesting, link, that you feel so passionately about the temporary worsening of depression induced by SSRIs, but with benzos, to you this is an acceptable side effect. I often wonder what your views would be like now if you were given benzos as a teenager, not SSRIs, and suffered as a consequence.
Your comments on Nardil. Again, I question their relevance because interference with REM sleep is often said to be one of the central antidepressant mechanisms, not only of MAOIs but SSRIs and some other antidepressants too. So if that were remedied then there is a risk the antidepressant response would vanish too. Therefore if Nardil cognitive impairment was down to REM it would seem that the cognitive impairment is central to the antidepressant (and possibly anxiolytic) response.
This study concludes:
"The main result of this study is that a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability. These data are in line with the knowledge of a lack of efficacy of benzodiazepines in depressive and most anxiety disorders, despite long term treatment. They also confirm the current guidelines which recommend prescribing serotoninergic antidepressants, and not benzodiazepines, when long term treatments are needed for severe and chronic affective disorders."
__________________________________________________1: Encephale. 2007 Jan-Feb;33(1):32-8.
[Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice]
Pélissolo A, Maniere F, Boutges B, Allouche M, Richard-Berthe C, Corruble E.
Service de Psychiatrie Adulte et CNRS UMR 7593, AP-HP, Hôpital Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75013 Paris.
Consumption rates of anxiolytic drugs, and especially of benzodiazepines, remain very high in France compared to other Western countries, whereas clinical guidelines limit their indications to short term treatments and only for some precise anxiety disorders. Recent epidemiologic surveys in the community indicated that more than 15% of people used once or more an anxiolytic drug in the past year. The issue of chronic treatments is particularly crucial because of their poor benefit/risk ratio in most anxiety disorders (limited efficacy, cognitive side effects, withdrawal and dependence problems). To address this important public health issue, and knowing that, in France, benzodiazepines are prescribed mainly by general physicians, our aims were to explore psychiatric diagnoses in GP's patients with chronic use of anxiolytic benzodiazepines. We included 4 425 patients consuming such drugs regularly for six months or more, and assessed their anxiety and depression symptoms through various clinical scales (Hospital Anxiety and Depressive scale - HAD, Clinical Global Impression scale - CGI, Sheehan Disability Scale - SDS, Cognitive Dependence to Benzodiazepines scale - CDB) and with the Mini International Neuropsychiatric Interview for DSM IV criteria. Only 2.2% of the subjects had neither anxious nor depressive symptoms as indicated by low scores on both subscores (less than 8) of the HAD scale, used as a screener. Nearly three quarters of the 4,257 subjects (73.2%), had CGI scores of at least 5 (markedly ill to extremely ill). Social and familial disability was also high in more than 40% of the sample (marked to extreme disruption according to SDS scores). About half of the sample had CDB scores suggesting a benzodiazepine dependence. According to the MINI, 85.1% of the patients had at least one current DSM IV diagnosis of affective disorder. The most frequent diagnoses were major depressive episode (60%), generalized anxiety disorder (61.2%), and panic disorder (22.5%). An anxiety and depressive comorbidity wad found in 41.9% of the subjects. Some methodological limitations must be taken into account in the discussion of our results, and especially the fact that the included patients were not supposed to be totally representative of all patients consuming anxiolytic benzodiazepines in general practice. However, the size of our sample is sufficiently large to limit possible biases in patient selection. The main result of this study is that a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability. These data are in line with the knowledge of a lack of efficacy of benzodiazepines in depressive and most anxiety disorders, despite long term treatment. They also confirm the current guidelines which recommend prescribing serotoninergic antidepressants, and not benzodiazepines, when long term treatments are needed for severe and chronic affective disorders. This epidemiologic study leads to the conclusion that a specific and attentive diagnostic assessment should be done in all patients receiving benzodiazepines for more than three months, in order to purpose in many cases other long term therapeutic strategies.
PMID: 17457292 [PubMed - indexed for MEDLINE]
--------------------------------------------------2: Psychopharmacology (Berl). 2006 Nov;188(4):472-81. Epub 2006 Aug 17.Click here to read Links
Effects of the amnesic drug lorazepam on complete and partial information retrieval and monitoring accuracy.
Izaute M, Bacon E.Laboratoire de Psychologie Sociale et Cognitive (LAPSCO-UMR 6024 CNRS), Universite Blaise Pascal, 34 Avenue Carnot, 63037, Clermont-Ferrand Cedex, France. Marie.Izaute@srvpsy.univ-bpclermont.fr
RATIONALE: In Koriat's accessibility model (Koriat, Psychol Rev, 100:609-639, 1993; Koriat, J Exp Psychol Gen, 124:311-333, 1995), when a person fails to recall a required target, he or she can nevertheless provide some partial information about the target. Moreover, individuals are able to provide feeling-of-knowing (FOK) judgments about the availability of the target in memory. The cues for the FOK evaluations reside in the products of the retrieval process itself. It was shown that the benzodiazepine lorazepam drug induces some impairment of memory. OBJECTIVES: The effects of the amnesic benzodiazepine lorazepam on the total and partial recall of recently learned material and on FOK ratings were investigated in healthy volunteers. METHODS: Twenty-eight healthy volunteers participated in the study: 14 of these received a capsule containing lorazepam (0.038 mg/kg) and 14 a placebo capsule. The material to be learned consisted of four-letter nonsense tetragrams with each letter providing partial information with regard to the four-letter target (Koriat, Psychol Rev, 100:609-639, 1993). RESULTS: The number of incorrect letters reported was higher for the lorazepam than for the placebo condition. The FOK magnitude was higher for the placebo participants than for the lorazepam participants. The predictive value of FOK for recognition was preserved by the drug. CONCLUSION: When studying four-letter nonsense letter strings, lorazepam participants present an impairment of episodic short-term memory and the drug has an effect on FOK estimates but not on the predictive accuracy of the FOK. The accessibility hypothesis of FOK was confirmed in this study and seems to retain some validity even under the effect of an amnesic drug.
PMID: 16915380 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Psychopharmacology (Berl). 2004 Mar;172(3):309-15. Epub 2003 Nov 28.Click here to read Links
Benzodiazepines and semantic memory: effects of lorazepam on the Moses illusion.
Izaute M, Paire-Ficout L, Bacon E.Laboratoire de Psychologie Sociale de la Cognition (LAPSCO-UMR 6024 CNRS), Universite Blaise Pascal, 34 Avenue Carnot, 63037 Clermont-Ferrand Cedex, France. Marie.Izaute@srvpsy.univ-bpclermont.fr
RATIONALE: When asked "How many animals of each kind did Moses take on the ark?", people fail to notice the distortion introduced by the impostor "Moses" and respond "two". It has been argued that the effect must be due to the existence of a partial-match process. In most situations, the form of a question is not likely to closely match the memory representation it queries. Thus, for the partial match hypothesis people ignore some semantic distortions. In the same vein, it has been shown that the benzodiazepine lorazepam drug induces some impairments of semantic memory as participants under lorazepam provide more incorrect recalls than placebo do with general information questions. OBJECTIVES: The aim of this study was to investigate the effects of the benzodiazepine lorazepam on the Moses illusion paradigm. METHOD: The effects of lorazepam (0.038 mg/kg) and of a placebo were investigated in 28 healthy volunteers. Twenty-two illusory questions were presented along with 72 normal general information questions. RESULTS: Lorazepam impaired the ability to detect the Moses illusion. Moreover, lorazepam participants appeared less biased to consider a question distorted than placebo participants. CONCLUSIONS: The temporary and reversible semantic memory impairments experienced by participants when falling into the Moses illusion are more frequent under lorazepam. The amnesic drug lorazepam may impair semantic processing as well as the strategic control of memory.
PMID: 14647957 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Psychopharmacology (Berl). 1995 Nov;122(2):187-93.Links
Encoding, remembering and awareness in lorazepam-induced amnesia.
Curran HV, Barrow S, Weingartner H, Lader M, Bernik M.Clinical Health Psychology, University College London, UK.
The effects of lorazepam (1,2 mg) and placebo on encoding, remembering and awareness were assessed in a study with 54 healthy volunteers. All subjects studied stimulus materials in a levels of processing (L-o-p) task. Half the subjects were assessed on an explicit memory task of word recognition and the other half were given an implicit memory task of word-stem completion. Following the implicit task, awareness of retrieval was further investigated by questions and by subjects' recollective experience in recognising the actual words they had completed from stems. L-o-p effects and marked lorazepam-induced impairments were found in the implicit task of word-stem completion although the interaction between L-o-p and drug effects emerged only as a trend in the data. Lorazepam-induced impairments on stem-completion may then be explained at least in part as being due to contamination by explicit retrieval processes, but we cannot rule out the possible role of drug effects on perceptual processes at encoding. Results from responses to "awareness" questions and from analysis of subsequent recollective experience indicated that subjects were not aware of using explicit retrieval during the implicit task. Results also replicated previous findings showing that both lorazepam and L-o-p independently affect performance in an explicit memory task of word recognition. Thus drug-induced deficits at encoding persist regardless of the level at which information is initially processed.
PMID: 8848535 [PubMed - indexed for MEDLINE]
--------------------------------------------------4: Psychopharmacology (Berl). 1996 Nov;128(2):139-49.Click here to read Links
Effects of oxazepam and lorazepam on implicit and explicit memory: evidence for possible influences of time course.
Stewart SH, Rioux GF, Connolly JF, Dunphy SC, Teehan MD.Department of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada.
The effects of oxazepam (30 mg), lorazepam (2 mg), and placebo on implicit and explicit memory were studied in two testing cycles, 100 and 170 min after drug administration. Thirty healthy volunteers were randomly assigned to one of three groups (placebo, oxazepam, or lorazepam) in a double-blind, independent groups design. Drug groups were equivalent prior to drug administration on a variety of cognitive measures. Following drug administration, both oxazepam and lorazepam equally impaired performance on a cued-recall explicit memory task relative to placebo, at both testing cycles. Relative to placebo, lorazepam markedly impaired priming on a word-stem completion implicit memory task, at both testing cycles. Consistent with previous work, oxazepam failed to produce impairments in priming on the word-stem completion task at 100 min post-drug administration. However, oxazepam was found significantly to impair priming on this latter task relative to placebo, at close to theoretical peak plasma concentration (i.e., 170 min post-drug administration). Explanations for the observed detrimental effect of oxazepam on implicit memory task performance are considered, including: possible time-dependent effects related to the relative rate of absorption of these two benzodiazepines (BZs); and potential contamination of the implicit memory task by explicit memory strategies during the second testing cycle.
PMID: 8956375 [PubMed - indexed for MEDLINE]
--------------------------------------------------5: Psychopharmacology (Berl). 1999 Dec;147(3):266-73.Click here to read Links
Lorazepam impairs both visual and auditory perceptual priming.
Vidailhet P, Danion JM, Chemin C, Kazès M.INSERM Unité 405, Département de Psychiatrie d'Adultes, Hôpitaux Universitaires de Strasbourg, France.
RATIONALE: Lorazepam has been repeatedly shown to impair both explicit memory and perceptual priming, a form of implicit memory, in the visual domain. However, the effects of this benzodiazepine on priming in other perceptual domains, such as auditory priming, have never been explored. OBJECTIVE: The present study investigated whether the deleterious effects of lorazepam on perceptual priming are restricted to the visual domain, or if they could be extended to the auditory domain. METHODS: Thirty-two healthy volunteers were randomly assigned to two parallel groups, placebo and lorazepam 0.038 mg/kg. The drug was administered orally, following a double-blind procedure. In the same subjects, perceptual priming was assessed in the auditory and visual domains using similar word-stem completion tasks, and explicit memory was explored using a free-recall task. RESULTS: Lorazepam markedly reduced free-recall performance for visually and auditorily presented words. Lorazepam equally impaired visual and auditory priming. In the auditory word-stem completion task, prior presentation of a word facilitated perception of its stem in the placebo group. This facilitation effect was not observed in the lorazepam group. The lorazepam-induced impairment of priming was not due to sedation or explicit contamination. CONCLUSION: These results indicate that the deleterious effects of lorazepam on priming are not restricted to the visual modality, but extend to the auditory modality.
PMID: 10639684 [PubMed - indexed for MEDLINE]
--------------------------------------------------6: Psychopharmacology (Berl). 2001 May;155(2):204-9.Click here to read Links
Lorazepam and diazepam impair true, but not false, recognition in healthy volunteers.
Huron C, Servais C, Danion JM.CNRS UMR 7593, Personnalités et Conduites Adaptatives, Hĵpital de la Pitié-Salpétrière, Paris, France.
RATIONALE: The deleterious effects of benzodiazepine on memory are well documented. However, their effects on false memories are unknown. OBJECTIVE: The aim of this study was to investigate the effects of lorazepam and diazepam on false memories and related states of awareness in healthy volunteers. METHODS: The Deese/Roediger-McDermott procedure was used in 36 healthy volunteers randomly assigned to one of three parallel groups (placebo, diazepam 0.3 mg/kg, lorazepam 0.038 mg/kg). Subjects studied lists of words semantically related to a non-presented theme word (critical lure). On a recognition memory task with both previously presented words and non presented critical lures, they were asked to give Remember, Know or Guess responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. RESULTS: The proportions of studied words correctly recognized and the proportions of Remember responses associated with true recognition were lower in the benzodiazepine groups than in the placebo group. In contrast, benzodiazepines did not significantly influence the proportions of critical lures falsely recognized or the proportions of Remember responses associated with false recognition. CONCLUSION: These results indicate that diazepam and lorazepam impair conscious recollection associated with true, but not false, memories.
PMID: 11401011 [PubMed - indexed for MEDLINE]
--------------------------------------------------7: Int Clin Psychopharmacol. 2002 Jan;17(1):19-26.Click here to read Links
Lorazepam, sedation, and conscious recollection: a dose-response study with healthy volunteers.
Huron C, Giersch A, Danion JM.Department of Psychology, Yale University, New Haven, CT, USA.
The role of sedation in the benzodiazepine-induced impairment of conscious recollection is still subject to debate. The aim of this study was to investigate further the role of sedation using the Remember-Know procedure and a physiological measure of sedation based on pupillography in addition to standard measures of sedation and attention (digit-symbol substitution task, symbol cancellation task, self-rated sedation). Twelve subjects were tested after the intake of placebo, lorazepam 0.026 mg/kg and lorazepam 0.038 mg/kg, administered in a randomized order, with a minimum interval of 8 days between each administration. On a recognition memory task, they were asked to give 'Remember', 'Know' or 'Guess' responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. Lorazepam selectively impaired recognition based on 'Remember' responses. This impairment was greater in the lorazepam 0.038 mg/kg than in the lorazepam 0.026 mg/kg groups. Measures of sedation were not correlated with the proportion of 'Remember' responses. These results suggest that sedation alone cannot account for the impairment of conscious recollection induced by lorazepam.
PMID: 11800502 [PubMed - indexed for MEDLINE]
--------------------------------------------------8: Clin Neuropharmacol. 2001 Mar-Apr;24(2):71-81.Click here to read Links
Pharmacokinetic and pharmacodynamic analysis of sedative and amnesic effects of lorazepam in healthy volunteers.
Blin O, Simon N, Jouve E, Habib M, Gayraud D, Durand A, Bruguerolle B, Pisano P.Fédération de Pharmacologie Médicale et Clinique et Pharmacocinétique, CHU Timone, Marseille, France.
This study describes for the first time the pharmacokinetic and pharmacodynamic modeling of the psychomotor and amnesic effects of a single 2-mg oral dose of lorazepam in healthy volunteers. Twelve healthy volunteers were included in this randomized, double-blinded, placebo-controlled two-way crossover study. The effect of lorazepam was examined for a battery of tests that explored mood, vigilance, psychomotor performance, and memory. The pharmacokinetic and pharmacodynamic modeling of these tests was performed using the indirect response model. Vigilance and psychomotor performance were significantly impaired. Short-term memory was not affected, but a paradoxical tendency to improvement of the score was observed 0.4 hours after drug intake. Significant impairment was observed for immediate and delayed cued verbal recall, for immediate and delayed free recall, and for picture recognition as well as for visual-verbal recall, but not for cued visual-spatial recall or priming. Globally, the different effects were greatest between 0.4 to 3 hours after dosing. However, the time course profile of the recovery period suggests a possible dissociation between the kinetics of the effects of lorazepam on vigilance, psychomotor performance, and visual episodic memory, on the one hand, and on verbal episodic memory, on the other. The pharmacokinetic and pharmacodynamic model used two compartments with first-order absorption to describe the lorazepam concentrations and an indirect response model with inhibition or stimulation of Kin to describe the effects. The mean values for calculated median effective concentration (EC50) derived from the pharmacokinetic and pharmacodynamic modeling of the different tests ranged from 11.3 to 39.8 ng/mL. According to these EC50 values, lorazepam seemed to be more potent on the delayed-recall trials than on the immediate-recall trials; similar observations were made concerning the free-recall versus cued-recall trials. The previously stated results suggest that the tests performed in this study represent sensitive measurements of the effects of lorazepam on the central nervous system. Moreover, the parameter values derived from pharmacokinetic and pharmacodynamic modeling, especially, the EC50 values, may provide sensitive indices that can be used to compare the central nervous system effects of benzodiazepines.
PMID: 11307041 [PubMed - indexed for MEDLINE]
--------------------------------------------------This is an example of how benzodiazepine GABA-A ligands can be improved to produce fewer amnesic effects:
9: Fundam Clin Pharmacol. 2001 Jun;15(3):209-16.Click here to read Links
Erratum in:
Fundam Clin Pharmacol. 2003 Oct;17(5):643.A double blind parallel group placebo controlled comparison of sedative and mnesic effects of etifoxine and lorazepam in healthy subjects [corrected].
Micallef J, Soubrouillard C, Guet F, Le Guern ME, Alquier C, Bruguerolle B, Blin O.Centre de Pharmacologie Clinique et d'Evaluations Thérapeutiques et Service de Pharmacologie Clinique, UMR-CNRS-FRE-Université de la Méditerranée, Développement et Pathologie du Mouvement, Hôpital de la Timone, 13385 Marseille cedex 5, France.
This paper describes the psychomotor and mnesic effects of single oral doses of etifoxine (50 and 100 mg) and lorazepam (2 mg) in healthy subjects. Forty-eight healthy subjects were included in this randomized double blind, placebo controlled parallel group study [corrected]. The effects of drugs were assessed by using a battery of subjective and objective tests that explored mood and vigilance (Visual Analog Scale), attention (Barrage test), psychomotor performance (Choice Reaction Time) and memory (digit span, immediate and delayed free recall of a word list). Whereas vigilance, psychomotor performance and free recall were significantly impaired by lorazepam, neither dosage of etifoxine (50 and 100 mg) produced such effects. These results suggest that 50 and 100 mg single dose of etifoxine do not induce amnesia and sedation as compared to lorazepam.
PMID: 11468032 [PubMed - indexed for MEDLIN
--------------------------------------------------10: Br J Clin Pharmacol. 1999 Oct;48(4):510-2.Click here to read Links
Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers.
Blin O, Jacquet A, Callamand S, Jouve E, Habib M, Gayraud D, Durand A, Bruguerolle B, Pisano P.Fédération de Pharmacologie Médicale et Clinique et Pharmacocinétique, Marseille, France.
AIMS: To describe the pharmacokinetic-pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers. METHODS: This was a randomized double-blind, placebo-controlled two-way cross-over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures. RESULTS: The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks. CONCLUSIONS: The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines.
PMID: 10583020 [PubMed - indexed for MEDLINE]
__________________________________________________More later.
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poster:Quintal
thread:774284
URL: http://www.dr-bob.org/babble/20070808/msgs/775023.html