J Clin Psychiatry. 2002 Nov;63(11):1020-7
Efficacy and safety of hydroxyzine in the treatment of generalized
anxiety disorder: a 3-month double-blind study.
Llorca PM, Spadone C, Sol O, Danniau A, Bougerol T, Corruble E, Faruch
M, Macher JP, Sermet E, Servant D.
Hopital Gabriel Montpied, Clermont-Ferrand, France.
BACKGROUND: The prevalence of generalized anxiety disorder (Generalized Anxiety Disorder (GAD))
represents an important public health issue. Hydroxyzine, an
antagonist of histamine receptors, showed both efficacy and safety in
previous short-term double-blind studies over placebo in this
pathology. The aim of the current study was to confirm those positive
results over a 3-month period in adult outpatients.
METHOD: This multicenter, parallel (hydroxyzine [50 mg/day];
bromazepam [6 mg/day]), randomized, double-blind, placebo-controlled
trial included 2 weeks of single-blind run-in placebo, 12 weeks of
double-blind randomized treatment, and 4 weeks of single-blind run-out
placebo. Three hundred thirty-four of 369 selected outpatients with a
diagnosis of Generalized Anxiety Disorder (GAD) according to DSM-IV criteria and a Hamilton Rating
Scale for Anxiety (HAM-A) total score >/= 20 were randomized before
entering the double-blind period. The primary outcome criterion was
the change in the HAM-A score from baseline to 12 weeks of
double-blind treatment with hydroxyzine compared with placebo.
RESULTS: In the intent-to-treat analysis, the mean +/- SD change in
HAM-A scores from baseline to endpoint was -12.16 +/- 7.74 for
hydroxyzine and -9.64 +/- 7.74 for placebo (p =.019). Results at
endpoint for percentage of responders (p =.003) and remission rates (p
=.028), Clinical Global Impressions-Severity scale score (p =.001),
maintenance of efficacy (p =.022), and Hospital Anxiety and Depression
scale score on day 84 (p =.008) also confirmed the efficacy of
hydroxyzine over placebo. The study showed no statistically
significant difference between hydroxyzine and bromazepam. Except for
drowsiness, which was more frequent with bromazepam, safety results
were comparable in the 3 groups.
CONCLUSION: Hydroxyzine showed both efficacy and safety in the
treatment of Generalized Anxiety Disorder (GAD) and appears to be an effective alternative treatment
to benzodiazepine prescription.
Hydroxyzine (Atarax, Vistaril) versus Benzodiazepines
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Hydroxyzine (Atarax, Vistaril) versus Benzodiazepines
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Acta Psychiatr Scand Suppl. 1998;393:102-8.
Recent clinical trials of hydroxyzine in generalized anxiety disorder.
Ferreri M, Hantouche EG. Hospital St Antoine, Paris, France.
Numerous clinical trials in the 1960s and 1970s have attested to the anxiolytic efficacy of hydroxyzine and its beneficial effect on sleep, as well as in reducing stress and anxiety associated with coronary disease. Experience with hydroxyzine has also shown a lack of organ toxicity and an absence of dependency. Recent controlled clinical trials with hydroxyzine have confirmed its efficacy (at a fixed dose of 50 mg) in generalized anxiety disorder--superiority over placebo on all anxiety measures from the first week with early target symptoms which are grouped in a cognitive component of anxiety. Efficacy was maintained throughout the 4 weeks of treatment and after abrupt discontinuation. In another controlled trial vs. lorazepam, hydroxyzine demonstrated greater and more rapid cognitive improvement.
Recent clinical trials of hydroxyzine in generalized anxiety disorder.
Ferreri M, Hantouche EG. Hospital St Antoine, Paris, France.
Numerous clinical trials in the 1960s and 1970s have attested to the anxiolytic efficacy of hydroxyzine and its beneficial effect on sleep, as well as in reducing stress and anxiety associated with coronary disease. Experience with hydroxyzine has also shown a lack of organ toxicity and an absence of dependency. Recent controlled clinical trials with hydroxyzine have confirmed its efficacy (at a fixed dose of 50 mg) in generalized anxiety disorder--superiority over placebo on all anxiety measures from the first week with early target symptoms which are grouped in a cognitive component of anxiety. Efficacy was maintained throughout the 4 weeks of treatment and after abrupt discontinuation. In another controlled trial vs. lorazepam, hydroxyzine demonstrated greater and more rapid cognitive improvement.
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I emailed these abstracts to a friend of mine (a British MD), and he sent me this interesting reply.
----------
Subj: Re: Non-addictive Alternative to Benzodiazepines
Date: 6/8/2005 4:19:25 PM Eastern Daylight Time
From: Name Suppressed
To: [email protected]
Sent from the Internet (Details)
Interesting. Have you read the original article? I'm going to be harsh, but that's my job when I read articles. Here are comments simply on the abstract.
3 months seems a very short period to assess follow-up. I would not be surprised if these patients were followed for longer that the effect would wear off. All anxiolytics are only licensed by the FDA in the US and its equivalent in the UK for short term use only. The reason is that no one has shown their benefits are sustained in the longer term.
Note a significant reduction in the placebo group which is about 75% of the reduction in the HAM-A compared with the treatment group. Was there a power calculation? Was the study correctly powered to demonstrate that this reduction in HAM-A is actually significant? Another way of asking the same question is to ask what the type B error p value was. This asks whether the reduction could have occured just be chance because the study was not large enough.
Also note that the standard error of 7.74 in both groups is very large and suggests that there was extensive variation in the HAM-A scores in both groups. Again this could invalidate the statistics used as the populations might not be Normal distribution.
What's missing from the abstracts includes whether the authors have a conflict of interest such as sponsorship from drug companies. How was the randomisation done and was it definitely blinded from the investigators? And there are many other points that can lead to a misleading study. Of course in a 250 word abstract one cannot cover them all so to be thorough we really have to read the actual article.
There is a distinct danger that some abstracts listed on medline are for studies that are actually poorly conducted. Medline needs to keep them there since people frequently refer to them and most people working in the field will be aware when an article has subsequently been discredited. This happened notoriously to the MMR autism article published in the Lancet no less as well as large study of stem cell transplantation in breast cancer run by an Italian professor who was shown to have conducted widespread scientific fraud and had falsified data. Interestingly it took a large study funded by American insurers to prove that this breast cancer study was false.
The major problem with benzodiazepines, hydroxyzine and pretty much all drugs for anxiety except SSRIs and SNRIs is the drowsiness. This sounds a pretty inoccuous side effect but can be severe enough to mean that driving is dangerous. That's why the inserts with the tablets always say people should not drive or operate machinery while on the drugs. It's not widely known that benzodiazepines impair perception, memory and conscious level meaning that while people are on benzodiazepines they may be less aware of their actions and less able to realise that the drug is impairing motor coordination. The same is true of alcohol that when people are really drunk they often think they are quite capable of driving etc. Judgement as to whether they are "ok" is often frequently blunted. These drugs impair pretty much all aspects of cognition including concentration, attention and memory recall.
Another side effect often not mentioned is that benzodiazepines impair REM sleep.
Anyway I digress but I hope this provides some food for thought. I am a little sceptical of proving anything just through abstracts on medline. Unfortunately my library subscriptions do not allow me access from home to either article so I can't read them or forward them to you, but if you find any other interesting abstracts do let me know and I'll see if I have time to read them.
----------
Subj: Re: Non-addictive Alternative to Benzodiazepines
Date: 6/8/2005 4:19:25 PM Eastern Daylight Time
From: Name Suppressed
To: [email protected]
Sent from the Internet (Details)
Interesting. Have you read the original article? I'm going to be harsh, but that's my job when I read articles. Here are comments simply on the abstract.
[email protected] wrote:Of course, hydroxyzine, like every drug, has its side effects, but...
J Clin Psychiatry. 2002 Nov;63(11):1020-7.
Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study.
Llorca PM, Spadone C, Sol O, Danniau A, Bougerol T, Corruble E, Faruch M, Macher JP, Sermet E, Servant D.
Hopital Gabriel Montpied, Clermont-Ferrand, France.
BACKGROUND: The prevalence of generalized anxiety disorder (Generalized Anxiety Disorder (GAD)) represents an important public health issue. Hydroxyzine, an antagonist of histamine receptors, showed both efficacy and safety in previous short-term double-blind studies over placebo in this pathology. The aim of the current study was to confirm those positive results over a 3-month period in adult outpatients.
3 months seems a very short period to assess follow-up. I would not be surprised if these patients were followed for longer that the effect would wear off. All anxiolytics are only licensed by the FDA in the US and its equivalent in the UK for short term use only. The reason is that no one has shown their benefits are sustained in the longer term.
Is this a meaningful clinical endpoint? I'm not familiar with the HAM-A score and therefore do not know if it is fully validated and widely accepted by professionals as an appropriate score. But a reduction of 12 in the HAM-A score compared with 9 in the placebo group might not really be clinically noticeable to the patients themselves. It could be too subtle a decrease to be useful.METHOD: This multicenter, parallel (hydroxyzine [50 mg/day]; bromazepam [6 mg/day]), randomized, double-blind, placebo-controlled trial included 2 weeks of single-blind run-in placebo, 12 weeks of double-blind randomized treatment, and 4 weeks of single-blind run-out placebo. Three hundred thirty-four of 369 selected outpatients with a diagnosis of Generalized Anxiety Disorder (GAD) according to DSM-IV criteria and a Hamilton Rating Scale for Anxiety (HAM-A) total score >/= 20 were randomized before entering the double-blind period. The primary outcome criterion was the change in the HAM-A score from baseline to 12 weeks of double-blind treatment with hydroxyzine compared with placebo. RESULTS: In the intent-to-treat analysis, the mean +/- SD change in HAM-A scores from baseline to endpoint was -12.16 +/- 7.74 for hydroxyzine and -9.64 +/- 7.74 for placebo (p =.019).
Note a significant reduction in the placebo group which is about 75% of the reduction in the HAM-A compared with the treatment group. Was there a power calculation? Was the study correctly powered to demonstrate that this reduction in HAM-A is actually significant? Another way of asking the same question is to ask what the type B error p value was. This asks whether the reduction could have occured just be chance because the study was not large enough.
Also note that the standard error of 7.74 in both groups is very large and suggests that there was extensive variation in the HAM-A scores in both groups. Again this could invalidate the statistics used as the populations might not be Normal distribution.
Results at endpoint for percentage of responders (p =.003) and remission rates (p =.028), Clinical Global Impressions-Severity scale score (p =.001), maintenance of efficacy (p =.022), and Hospital Anxiety and Depression scale score on day 84 (p =.008) also confirmed the efficacy of hydroxyzine over placebo. The study showed no statistically significant difference between hydroxyzine and bromazepam. Except for drowsiness, which was more frequent with bromazepam, safety results were comparable in the 3 groups. CONCLUSION: Hydroxyzine showed both efficacy and safety in the treatment of Generalized Anxiety Disorder (GAD) and appears to be an effective alternative treatment to benzodiazepine prescription.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 12444816 [PubMed - indexed for MEDLINE]
What's interesting here is they reiterate the use of these drugs in the short term only. Note that in the first trial the participants were only on the drugs for 12 weeks and it was then abruptly stopped (or actually switched over to placebo). It's very difficult to comment further on review articles as they only summarise trials and therefore one must really go back to the original trials to review them with a critical mind.Psychiatr Scand Suppl. 1998;393:102-8.
Recent clinical trials of hydroxyzine in generalized anxiety disorder.
Ferreri M, Hantouche EG.
Hopital St Antoine, Paris, France.
Numerous clinical trials in the 1960s and 1970s have attested to the anxiolytic efficacy of hydroxyzine and its beneficial effect on sleep, as well as in reducing stress and anxiety associated with coronary disease. Experience with hydroxyzine has also shown a lack of organ toxicity and an absence of dependency. Recent controlled clinical trials with hydroxyzine have confirmed its efficacy (at a fixed dose of 50 mg) in generalized anxiety disorder--superiority over placebo on all anxiety measures from the first week with early target symptoms which are grouped in a cognitive component of anxiety. Efficacy was maintained throughout the 4 weeks of treatment and after abrupt discontinuation. In another controlled trial vs. lorazepam, hydroxyzine demonstrated greater and more rapid cognitive improvement.
Publication Types:
Review
Review, Tutorial
PMID: 9777055 [PubMed - indexed for MEDLINE
What's missing from the abstracts includes whether the authors have a conflict of interest such as sponsorship from drug companies. How was the randomisation done and was it definitely blinded from the investigators? And there are many other points that can lead to a misleading study. Of course in a 250 word abstract one cannot cover them all so to be thorough we really have to read the actual article.
There is a distinct danger that some abstracts listed on medline are for studies that are actually poorly conducted. Medline needs to keep them there since people frequently refer to them and most people working in the field will be aware when an article has subsequently been discredited. This happened notoriously to the MMR autism article published in the Lancet no less as well as large study of stem cell transplantation in breast cancer run by an Italian professor who was shown to have conducted widespread scientific fraud and had falsified data. Interestingly it took a large study funded by American insurers to prove that this breast cancer study was false.
The major problem with benzodiazepines, hydroxyzine and pretty much all drugs for anxiety except SSRIs and SNRIs is the drowsiness. This sounds a pretty inoccuous side effect but can be severe enough to mean that driving is dangerous. That's why the inserts with the tablets always say people should not drive or operate machinery while on the drugs. It's not widely known that benzodiazepines impair perception, memory and conscious level meaning that while people are on benzodiazepines they may be less aware of their actions and less able to realise that the drug is impairing motor coordination. The same is true of alcohol that when people are really drunk they often think they are quite capable of driving etc. Judgement as to whether they are "ok" is often frequently blunted. These drugs impair pretty much all aspects of cognition including concentration, attention and memory recall.
Another side effect often not mentioned is that benzodiazepines impair REM sleep.
Anyway I digress but I hope this provides some food for thought. I am a little sceptical of proving anything just through abstracts on medline. Unfortunately my library subscriptions do not allow me access from home to either article so I can't read them or forward them to you, but if you find any other interesting abstracts do let me know and I'll see if I have time to read them.
This is not medical advice. Please consult your physician.