Benzodiazepines
Treatment for Panic Disorders
Why Benzodiazepines?
• There is a great deal of
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research and a great
deal of controversy
Benzodiazepine is a class
of anxiolytic compounds
that can be subdivided
into groups based on
their halflife and potency
Includes Xanax and
Valium
History
• The discovery of Chlordiazepoxide as Valium was
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made by Leo Sternback in Poland during the
1940s
Benzodiazepines were introduced to the general
public in the early 1960s as tranquilizers. They
were touted as something slightly less than a
miracle drug.
In the 1970s there was a strong public outcry
because of its side effects and their use dropped
by 25%.
History
• In 1985, 81 million prescriptions were filled in the US for
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a total of 1.5 billion dollars spent (Michelson 1991)
Despite its shortcomings and controversial notoriety it is
still the most widely used anxiolytic compound today.
(Gonzalea-Pardo 2006)
15% of the population has reported using this
medication with a third of these reporting dependence
on the tranquilizer.
Approximately 2 % (3 million) of the population reports
having taken the drug on a daily basis for over a year
History
• The majority of works published today
regarding the use of benzodiazepines have
to do with how to treat the dependency
on the medication, and to a lesser extent,
how it compares with talk therapies.
Alprazolam in Panic Disorder and
Agoraphobia:
Results from a Multicentre trial
James Ballenger
• Most articles cite this particular research
article as their base of information.
• The article was published in 1988 by a
team of 8 doctors and researchers
working across North America and
Australia.
Study 1
• 526 participants began the 8 week ,
parallel-groups, double blind, placebocontrolled, flexible dose randomized study
• The goal was to provide an empirical base
on which other work could be founded.
• The results gave Alprazolam widespread
acceptance equal to that of tricyclic
antidepressants and SSRIs
Study 1
• Participants were administered an
increasing dose of Alprazolam that
reached 6mg/d and would not exceed a
dose of 10mg/d
• This dose was shown to produce the most
effective results
• Doses of 2-3mg/d were sufficient to effect
some change in condition
Study 1
• The parameters of the study strictly
prohibited behavioral treatments during
the 8 week period
• But since 63% of participants had
previously received psychiatric treatment,
a substantial number of individuals began
the study with some type of anxiolytic
medication in their system
Results
Study 1 Limitations
• A limitation to the study was that a
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disproportionately large number of participants
in the placebo group dropped out
The results seem to indicate only a small effect,
The individuals who did quit the study cited a
lack of change as their motivation
If all those who began had completed the study,
the results would have been more distinct.
Diazepam Versus Alprazolam for
the Treatment of Panic Disorders
• This study was conducted in 1995 by a
team of 8 researchers, some of whom had
worked on the previous study
• Intends to compare Diazepam, a high
halflife, less potent benzodiazepine with
Alprazolam to validate the use of
Diazepam as an anxiolytic compound
Study 2
• The study examined the effects of both
medications and placebos on 241
individuals who met the criteria for panic
disorders
• It lasted 8 weeks and was a parallelgroup, double blind, placebo controlled
randomized assignment study
Study 2
• Found effects similar to those in study 1 but
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the researchers addressed some of the
limitations of the first study:
They restricted patient use of other
medications
Permitted for a week long wash out period
Had a more stringent screening process to
eliminate comorbidity
Based their dose on studies testing for the
optimum dose
Study 2
• It establishes Diazepam as a formidable
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treatment alternative, equally as effective as
Alprazolam
Limitation:
-Despite their efforts, the dropout rate in the
placebo group was equally problematic as in the
first study.
Some studies have reported attrition rates of up
to 40%
How Benzodiazepines work
• These minor tranquilizers exert their effect
by activating the inhibitory GABA
receptors found throughout the nervous
system.
• They are an effective treatment for
generalized panic disorders and have the
ability to reduce the frequency of panic
attacks
• Tranquilizers have a receptor site
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on the GABA mediated ion
channels
When a molecule binds to the
channel, Chlorine ions are
permitted to enter creating a
hyperpolarization of the
membrane
Alcohol and barbiturates act
similarly and so produce effects
similar to those of tranquilizers.
It is because of this morphology
that mixing alcohol with the
medication can result in an
overdose.
How Benzodiazepines work
• Anxiety and panic disorders supposedly
result from a lack of GABA
neurotransmitters in the CNS, the limbic
system and the occipital lobes.
• Increasing the general GABA activity in the
brain relieves the anxiety
• There are three types of GABA gated
channels: Subtype A, B and C
GABA subtype A receptor complex
• Most relevant to the treatment of panic disorders
• Of the four GABA-sensitive receptor sites, the three ‘a’
sites are also sensitive to benzodiazepine
How Benzodiazepines work
• They work almost immediately, unlike the
SSRIs which may require an extended
period of time before their effects are
appreciated
• There is a high compliance rate with, and
high tolerance for this therapy, unlike SSRI
therapies
• Very few patients are dissatisfied or do not
respond to the medication
Where’s the Problem?
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The major pitfall of this therapy is that, since it works
indiscriminately on all GABA receptors by increasing
their activity, there are numerous side effects:
Drowsiness
Memory impairment
Sedation
Dizziness
Shock related to drastic changes in dosage
There is an elevated risk of coma or death if the
medication is taken with other tranquilizers
Side effects in humans
Drowsiness
Lightheadedness
Dry mouth
Depression
Nausea, vomiting
Insomnia
Confusion
Palpitations
Nasal congestion
Blurred vision
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Side effects in animal models
• Research done on rats has found that the
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prolonged exposure to the medication can
cause:
Decreased birth weight by 7%
Decreased litter size by 10%
Decreased adult weight
Increased liver and kidney size by 30 and 14%
respectively
Decreased prostate weight by 10%
Dependence
• A large number of those taking the drug become
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dependent after prolonged exposure
With certain types of medication requiring
multiple daily administration, withdrawal can
become problematic as the effect of the
medication wares off
Much work has been done to examine the types
of medication that can alleviate the symptoms of
withdrawal
Withdrawal
• The main effect of withdrawal is serious rebound
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of anxious symptoms.
When the therapy is abruptly discontinued,
because the brain has developed dependency,
there is a net decrease of active GABA receptors
and a return of anxious feelings
Treatments for withdrawal have concentrated on
increasing the number of inhibitory receptors
and increasing GABA production without running
the risk of inducing seizures (a rarely but
reported side effect of tranquilizer antagonists)
Dosage
• The risks related to dependence and withdrawal
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make dose regulation very important
Typically the dose will begin very low and will,
over the course of a few weeks, increase to a level
where overdose symptoms begin to appear.
The dose is subsequently reduced
Most research suggests that the effects are
maximal at highest doses.
But beneficial effects have been observed at low
dose administration.
Tolerance is developed to a certain extent but it
does not become problematic
Alternatives
• Because of the vicious side effects,
alternatives have been sought
• Promising results come from medications
already used for the treatment of seizures
• These anticonvulsants work as well at the
GABA gated channels but work only to
increase GABA levels and do not work as
agonists
Selective GABAergic Treatment for
Panic
• This stud was conducted to evaluate and
review the effectiveness of the
anticonvulsants
• Vigabatrin and Tiagabine work solely at
the synaptic clef to increase GABA levels
• In doing so it reduces the side effects
associated with other tranquilizers.
Study 3
• Anticonvulsants as an
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alternative
Work by preventing
degradation and
reuptake
Tiagabine (TGB)
inhibits reuptake
Vigabatrin (VGB)
inhibits degradation
Study 3
• Though it is a review article, it presents
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specific points that boost our confidence
in anticonvulsant therapies
I believe that therapy with antiepileptic
medication is the future:
Benefits of benzodiazepines
Few of the side effects
Apparently no dependency
Evaluation
• Remarkable treatment both in its
effectiveness and addictive potency:
- Works to reduce the symptoms of panic
and anxiety relatively rapidly
- Is tolerated by most patients
- But creates dependency and must be
taken with care on a daily basis
Evaluation
• Prolonged use is problematic and so must
be used in conjunction with other
psychotherapies or pharmacotherapies
• Yet some psychotherapists have refused to
treat individuals taking the medications
because of fears related to the
overpowering effects of withdrawal
Evaluation
• A major concern is that individuals present
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themselves with symptoms of anxiety yet do not
disclose a history of alcohol abuse. This results
in the prescription for a tranquilizer to treat the
anxiety
Almost half of the cases of anxiety reported to
the Royal College of Physicians are related to
alcohol or benzodiazepine abuse.
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Further research
• Because most of the benzodiazepines work
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indiscriminately on all GABA gated channels it
make sense to develop a compound with an
affinity to act solely on GABA subtype A
transmitters
The development of a compound that does
accumulate in the body and that does not
metabolize as rapidly would reduce the severity
of withdrawal symptoms and would reduce the
frequency of administration