Benzodiazepines Benzodiazepines

Treatment for Panic DisordersTreatment for Panic Disorders

Why Benzodiazepines?Why Benzodiazepines?

• There is a great deal of There is a great deal of research and a great research and a great deal of controversy deal of controversy

• Benzodiazepine is a Benzodiazepine is a class of anxiolytic class of anxiolytic compounds that can compounds that can be subdivided into be subdivided into groups based on their groups based on their halflife and potencyhalflife and potency

• Includes Xanax and Includes Xanax and ValiumValium

HistoryHistory

• The discovery of Chlordiazepoxide as The discovery of Chlordiazepoxide as Valium was made by Leo Sternback in Valium was made by Leo Sternback in Poland during the 1940s Poland during the 1940s

• Benzodiazepines were introduced to the Benzodiazepines were introduced to the general public in the early 1960s as general public in the early 1960s as tranquilizers. They were touted as tranquilizers. They were touted as something slightly less than a miracle drug.something slightly less than a miracle drug.

• In the 1970s there was a strong public In the 1970s there was a strong public outcry because of its side effects and their outcry because of its side effects and their use dropped by 25%. use dropped by 25%.

HistoryHistory

• In 1985, 81 million prescriptions were filled in the In 1985, 81 million prescriptions were filled in the US for a total of 1.5 billion dollars spent US for a total of 1.5 billion dollars spent (Michelson 1991)(Michelson 1991)

• Despite its shortcomings and controversial Despite its shortcomings and controversial notoriety it is still the most widely used anxiolytic notoriety it is still the most widely used anxiolytic compound today. (Gonzalea-Pardo 2006)compound today. (Gonzalea-Pardo 2006)

• 15% of the population has reported using this 15% of the population has reported using this medication with a third of these reporting medication with a third of these reporting dependence on the tranquilizer.dependence on the tranquilizer.

• Approximately 2 % (3 million) of the population Approximately 2 % (3 million) of the population reports having taken the drug on a daily basis for reports having taken the drug on a daily basis for over a yearover a year

HistoryHistory

• The majority of works published The majority of works published today regarding the use of today regarding the use of benzodiazepines have to do with how benzodiazepines have to do with how to treat the dependency on the to treat the dependency on the medication, and to a lesser extent, medication, and to a lesser extent, how it compares with talk therapies. how it compares with talk therapies.

Alprazolam in Panic Disorder and Alprazolam in Panic Disorder and Agoraphobia: Agoraphobia: Results from a Multicentre trialResults from a Multicentre trialJames BallengerJames Ballenger

• Most articles cite this particular Most articles cite this particular research article as their base of research article as their base of information.information.

• The article was published in 1988 by a The article was published in 1988 by a team of 8 doctors and researchers team of 8 doctors and researchers working across North America and working across North America and Australia.Australia.

Study 1Study 1

• 526 participants began the 8 week , 526 participants began the 8 week , parallel-groups, double blind, placebo- parallel-groups, double blind, placebo- controlled, flexible dose randomized controlled, flexible dose randomized studystudy

• The goal was to provide an empirical The goal was to provide an empirical base on which other work could be base on which other work could be founded. founded.

• The results gave Alprazolam widespread The results gave Alprazolam widespread acceptance equal to that of tricyclic acceptance equal to that of tricyclic antidepressants and SSRIsantidepressants and SSRIs

Study 1Study 1

• Participants were administered an Participants were administered an increasing dose of Alprazolam that increasing dose of Alprazolam that reached 6mg/d and would not reached 6mg/d and would not exceed a dose of 10mg/dexceed a dose of 10mg/d

• This dose was shown to produce the This dose was shown to produce the most effective resultsmost effective results

• Doses of 2-3mg/d were sufficient to Doses of 2-3mg/d were sufficient to effect some change in conditioneffect some change in condition

Study 1Study 1

• The parameters of the study strictly The parameters of the study strictly prohibited behavioral treatments during prohibited behavioral treatments during the 8 week periodthe 8 week period

• But since 63% of participants had But since 63% of participants had previously received psychiatric previously received psychiatric treatment, a substantial number of treatment, a substantial number of individuals began the study with some individuals began the study with some type of anxiolytic medication in their type of anxiolytic medication in their systemsystem

ResultsResults

Study 1 LimitationsStudy 1 Limitations

• A limitation to the study was that a A limitation to the study was that a disproportionately large number of participants disproportionately large number of participants in the placebo group dropped outin the placebo group dropped out

• The results seem to indicate only a small The results seem to indicate only a small effect, effect,

• The individuals who did quit the study cited a The individuals who did quit the study cited a lack of change as their motivationlack of change as their motivation

• If all those who began had completed the If all those who began had completed the study, the results would have been more study, the results would have been more distinct. distinct.

Diazepam Versus Alprazolam Diazepam Versus Alprazolam for the Treatment of Panic for the Treatment of Panic DisordersDisorders• This study was conducted in 1995 by a This study was conducted in 1995 by a

team of 8 researchers, some of whom team of 8 researchers, some of whom had worked on the previous studyhad worked on the previous study

• Intends to compare Diazepam, a high Intends to compare Diazepam, a high halflife, less potent benzodiazepine halflife, less potent benzodiazepine with Alprazolam to validate the use of with Alprazolam to validate the use of Diazepam as an anxiolytic compoundDiazepam as an anxiolytic compound

Study 2Study 2

• The study examined the effects of The study examined the effects of both medications and placebos on both medications and placebos on 241 individuals who met the criteria 241 individuals who met the criteria for panic disorders for panic disorders

• It lasted 8 weeks and was a parallel-It lasted 8 weeks and was a parallel-group, double blind, placebo group, double blind, placebo controlled randomized assignment controlled randomized assignment study study

Study 2Study 2

• Found effects similar to those in study 1 Found effects similar to those in study 1 but the researchers addressed some of but the researchers addressed some of the limitations of the first study: the limitations of the first study:

1.1. They restricted patient use of other They restricted patient use of other medicationsmedications

2.2. Permitted for a week long wash out Permitted for a week long wash out periodperiod

3.3. Had a more stringent screening process Had a more stringent screening process to eliminate comorbidityto eliminate comorbidity

4.4. Based their dose on studies testing for Based their dose on studies testing for the optimum dosethe optimum dose

Study 2Study 2• It establishes Diazepam as a formidable It establishes Diazepam as a formidable

treatment alternative, equally as effective treatment alternative, equally as effective as Alprazolamas Alprazolam

• Limitation: Limitation: -Despite their efforts, the dropout rate in -Despite their efforts, the dropout rate in the placebo group was equally problematic the placebo group was equally problematic as in the first study. as in the first study.

• Some studies have reported attrition rates Some studies have reported attrition rates of up to 40%of up to 40%

How Benzodiazepines workHow Benzodiazepines work

• These minor tranquilizers exert their These minor tranquilizers exert their effect by activating the inhibitory effect by activating the inhibitory GABA receptors found throughout GABA receptors found throughout the nervous system. the nervous system.

• They are an effective treatment for They are an effective treatment for generalized panic disorders and have generalized panic disorders and have the ability to reduce the frequency of the ability to reduce the frequency of panic attacks panic attacks

• Tranquilizers have a receptor Tranquilizers have a receptor site on the GABA mediated site on the GABA mediated ion channelsion channels

• When a molecule binds to the When a molecule binds to the channel, Chlorine ions are channel, Chlorine ions are permitted to enter creating a permitted to enter creating a hyperpolarization of the hyperpolarization of the membranemembrane

• Alcohol and barbiturates act Alcohol and barbiturates act similarly and so produce similarly and so produce effects similar to those of effects similar to those of tranquilizers.tranquilizers.

• It is because of this It is because of this morphology that mixing morphology that mixing alcohol with the medication alcohol with the medication can result in an overdose.can result in an overdose.

How Benzodiazepines workHow Benzodiazepines work

• Anxiety and panic disorders Anxiety and panic disorders supposedly result from a lack of supposedly result from a lack of GABA neurotransmitters in the CNS, GABA neurotransmitters in the CNS, the limbic system and the occipital the limbic system and the occipital lobes.lobes.

• Increasing the general GABA activity Increasing the general GABA activity in the brain relieves the anxietyin the brain relieves the anxiety

• There are three types of GABA gated There are three types of GABA gated channels: Subtype A, B and Cchannels: Subtype A, B and C

GABA subtype A receptor GABA subtype A receptor complexcomplex• Most relevant to the treatment of panic disordersMost relevant to the treatment of panic disorders

• Of the four GABA-sensitive receptor sites, the Of the four GABA-sensitive receptor sites, the three ‘a’ sites are also sensitive to three ‘a’ sites are also sensitive to benzodiazepinebenzodiazepine

How Benzodiazepines workHow Benzodiazepines work

• They work almost immediately, They work almost immediately, unlike the SSRIs which may require unlike the SSRIs which may require an extended period of time before an extended period of time before their effects are appreciatedtheir effects are appreciated

• There is a high compliance rate with, There is a high compliance rate with, and high tolerance for this therapy, and high tolerance for this therapy, unlike SSRI therapiesunlike SSRI therapies

• Very few patients are dissatisfied or Very few patients are dissatisfied or do not respond to the medicationdo not respond to the medication

Where’s the Problem?Where’s the Problem?

• The major pitfall of this therapy is that, since it The major pitfall of this therapy is that, since it works indiscriminately on all GABA receptors by works indiscriminately on all GABA receptors by increasing their activity, there are numerous increasing their activity, there are numerous side effects:side effects:

1.1. DrowsinessDrowsiness2.2. Memory impairmentMemory impairment3.3. SedationSedation4.4. DizzinessDizziness5.5. Shock related to drastic changes in dosageShock related to drastic changes in dosage6.6. There is an elevated risk of coma or death if the There is an elevated risk of coma or death if the

medication is taken with other tranquilizersmedication is taken with other tranquilizers

Side effects in humansSide effects in humansDrowsinessDrowsiness 49.4 49.4

Lightheadedness Lightheadedness

24.0 24.0

Dry mouth Dry mouth 13.0 13.0

Depression Depression 17.0 17.0

Nausea, vomiting Nausea, vomiting 10.0 10.0

Insomnia Insomnia 6.7 6.7

Confusion Confusion 14.1 14.1

Palpitations Palpitations 7.2 7.2

Nasal congestion Nasal congestion 7.2 7.2

Blurred vision Blurred vision 9.1 9.1

Side effects in animal Side effects in animal modelsmodels• Research done on rats has found that the Research done on rats has found that the

prolonged exposure to the medication prolonged exposure to the medication can cause:can cause:

1.1. Decreased birth weight by 7%Decreased birth weight by 7%2.2. Decreased litter size by 10%Decreased litter size by 10%3.3. Decreased adult weightDecreased adult weight4.4. Increased liver and kidney size by 30 and Increased liver and kidney size by 30 and

14% respectively14% respectively5.5. Decreased prostate weight by 10%Decreased prostate weight by 10%

DependenceDependence

• A large number of those taking the drug A large number of those taking the drug become dependent after prolonged exposurebecome dependent after prolonged exposure

• With certain types of medication requiring With certain types of medication requiring multiple daily administration, withdrawal can multiple daily administration, withdrawal can become problematic as the effect of the become problematic as the effect of the medication wares offmedication wares off

• Much work has been done to examine the Much work has been done to examine the types of medication that can alleviate the types of medication that can alleviate the symptoms of withdrawalsymptoms of withdrawal

WithdrawalWithdrawal• The main effect of withdrawal is serious The main effect of withdrawal is serious

rebound of anxious symptoms.rebound of anxious symptoms.• When the therapy is abruptly discontinued, When the therapy is abruptly discontinued,

because the brain has developed because the brain has developed dependency, there is a net decrease of active dependency, there is a net decrease of active GABA receptors and a return of anxious GABA receptors and a return of anxious feelingsfeelings

• Treatments for withdrawal have concentrated Treatments for withdrawal have concentrated on increasing the number of inhibitory on increasing the number of inhibitory receptors and increasing GABA production receptors and increasing GABA production without running the risk of inducing seizures without running the risk of inducing seizures (a rarely but reported side effect of (a rarely but reported side effect of tranquilizer antagonists)tranquilizer antagonists)

DosageDosage• The risks related to dependence and withdrawal The risks related to dependence and withdrawal

make dose regulation very importantmake dose regulation very important• Typically the dose will begin very low and will, Typically the dose will begin very low and will,

over the course of a few weeks, increase to a over the course of a few weeks, increase to a level where overdose symptoms begin to level where overdose symptoms begin to appear. appear.

• The dose is subsequently reducedThe dose is subsequently reduced• Most research suggests that the effects are Most research suggests that the effects are

maximal at highest doses.maximal at highest doses.• But beneficial effects have been observed at But beneficial effects have been observed at

low dose administration.low dose administration.• Tolerance is developed to a certain extent but it Tolerance is developed to a certain extent but it

does not become problematicdoes not become problematic

AlternativesAlternatives

• Because of the vicious side effects, Because of the vicious side effects, alternatives have been soughtalternatives have been sought

• Promising results come from Promising results come from medications already used for the medications already used for the treatment of seizurestreatment of seizures

• These anticonvulsants work as well These anticonvulsants work as well at the GABA gated channels but work at the GABA gated channels but work only to increase GABA levels and do only to increase GABA levels and do not work as agonistsnot work as agonists

Selective GABAergic Treatment Selective GABAergic Treatment for Panicfor Panic

• This stud was conducted to evaluate This stud was conducted to evaluate and review the effectiveness of the and review the effectiveness of the anticonvulsantsanticonvulsants

• Vigabatrin and Tiagabine work solely Vigabatrin and Tiagabine work solely at the synaptic clef to increase GABA at the synaptic clef to increase GABA levelslevels

• In doing so it reduces the side effects In doing so it reduces the side effects associated with other tranquilizers. associated with other tranquilizers.

Study 3Study 3

• Anticonvulsants as Anticonvulsants as an alternativean alternative

• Work by preventing Work by preventing degradation and degradation and reuptakereuptake

• Tiagabine (TGB) Tiagabine (TGB) inhibits reuptakeinhibits reuptake

• Vigabatrin (VGB) Vigabatrin (VGB) inhibits inhibits degradationdegradation

Study 3Study 3

• Though it is a review article, it Though it is a review article, it presents specific points that boost our presents specific points that boost our confidence in anticonvulsant confidence in anticonvulsant therapiestherapies

• I believe that therapy with I believe that therapy with antiepileptic medication is the future:antiepileptic medication is the future:

1.1. Benefits of benzodiazepinesBenefits of benzodiazepines2.2. Few of the side effectsFew of the side effects3.3. Apparently no dependencyApparently no dependency

EvaluationEvaluation

• Remarkable treatment both in its Remarkable treatment both in its effectiveness and addictive potency:effectiveness and addictive potency:

- Works to reduce the symptoms of Works to reduce the symptoms of panic and anxiety relatively rapidlypanic and anxiety relatively rapidly

- Is tolerated by most patientsIs tolerated by most patients

- But creates dependency and must be But creates dependency and must be taken with care on a daily basistaken with care on a daily basis

EvaluationEvaluation

• Prolonged use is problematic and so Prolonged use is problematic and so must be used in conjunction with other must be used in conjunction with other psychotherapies or pharmacotherapiespsychotherapies or pharmacotherapies

• Yet some psychotherapists have Yet some psychotherapists have refused to treat individuals taking the refused to treat individuals taking the medications because of fears related to medications because of fears related to the overpowering effects of withdrawal the overpowering effects of withdrawal

EvaluationEvaluation

• A major concern is that individuals present A major concern is that individuals present themselves with symptoms of anxiety yet themselves with symptoms of anxiety yet do not disclose a history of alcohol abuse. do not disclose a history of alcohol abuse. This results in the prescription for a This results in the prescription for a tranquilizer to treat the anxietytranquilizer to treat the anxiety

• Almost half of the cases of anxiety reported Almost half of the cases of anxiety reported to the Royal College of Physicians are to the Royal College of Physicians are related to alcohol or benzodiazepine abuse.related to alcohol or benzodiazepine abuse.

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Further researchFurther research

• Because most of the benzodiazepines work Because most of the benzodiazepines work indiscriminately on all GABA gated channels indiscriminately on all GABA gated channels it make sense to develop a compound with it make sense to develop a compound with an affinity to act solely on GABA subtype A an affinity to act solely on GABA subtype A transmitterstransmitters

• The development of a compound that does The development of a compound that does accumulate in the body and that does not accumulate in the body and that does not metabolize as rapidly would reduce the metabolize as rapidly would reduce the severity of withdrawal symptoms and would severity of withdrawal symptoms and would reduce the frequency of administration reduce the frequency of administration