Prof. Muhammad Riaz BhattiProf. Muhammad Riaz BhattiMBBS(K.E.), DPM., RCP&RCS(Dublin), MCCEE (Canada)

FRSH(Lond), MRCPsych,(Lond) FRCPsych.,(Lond)

Chairman Academic Department of Chairman Academic Department of Psychiatry & Behavioural Sciences, Psychiatry & Behavioural Sciences,

King Edward Medical University / King Edward Medical University / Mayo Hospital, Lahore.Mayo Hospital, Lahore.

President Psychiatric Welfare AssociationPresident Psychiatric Welfare Association

Past President Pakistan Psychiatric SocietyPast President Pakistan Psychiatric Society

Evolving Role of Evolving Role of Benzodiazepines Benzodiazepines in the Treatment in the Treatment

of Anxietyof Anxiety

An unpleasant emotional state consisting

of psycho-physiological response to

anticipation of unknown, unreal or

imaginary danger. It can be either

physiological as an over prepared state or

pathological as a disproportional reaction

to any stressful stimuli, which may

interfere with daily life activities.

Diagnostic and Statistical Manual(DSM-

IV)

ANXIETYANXIETY

• Anxiety presents with cardiac symptomsAnxiety presents with cardiac symptoms

• Anxious patients with no evidence of Anxious patients with no evidence of organic heart disease commonly report organic heart disease commonly report unexplained CV symptoms that are unexplained CV symptoms that are frequently chronic and associated with frequently chronic and associated with great subjective distress.great subjective distress.

• They often lead to impaired functioning, They often lead to impaired functioning, lost days from work & considerable lost days from work & considerable economic cost.economic cost.

AnxietyAnxiety

Cardiovascular symptoms of Cardiovascular symptoms of AnxietyAnxiety

Anxiety may present with cardiac symptomsAnxiety may present with cardiac symptomsIncreased cardiac awarenessIncreased cardiac awareness

•PalpitationsPalpitations•Chest painChest pain•DyspneaDyspnea•SweatingSweating•TremorsTremors

Anxiety & HypertensionAnxiety & Hypertension

Many studies show that anxiety has an influence on Many studies show that anxiety has an influence on blood pressure.blood pressure.

• The degree of anxiety was positively associated The degree of anxiety was positively associated with diastolic pressurewith diastolic pressure

• the influence of happiness anger and anxiety on the blood the influence of happiness anger and anxiety on the blood pressure of borderline hypertension.pressure of borderline hypertension.

• Among middle aged men …. Anxiety levels are Among middle aged men …. Anxiety levels are predictive of later incidence of hypertensionpredictive of later incidence of hypertension

• psychological predictors of hypertension in the Framingham psychological predictors of hypertension in the Framingham study. Is there tension is hypertensionstudy. Is there tension is hypertension

““Anxiety, as either cause or effect, Anxiety, as either cause or effect, accompanies many medical illness and accompanies many medical illness and

the the use of anti-anxiety drugs as use of anti-anxiety drugs as concomitant therapyconcomitant therapy can reduce can reduce

morbidity and improve prognosis.”morbidity and improve prognosis.”

Psychother Psychosom 1988, 49(2):63-80Psychother Psychosom 1988, 49(2):63-80

Evolving Role of Benzodiazepines in Evolving Role of Benzodiazepines in Anxiety DisordersAnxiety Disorders

• Historical trends and the use of multiple classes Historical trends and the use of multiple classes of compounds as anxiolyticsof compounds as anxiolytics

• Current trends and patterns of drug prescriptions Current trends and patterns of drug prescriptions for anxiety disordersfor anxiety disorders

• Rationale and indications for usage of Rationale and indications for usage of benzodiazepines in anxietybenzodiazepines in anxiety

• ConclusionsConclusions

DSM=Diagnostic and Statistical Manual; GAD=generalized anxiety disorder; OCD=obsessive-compulsive disorder; PTSD=posttraumatic stress disorder.

Anxiety DisordersAnxiety Disorders

SocialSocialanxietyanxietydisorderdisorder

PanicPanicdisorderdisorder OCDOCD GADGAD PTSDPTSD

DMS-IV Spectrum of Anxiety DisordersDMS-IV Spectrum of Anxiety Disorders

Currently Available Interventions Currently Available Interventions for Anxiety Disordersfor Anxiety Disorders

• AntidepressantsAntidepressants– Selective serotonin reuptake inhibitors (SSRIs)Selective serotonin reuptake inhibitors (SSRIs)– Serotonin-norepinephrine reuptake inhibitors (SNRIs)Serotonin-norepinephrine reuptake inhibitors (SNRIs)– Other new agentsOther new agents– Tricyclic antidepressants (TCAs)Tricyclic antidepressants (TCAs)– Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs)

• High-potency benzodiazepinesHigh-potency benzodiazepines– AlprazolamAlprazolam– ClonazepamClonazepam

• Other compoundsOther compounds– AzapironesAzapirones– AnticonvulsantsAnticonvulsants– B-blockersB-blockers

• Cognitive-behavior therapyCognitive-behavior therapy

• Combination treatmentsCombination treatments

Evolution in the Treatment of Anxiety Evolution in the Treatment of Anxiety DisordersDisorders

BenzodiazepinesBenzodiazepines

(Buspirone)(Buspirone)

TCAsTCAs

SSRIs & SNRIs

SSRIs & SNRIsCBTCBT CombosCombos

CBT=cognitive-behavioral therapy; SSRIs=selective serotonin reuptake inhibitors; SNRIs=serotonin and norepinephrine reuptake inhibitors; TCAs=tricyclic antidepressants.

Drug Use in Generalized Anxiety DisorderDrug Use in Generalized Anxiety Disorder(Percent of Total Rxs)(Percent of Total Rxs)

NDTI MAT August 2001.

15

12

9

5

4

22

10

4

4

6 9

Alprazolam

Paroxetine

Lorazepam

Clonazepam

Buspirone

Venlafaxine/Venlafaxine XR

Sertraline

Diazepam

Citalopram

Nefazodone

Other

Drug Use in Panic Disorder Drug Use in Panic Disorder (Percent of Total Rxs)(Percent of Total Rxs)

BZD=benzodiazepine; Rxs=prescriptions.NDTI MAT August 2001.

Total BZD=42%

12 Other 21 Alprazolam

21 Paroxetine

Sertraline 10

Fluoxetine 5

Diazepam 3Buspirone 2

Lorazepam 5

Citalopram 6

Venlafaxine/

Venlafaxine XR 2

13 Clonazepam

Pharmacotherapy received by Panic Disorder Pharmacotherapy received by Panic Disorder patients in the HARP study (1989-2001)patients in the HARP study (1989-2001)

0%

10%

20%

30%

40%

50%

60%

Baseline(n=429)

Year 2(n=424)

Year 4(n=382)

Year 6(n=364)

Year 8(n=343)

Year 10(n=304)

SSRI only Benz only SSRI + benz Neither

SE Bruce et al, poster presented at the 22nd ADAA meeting, March 2002

Current Diagnostic TrendsCurrent Diagnostic Trends

• Recognize symptom dimensions (e.g., anxiety, Recognize symptom dimensions (e.g., anxiety, panic) rather than DSM-IV syndromes (e.g., panic) rather than DSM-IV syndromes (e.g., generalized anxiety disorder, panic disorder)generalized anxiety disorder, panic disorder)

• Anxious patients may present without psychiatric Anxious patients may present without psychiatric symptoms, but rather with multiple unexplained symptoms, but rather with multiple unexplained physical symptomsphysical symptoms

• Patients with comorbid medical illnesses and Patients with comorbid medical illnesses and anxiety may appear as “difficult patients” who anxiety may appear as “difficult patients” who are not compliant or do not respond to are not compliant or do not respond to treatments of their medical illnesstreatments of their medical illness

Current Treatment OptionsCurrent Treatment Options

• Benzodiazepines are typically viewed are Benzodiazepines are typically viewed are combined with antidepressants, or are combined with antidepressants, or are used in patients who are intolerant to used in patients who are intolerant to antidepressantsantidepressants

• Cognitive-behavioral therapy also is Cognitive-behavioral therapy also is effectiveeffective

Sites of Action - BenzodiazepinesSites of Action - Benzodiazepines

Agents that boost output from either GABA or serotonin neurons each Agents that boost output from either GABA or serotonin neurons each have at least 2 chanceshave at least 2 chances – from both outside and inside the amygdala – from both outside and inside the amygdala to diminish the likelihood of anxiety and fearto diminish the likelihood of anxiety and fear

Fear

Stahl SM. J Clin Psychiatry 63:9, 2002

SSRIs for Anxiety Disorders: SSRIs for Anxiety Disorders: DisadvantagesDisadvantages

• Onset of action delayed usually for days to Onset of action delayed usually for days to weeksweeks

• May activate and transiently worsen anxiety at May activate and transiently worsen anxiety at onset of treatmentonset of treatment

• Sexual dysfunction is commonSexual dysfunction is common

• May induce withdrawal reactions when May induce withdrawal reactions when discontinueddiscontinued

• Weight gainWeight gain

Benzodiazepines for Anxiety Benzodiazepines for Anxiety Disorders: AdvantagesDisorders: Advantages• Rapid onsetRapid onset

• Can be useful as needed for breakthrough Can be useful as needed for breakthrough symptomssymptoms

• SSRI therapy augmented by benzodiazepines SSRI therapy augmented by benzodiazepines may enhance adherence to treatment and may enhance adherence to treatment and alleviate activating symptoms of SSRIsalleviate activating symptoms of SSRIs

• No or mild sexual dysfunctionNo or mild sexual dysfunction

• Safe with good tolerabilitySafe with good tolerability

Ballenger et al. J Clin Psychiatry. 1998;59(suppl 9):51.Furukawa et al. J Affect Disord. 2001;65:173.Goddard et al. Arch Gen Psychiatry. 2001;58:681.

.

Benzodiazepines for Anxiety Benzodiazepines for Anxiety Disorders: DisadvantagesDisorders: Disadvantages

• Potential early sedation and incoordinationPotential early sedation and incoordination

• Risk for withdrawal reactions with abrupt Risk for withdrawal reactions with abrupt discontinuation (usually a re-emergence of discontinuation (usually a re-emergence of anxiety symptoms)anxiety symptoms)

• Low but definite abuse potential, Low but definite abuse potential, especially in polysubstance abusersespecially in polysubstance abusers

Ninan. J Clin Psychiatry. 1999;60(suppl 22).Petursson and Lader. Br J Addict. 1981;76:133.

Is Long-term Benzodiazepine Is Long-term Benzodiazepine Treatment Justified? Treatment Justified?

• Family, spouse can corroborateFamily, spouse can corroborate– Continued benefitContinued benefit– No nonmedical benzodiazepine useNo nonmedical benzodiazepine use– No benzodiazepine-related toxicityNo benzodiazepine-related toxicity

• ConsultationConsultation– More clinical clarity More clinical clarity – Less medicolegal liabilityLess medicolegal liability

• Document rationale in patient recordDocument rationale in patient record

DuPont and DuPont. Clinical Textbook of Addictive Disorders. 1998.

Combining AntidepressantsCombining Antidepressantswith Benzodiazepineswith Benzodiazepines

• Provides rapid anxiolysis during Provides rapid anxiolysis during antidepressant lagantidepressant lag

• Decreases early anxiety associated with Decreases early anxiety associated with initiation of antidepressantinitiation of antidepressant

• Treats residual anxiety with antidepressant Treats residual anxiety with antidepressant treatmenttreatment

• Prevents and treats potentially depressive Prevents and treats potentially depressive effects of benzodiazepineseffects of benzodiazepines

Clinical Anxiety:Clinical Anxiety:Case StudyCase Study

Patient HistoryPatient History

• 23-year old woman23-year old woman

• Successful professional, married with 2 Successful professional, married with 2 childrenchildren

• First panic attack: presented to First panic attack: presented to emergency room with complaints of chest emergency room with complaints of chest pains and fear of having a heart attackpains and fear of having a heart attack

• Cardiac workup negative for ischemiaCardiac workup negative for ischemia

Patient History (cont.)Patient History (cont.)

• Second panic attack: presented to hospital with Second panic attack: presented to hospital with chest pains, dizziness, shortness of breath, and chest pains, dizziness, shortness of breath, and palpitationspalpitations

• Second cardiac workup negativeSecond cardiac workup negative

• Results revealed no other significant physical Results revealed no other significant physical findingsfindings

• ER/ED MD recommended follow up with primary ER/ED MD recommended follow up with primary care physiciancare physician

• Diagnosed with clinical anxiety and panic attacksDiagnosed with clinical anxiety and panic attacks

Management QuestionsManagement Questions

• In ER/ED:In ER/ED:– Prescribe SSRI?Prescribe SSRI?– Prescribe antidepressant?Prescribe antidepressant?– Prescribe benzodiazepine?Prescribe benzodiazepine?– Wait for office visit?Wait for office visit?

• Office visit follow up:Office visit follow up:– How would you decide on therapeutic How would you decide on therapeutic

approach?approach?

ConclusionsConclusions

• Although “officially” benzodiazepines are Although “officially” benzodiazepines are currently considered second line for currently considered second line for anxiety disorders, they are still the most anxiety disorders, they are still the most frequently prescribedfrequently prescribed

• Benzos are especially useful at the Benzos are especially useful at the beginning of treatment with SSRIs, beginning of treatment with SSRIs, treating residual anxiety in patients on treating residual anxiety in patients on SSRIs, and those who do not respond to SSRIs, and those who do not respond to or do not tolerate SSRIsor do not tolerate SSRIs