4/6/2015. Melinda C. Joyce declare(s) no conflicts of interest, real or apparent, and no financial interests in any company, product, or service

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1 Benzodiazepines and Other Anxiety Medications: Rescue or Maintenance? Disclosure Melinda C. Joyce declare(s) no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. KENTUCKY COALITION OF NURSE PRACTITIONERS AND MIDWIVES APRIL, 2015 Objectives Review the use and guidelines for benzodiazepines and other antianxiety medications Review the literature of benzodiazepine use and DEA prescribing guidelines Discuss potential for abuse and addiction, especially in elderly patients Anxiety Disorders Anxiety is an umbrella term encompassing several psychiatric disorders Most common Generalized Anxiety Disorder (GAD) Social lanxiety Panic Attack/Disorders Phobias In the past, obsessive-compulsive disorder (OCD) and post-traumatic disorder (PTSD) were also considered anxiety disorders but in the most recent Diagnostic Statistical Manual-5 (DSM-5) these disorders have been moved to other categories Globally, approximately 4.5% of the population (worldwide) suffer from an anxiety disorder Most prevalent psychiatric condition in the US other than substance abuse Prognosis depends on the type of anxiety disorder Anxiety Disorders Pathophysiology of Anxiety Disorders Anxiety Disorders Specific phobia Social anxiety disorder Panic disorder Panic attack Agoraphobia Generalized anxiety disorder Substance/medication-induced anxiety disorder Anxiety disorder due to another medical condition Unspecified anxiety disorder Not fully understood, but thought to be linked to dysregulation of neurotransmitters Gamma-aminobutyric aminobutyric acid Serotonin Dopamine Norepinephrine Brain s amygdala also appears to key in modulating fear and anxiety Patients with anxiety disorders often show heightened amygdala responses to anxiety cues 1

2 Generalized Anxiety Disorder (GAD) Generalized Anxiety Disorder (GAD) Common, chronic disorder that can be highly debilitating Patients with GAD experience non-specific persistent fear and worry about situations or objects in the absence of real danger The persistent worry is excessive and unrealistic and often about everyday things Approximately 5% of people develop GAD over the course of their lifetime Develops early in life and can have been long-term ramifications Does seem to have a genetic predisposition Very important to rule out drug-induced anxiety or other medical causes Much more common in women than men If left untreated, may eventually interfere with the ability to carry out activities of daily living Long-term remission rates are discouraging with only 25% in full remission after 2 years Symptoms of GAD Illnesses Associated with GAD Diagnostic criteria stipulate that an individual must have three or more symptoms most days of the week for at least six months Agoraphobia (fear and avoidance of places or situations that increase panic and may make the patient feel trapped, helpless, or embarrassed) may signal a more severe anxiety Women may also exhibit more physical symptoms while men are more likely to exhibit psychological symptoms Increased Motor Tension Autonomic Hyperactivity Increased Vigilance Easily fatigued Shortness of breath Feeling keyed up or hyper Restlessness Rapid heartbeat Increased startling Muscle tension Dry mouth Impaired concentration Sleep disturbances Dizziness Irritability Cold hands Any chronic disease can have a component of anxiety Gastroesophageal reflux disease Irritable bowel disease Heart disease Thyroid disorders both hypo and hyperthyroidism Menopause Stroke Pulmonary disorders COPD, Asthma Migraine headache Cancer There are high rates of co-morbidity with other psychiatric disorders, especially depression and substance abuse Drugs Associated with GAD Treatment Options: Non-Pharmacologic Caffeine Nicotine Alcohol Antibiotics Fluoroquinolones Corticosteroids Stimulants Amphetamines; Methlyphenidate Sympathomimetics Pseudoephedrine; Phenylephrine Illicit substances Cocaine; Bath salts; Methamphetamine; MDMA (Ecstasy); Marijuana Cognitive behavior therapy (CBT) Focuses on identification, understanding, and changing thought and behavior patterns Counseling can be very beneficial Some studies show benefit with as little as 8 weeks of therapy Exposure Therapy Process for reducing fear and anxiety responses to specific triggers Exercise Yoga Diet Reduction of caffeine, processed sugars 2

3 Social Anxiety Disorder (SAD) Social Anxiety Disorder (SAD) Also known as social phobia Intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction Can be specific to a particular social situation, such as public speaking or can manifest in most all social situations Symptoms often include blushing, sweating, and difficulty speaking Typical age of onset is 13 years of age 30% of people with SAD report having symptoms for more than 10 years before seeking help Avoidance of the situation can be very problematic and in severe cases, lead to complete isolation Not the same as shyness Panic Attack/ Disorder Phobias With panic disorder, a person has brief attacks of intense terror and apprehension, often accompanied by symptoms such as trembling, shaking, confusion, dizziness, nausea, and difficulty breathing Attacks can be triggered by stress or fear or the cause may not be known In addition to the attacks, a diagnosis of pain disorder requires that the attacks have chronic consequences Worry over the attacks potential implications Persistent fear of future attacks Significant changes in behaviors related to the attacks Hypervigilance of body functioning during the attacks Often begins in young adulthood The largest category of anxiety disorders, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation Between 5 and 12% of the population worldwide suffer from phobic disorders Typically anticipate terrifying consequences from encountering the object of their fear Can be anything animal; location (such as heights); particular situation Patients usually realize that their fear is not proportional to the actual potential danger but are still overwhelmed by it Patients typically work hard to avoid the object of their phobia, which can significantly impact their quality of life Pharmacotherapy is generally not beneficial Treatment Options Anxiety Disorder First-Line Agents Second-Line Agents Alternatives Generalized Anxiety Disorder SSRIs SNRIs Social Anxiety Disorder SSRIs SNRIs Panic Disorders SSRIs SNRIs Benzodiazepines Buspirone TCAs Pregabalin Quetapine Clonazepam Gabapentin Pregabalin Benzodiazepines TCAs Phenelzine First-Line Agents Not all SSRIs or SNRIs are indicated as treatment options Phobias are not generally treated with medication 3

4 Selective Serotonin Reuptake Inhibitors (SSRIs) Widely prescribed medications for depression, some SSRIs also have an indication for the treatment of anxiety disorders Increases the amount of serotonin available in the brain at the synapse Decreases the amount of serotonin in the neuronal cells by inhibiting the reuptake The mechanism of action for anxiety is not completely understood, but is thought to involve modulation of receptor activation of certain neurotransmitters, such as serotonin, dopamine, and norepinephrine It is theorized that by activating stress-adapting pathways, the SSRIs reduce the somatic anxiety symptoms and the patient s general distress Sertraline (Zoloft) is generally considered to be the gold standard SSRIs Although the mechanism of action is the same, there are differences between the agents If a patient does not tolerate or respond to one SSRI, switch to another SSRI before changing class or adding another agent It is important to taper off to avoid withdrawal-like symptoms Usually over a 2 week timeframe Use in pregnancy will depend on the agent, although most are classified as either a Category C or D Look at risk/benefit The anti-anxiety effects may take 2 to 4 weeks for response For acute therapy, 8 to 12 weeks, the response rates are between 60 and 68% with a 30% remission rate CNS stimulation: SSRIs Side Effects Anxiety, nervousness, insomnia GI effects: nausea, vomiting, diarrhea Usually transient Take medication with food Taper dosage upward Anorexia May see some weight loss at first, but usually any weight loss is temporary Lowered seizure threshold SSRIs Side Effects Sexual dysfunction may be as high as 30-50% in both men and women May be dose-related Often a reason for non-adherence Sildenafil (Viagra) does seem to be effective for sexual dysfunction caused by antidepressants Hyponatremia May be seen in elderly patients Monitor at baseline QT-Interval Prolongation Has been noted with citalopram Consider ECG and measurement of QT-interval in patients with pre-existing cardiac disease Subtle Differences Paroxetine (Paxil) First antidepressant associated with an increase in suicidal tendency in children and adolescents Seems to cause more weight gain than other SSRIs More sexual dysfunction may be related to higher doses needed for effect Withdrawal can be seen important to taper dosage and not abruptly stop Should not be used in pregnancy category D Potential cardiac anomalies Psychiatric issues in the infant jitteriness; constant crying; insomnia may be related to withdrawal as paroxetine easily crosses the placental barrier Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine (Effexor; Effexor XR); Duloxetine (Cymbalta); Desvenlafaxine (Pristiq) Potentiate neurotransmitter activity in the CNS by inhibiting the neural uptake of both serotonin and norepinephrine i May be useful for post-traumatic stress disorder (PTSD) along with psychotherapy Also useful as an adjunct for pain management Often considered to be the next class of antidepressant to try when SSRIs are not effective Venlafaxine ER is commonly used for anxiety disorders Pregnancy category C 4

5 SNRI Adverse Effects Tri-Cyclic Antidepressants GI Nausea, vomiting, diarrhea Usually transient Starting with a low dose and slowly titrating upwards can be beneficial Elevated blood pressure Monitor at baseline and regularly during treatment Starting with a low dose and slowly titrating upwards can be beneficial Headache Typically transient Sexual dysfunction May not be quite as common as with the SSRIs, but may occur Amitriptyline (Elavil); Doxepin (Sinequan); Imipramine (Tofranil) Affect both norepinephrine and serotonin In addition to being used for depression and anxiety, often used for other issues, such as low-dose for sleep; migraine prophylaxis; adjunct for pain Generally not a first-line agent for anxiety because of the cardiovascular and anticholinergic effects Imipramine is most often used for anxiety Takes about 2 to 3 weeks to see clinical effect Must always be concerned about the potential for suicide potentially fatal cardiac arrhythmias No antidote Some recommend baseline EKG before initiation Total dosage can be given at bedtime to help alleviate side effects Sedation Tri-Cyclic Antidepressants Side Effects Anticholinergic Effects Constipation; Dry mouth; Blurred vision; Urinary retention Hypotension Sit or stand slowly Weight gain Overdose cardiac effects Potentially life-threatening arrhythmias Serotonin Syndrome (SS) Potentially life-threatening condition that is clinically avoidable through medication vigilance Can be seen from most of the antidepressants Occurs when drugs acutely elevate serotonin levels in the CNS, promoting a rapid development of symptoms Clinical triad of autonomic hyperactivity, neuromuscular changes, and altered mental status Mild Hyperreflexia, tremor, clonus, shivering, diaphoresis, tachycardia Moderate Hypertension, mydriasis, hyperactive bowel sounds, mild agitation, tachycardia, febrile (core temperature < 106) Severe Hyperthermia (core temperature > 106), severe hypertension, hypervigilance, hypertonicity, delirium, coma Serotonin Syndrome Treatment of SS Mechanism behind serotonergic activity with proserotonergic poseoto egcagents include: release of serotonin Inhibition of serotonin metabolism presynaptic uptake serotonin formation Proserotonergic agents include: SSRIs SNRIs Tricyclic antidepressants Buproprion St John s Wort Opioids Anti-emetics Certain antibiotics STOP proserotonergic agent Supportive care Control of hyperthermia and agitation Antipyretics do not work Muscular activity not from a hypothalamic response Cyproheptadine (Periactin) may help block serotonin receptors in the CNS Chlorpromazine (Thorazine) or olanzapine (Zyprexa) can be used if a parenteral agent is required 5

6 4/6/2015 Precautions Suicidality Significant Warning - Applies to all classes of antidepressants Black-boxed warning Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders Must closely monitor behaviors, especially in the first few months of treatment and whenever there is an increase or decrease in dosage Benzodiazepines Monitor weekly in the first few weeks, especially in patients with co-morbid depression or those patients at high risk Drugs for Anxiety, Depression, and Insomnia in the 1950s History of the Benzodiazepines Chemist, Leo Sternbach first identified the compound chlordiazepoxide First marketed in the early 1960s by the Hoffman-LaRoche Hoffman LaRoche company Chlordiazepoxide (Librium) 1960 Diazepam (Valium) 1963 At the time, there were few drugs available to treat anxiety, depression, or insomnia Available agents at the time were considered to be habit forming and had multiple side effects Drug or Drug Class Side Effects and Concerns Chloral hydrate Potential dependence Acute toxicity from an overdose included nausea, vomiting, confusion seizures, confusion, seizures irregular breathing, breathing and cardiac arrhythmias slowly progressing to coma Barbiturates Sleepiness and somnolence are serious side effects Respiratory depression is common Dependence and addiction are likely Accidental or suicide overdose often fatal Meprobamate Dependence and addiction are likely Neurological side effects ataxia, dizziness, paradoxical excitement, headache, paresthesia, slurred speech, somnolence Lethal in an overdose Benzodiazepines Karen Ann Quinlan Initially appeared to be less toxic and less likely to cause dependence than the older drugs A specific improvement was the lack of respiratory depression Medical professionals immediately jumped on the benzo bandwagon In the mid-to-late 1970s, benzodiazepines topped all most frequently prescribed lists Diazepam (Valium) became a symbol of our fast-paced, heavily stressed society Central theme of the book Valley of the Dolls The rock hit by the Rolling Stones, Mother s Little Helper, was about benzodiazepine use Celebrity overdoses of benzodiazepines and other medications were tabloid fodder Marilyn Monroe; Anna Nicole Smith; Heath Ledger Controversial case in the mid-1970s about a young woman who became comatose after a benzodiazepine overdose The situation challenged end-of-life care As a result of a diazepam-alcohol overdose, Quinlan went into a persistent vegetative state and remained unresponsive for 10 years The family worked through the court systems to be allowed to disconnect her supportive care Initially, the New Jersey Supreme Court ruled that the family should not be allowed to decide whether to remove her from life support but then later reversed that decision It has been stated that Karen Ann Quinlan changed how we look at the decisions about death 6

7 Mechanism of Action The exact mechanism of action is not completely understood Took researchers about 15 years to determine that the benzodiazepines impact gamma-aminobutyric acid (GABA), which is chiefly an inhibitory neurotransmitter When benzodiazepines bind to this neuroinhibitory receptor, neurons are then less excitable The skeletal muscle relaxation is produced by inhibiting spinal polysynaptic afferent pathways The anticonvulsant properties are due to enhanced presynaptic inhibition Benzodiazepine Usage by Age Group Classification of Benzodiazepines Indications Benzodiazepine Peak Onset (Hrs) Half-Life (Hrs) Comparative Oral Dose Long-Acting Chlordiazepoxide (Librium) mg Diazepam (Valium) mg Intermediate-Acting Alprazolam (Xanax) mg Clonazepam (Klonopin) mg Lorazepam (Ativan) mg Oxazepam (Serax) mg Short-Acting Midazolam (Versed) Have anxiolytic, sedative, muscle relaxation, and anticonvulsant properties Alcohol withdrawal (short-term) Oxazepam (Serax) often preferred because of lack of metabolite Generalized anxiety disorders (short-term) No agent clearly superior Insomnia both sleep onset and sleep maintenance Panic attacks Pre-procedure sedation Muscle relaxer for spasms or dystonia Status epilepticus or refractory tonic-clonic seizures Adverse Effects Tolerance Sedation Lethargy Respiratory depression Impaired motor skills Impaired judgment Cognitive dysfunction Delirium Short-term memory impairment Anterograde amnesia Ataxia Depressed mood Exacerbation of COPD, sleep apnea Paradoxical disinhibition May see an increase in anxiety, irritability, or agitation in the elderly or in children Tolerance to hypnotic effects develops rapidly, within a few days or weeks of regular use Some poor sleepers will report continued efficacy of the benzodiazepines because they prevent rebound insomnia (a withdrawal symptom) Tolerance to anxiolytic effects develops more slowly, over a few months Escalation of dosage and chronic use of benzodiazepines cause additional adverse effects including depression and excessive sedation 7

8 Criteria for Dependence Criteria for Dependence 1. Tolerance as defined as either a need for markedly increased amounts of the substance to achieve the clinical effect, or a markedly diminished effect with continued use of the same amount of the substance 2. Withdrawal as defined by either the characteristic withdrawal syndrome for the substance, or the same or similar substance is taken to avoid withdrawal symptoms 3. The substance is taken in larger amounts or over a longer period than intended 4. There is a persistent desire or unsuccessful attempts to cut down or control substance use 5. Time is spent in activities necessary to obtain the substance 6. Important activities are given up or reduced because of substance abuse 7. The substance use is continued despite knowledge of having a problem caused or exacerbated by the substance Alprazolam SAMHSA Data, The Dawn Report December, 2014 Although abuse of the opioids, especially hydrocodone and oxycodone are more likely to be discussed, abuse of benzodiazepines is also prevalent Alprazolam (Xanax) is the most widely abused benzodiazepine, ranking third behind hydrocodone and oxycodone Alprazolam is quickly absorbed, which leads to euphoria Alprazolam 2 mg consistently brings $3.00/tablet on the illicit market, making it lucrative Emergency room visits for alprazolam overdose doubled between 2005 and 2010 More toxic in an overdose setting than the other benzodiazepines More difficult to taper off for discontinuation Non-medical uses of alprazolam can quickly lead to physical dependence and if combined with alcohol or opiates can enhance the effects of all of the agents Withdrawal Management of Withdrawal The existence of a benzodiazepine withdrawal syndrome has been abundantly demonstrated Withdrawal can be mild and short-lived or severe and protracted Severity is often associated with prolonged or high-dose use, shortacting benzodiazepines, certain personality types, and underlying anxiety Exacerbation of anxiety or insomnia Sweating, night sweats Perceptual distortions Depersonalization Hallucinations (both visual and auditory) Tingling, numbness, altered sensation Formication Sensory hypersensitivity Muscle twitching Confusion Seizures Has often been associated with a traumatic process for both the patient and the provider Key strategies for successful discontinuation are gradual dosage tapering and psychological support Psychological support is necessary with panic disorder Benzodiazepines should never be abruptly stopped With use over one year, taper only after the condition being treated is well controlled Several different withdrawal strategies are often employed Not one best strategy If patients cannot tolerate a direct taper, can switch to clonazepam (Klonopin) at an equivalent dose and then taper off the clonazepam using a direct taper approach 8

9 Management of Withdrawal Management of Withdrawal Direct Taper Option 1 Decrease by 25% the first week, by 25% the second week, than by 10% every week after that Monitor patient for withdrawal or worsening of condition treated. If needed, continue present dose for a few extra weeks or return to higher dose Direct Taper Option 2 Taper to diazepam 10 mg or equivalent, maintain that dose for one to two months, then taper over 4 to 8 weeks Direct Taper Option 3 Taper by 10% every 1 to 2 weeks until 20% of the original dose is reached. Then taper by 5% every 2 to 4 weeks Direct Taper Option 4 Taper by no more than diazepam 5 mg or equivalent every week. When diazepam 20 mg or equivalent is reached, slow the rate of taper to 1 to 2 mg diazepam or equivalent every week Use in the Elderly Especially susceptible to the sedative effects of the benzodiazepines Partly due to reduced metabolism from aging Beers Criteria List for potentially inappropriate medication use in the elderly Avoid benzodiazepines (any type) for treatment of insomnia, agitation, or delirium All benzodiazepines increase risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults If benzodiazepines are used, the dose should always be half of the usual adult dose Use in the ICU The most commonly used benzodiazepines in the ICU for sedation include midazolam and lorazepam, although other agents, such as propofol may be a better choice Both agents are lipophilic, which allows for a quicker cross of the blood-brain barrier Midazolam is quicker than lorazepam The lipophilicity also causes both midazolam and lorazepam to accumulate in adipose tissues resulting in a longer response Those issues plus potential issues from potential impaired metabolism can make the effects of the benzodiazepines linger and cloud a patient s neurological assessment This effect can last several days if continuous infusions are administered Other issues of concern include the potential respiratory depression and paradoxical agitation Most valuable for patients with seizure disorders because of the anticonvulsant effects Buspirone (BuSpar) Other Agents Structurally and pharmacologically unlike the benzodiazepines Does not have anticonvulsant, muscle relaxation, motor impairment, or dependence properties Serotonin partial agonist Often considered to be a second-line option for anxiety because of: Inconsistent reports of efficacy (especially long-term) Very gradual onset of action- at least 2 weeks or longer Lack of efficacy for any other potential concurrent depressive disorders Best use may be for patients with substance abuse issues as it has a very low potential for dependence 9

10 4/6/2015 Buspirone Pharmacokinetic profile requires that the drug be dosed 2 to 3 times a day, which could impact compliance Adverse Reactions Dizziness; Most Quetiapine (Seroquel XR) Includes nausea; headache; dysphoria (at higher doses) side effects are self-limiting and transient The dose of buspirone can be titrated in increments of 5 mg/day every 2 to 3 days as needed Maximum benefit may not be seen for up to 6 weeks First atypical antipsychotic agent approved for the acute and maintenance treatment of bipolar depressive episodes Especially Sedation Can be beneficial in patients with anxiety with insomnia Some controversy on whether this agent should be used for sleep in patients with no other psychotic symptoms QT-interval QT interval prolongation Metabolic syndrome should have baseline labs and then monitor every 3 to 6months Weight gain (BMI) Waist circumference Fasting lipids Glucose Blood pressure Extrapyramidal side effects May see abuse, especially in correctional facilities Once daily dosing Should be taken on an empty stomach for best absorption Pregabalin (Lyrica) Structural analog of GABA that is indicated for pain associated with diabetic peripheral neuropathy or postherpetic neuralgia Also indicated as adjunctive therapy for refractory partial seizures Does not have a FDA indication for anxiety, but is used as a secondline agent Mechanism of action is thought to involve alpha-2 delta receptors that modulate nerve transmissions in the brain and spinal cord. It is a scheduled drug Schedule V Akathisia Pregabalin Precautions Renal insufficiency p, including g alcohol CNS depressants, Important to taper dose (at least over 1 week) upon discontinuation to minimize seizure risk no matter reason for using the medication Thrombocytopenia More common adverse effects if anxiety or insomnia is prevalent Although not a FDA-approved indication, quetiapine is used as a second-line agent for anxiety Do see differences between the immediate release and the extended release forms Quetiapine both manic and mixed episodes Also indicated for adjunctive therapy with major depressive disorder Phenelzine (Nardil) Nardil) MAO-Inhibitor, most often used for refractory types of depression Thought to act by increasing endogenous concentrations of norepinephrine, dopamine, and serotonin through the inhibition of the enzyme monoamine oxidase Significant drug-drug interactions can lead to a hypertensive crisis Sympathomimetics SSRIs, SNRIs, Tricyclic antidepressants General anesthesia CBC at baseline and periodically during treatmet Dizziness, drowsiness, dry mouth, peripheral edema, blurred vision, weight gain, difficulty concentrating, euphoria (?) Monoamine oxidase is responsible for the breakdown of these neurotransmitters Wait at least five weeks for a wash-out period Stop MAO-inhibitors for at least 10 days prior to elective surgery Significant drug-food interactions can lead to a hypertensive crisis Foods high in tyramine 10

11 Phenelzine Adverse Effects Hypertensive crisis Blood pressure should be closely monitored Watch for potential drug-drug and drug-food interactions Orthostatic hypotension CNS effects Delirium, drowsiness, dizziness, euphoria, headache, insomnia, twitching GI effects Constipation Neuromuscular Paresthesia, tremor, weakness Ocular Blurred vision, nystagmus Pharmacologic Treatments of Anxiety Disorders Generalized Anxiety Disorder Ideally, the goal of treatment is remission, but realistically, this may not be achievable Treatment options include pharmacotherapy and psychological therapy Either alone or in combination Treatment choice will depend on factors such as availability of psychological treatment, patient preference, response history, disease severity, co-morbid conditions, potential drug-drug interactions, and adverse effects Patients should be educated about their disorder and what to expect from treatment The Hamilton Anxiety Rating Scale can be a useful monitoring tool SSRI First-Line Agents Escitalopram (Lexapro)* 10 mg once daily Sertraline (Zoloft) 50 mg once daily Paroxetine (Paxil)* 20 mg once daily SNRI Venlafaxine ER (Effexor ER)* mg once daily Duloxetine (Cymbalta)* mg once daily * - FDA approved indication Benzodiazepines Second-Line Agents Alprazolam (Xanax)* 0.25 mg two to three times a day Buspirone (BuSpar)* 75mgtwicedaily 7.5 Pregabalin (Lyrica) 50 mg three times a day TCAs Imipramine 10-25mg once daily, titrated to 50 to 100 mg total daily dose Quetiapine XR (Seroquel XR) 50 mg at bedtime, titrated to 150 mg at bedtime * - FDA approved indication 11

12 Pearls for GAD Treatment Social Anxiety Disorder Antidepressants are considered the first-line agents in the management of GAD Although very efficacious, the anti-anxiety response of the antidepressants is usually delayed by 2 to 4 weeks but should be the preferred agents for long-term maintenance therapy Important to monitor for suicidal ideation and side effects Second line agents: No benzodiazepine clearly superior in the treatment of GAD Consider agent with medium or long half-life Clonazepam (Klonopin); lorazepam (Ativan); diazepam (Valium) Shorter acting agents pose higher risk of withdrawal, rebound, and dependence Alprazolam (Xanax) Ideally for short-term use only until the effects of the antidepressant starts to work The goals of therapy in the acute phase of treatment are to reduce physiologic symptoms of anxiety (tachycardia, flushing, sweating), social anxiety, and phobic avoidance The duration of this phase can be from 4 to 12 weeks, depending on the drug therapy The goals in the continuation phase (3 to 6 months) are to extend the therapeutic benefits, especially the patient s ability to participate in social activities, and improve quality of life Even modest reductions in avoidance and discomfort are highly valued At least a 1 year medication maintenance is recommended to maintain improvement and decrease the rate of relapse Long-term goal is remission with the disappearance of the core symptoms of social anxiety, little or no anxiety, and no functional impairment First-Line Agents SSRI Escitalopram (Lexapro)* 5-10 mg once daily Citalopram (Celexa) 20 mg once daily Sertraline (Zoloft) 50 mg once daily Paroxetine (Paxil)* 20 mg once daily Paroxetine CR (Paxil CR) 12.5* mg po daily SNRI Venlafaxine ER (Effexor ER)* 75 mg once daily * - FDA approved indication Benzodiazepines Second-Line Agents Clonazepam (Klonopin) 1-4 mg po daily usually as an augmentation Buspirone (BuSpar) 10 mg twice daily Pregabalin (Lyrica) 100 mg three times a day Quetiapine XR (Seroquel XR) 25 mg at bedtime Phenelzine (Nardil) 15 mg at bedtime * - FDA approved indication Pearls for Treatment of Social Anxiety Disorder Patients with generalized social anxiety disorder should be treated aggressively Obstacles to effective treatment include Avoidance of therapy secondary to fear and shame Treatment directed toward somatic symptoms or concurrent conditions Financial barriers Patients often respond more slowly and less completely than patient with other anxiety disorders Pharmacotherapy plus cognitive behavioral therapy generally will have the greater likelihood of maintaining response 12

13 Pearls for Treatment of Social Anxiety Disorder Panic Disorders Antidepressants are the first-line choices Benzodiazepines are commonly used in patients who cannot tolerate or fail to respond to the antidepressants If a benzodiazepine, such as clonazepam is used, a tapering regimen should be employed after 6 months If a patient is switched from another antidepressant to phenelzine, a washout period should be followed to help decrease any potential adverse drug-drug interactions The goal of therapy in panic disorder is remission Patients should be free of panic attacks, have no or minimal anticipatory anxiety and agoraphobic avoidance and have no functional impairment If agoraphobia is present, resolution of avoidance tends to occur slowly Adding psychosocial treatment to pharmacotherapy may improve long-term outcomes by reducing the likelihood of relapse when pharmacotherapy is stopped First-Line Agents SSRI Escitalopram (Lexapro) mg once daily Citalopram (Celexa) 20 mg once daily Fluoxetine (Prozac) 10 mg once daily Sertraline (Zoloft) 25 mg once daily Paroxetine (Paxil)* 10 mg once daily SNRI Venlafaxine ER (Effexor ER)* 37.5 mg once daily * - FDA approved indication Benzodiazepines Second-Line Agents Alprazolam (Xanax)* 0.25 mg three times a day Alprazolam XR (Xanax XR) 05to1mgdaily 0.5 Clonazepam (Klonopin)* 1-4 mg po daily Diazepam (Valium) 2-5 mg three times a day Lorazepam (Ativan) mg three times a day Imipramine (Tofranil) 75 mg po daily Phenelzine (Nardil) 15 mg at bedtime * - FDA approved indication Pearls for Treatment of Panic Disorder Panic disorder is treated effectively with antidepressant therapy Although the SSRIs are considered to be first-line agents, benzodiazepines are the most commonly used drugs for panic disorder The use of the benzodiazepines i should be limited it to short-term t treatmentt t In the acute phase, treatment with a benzodiazepine should be limited to one month while the antidepressant is being slowly tapered upwards The slow taper is necessary to not exacerbate the panic disorder from potential side effects, such as nervousness, jitteriness, or insomnia If patients are prescribed a benzodiazepine into the maintenance phase, patients are more likely to suffer a relapse whenever attempts are made to discontinue the benzodiazepine Must use alprazolam carefully due to abuse potential 13

14 Pregnancy Special Populations Symptoms of anxiety can develop or worsen during or after pregnancy Not a lot of literature on how to best treat anxiety disorders during pregnancy SSRIs, such as fluoxetine (Prozac) or sertraline (Zoloft) are recommended d for use SSRIs have been associated with a slight increased risk for pulmonary hypertension during the third trimester Other potential issues in the neonate include irritability, poor feeding, and sleep disturbances Paroxetine (Paxil) should be avoided in pregnant women because of risk of cardiovascular malformations Pregnancy Category D Pregnancy Pregnancy Benzodiazepine therapy should generally be avoided in pregnancy During the first trimester, cleft lip, cleft palate, and other tetratogenic effects may be seen During the third trimester, sedation, withdrawal symptoms, and floppy baby syndrome can be seen Hypotonia, low Apgar scores, and hypothermia Alprazolam (Xanax) should be avoided during pregnancy because of neonatal withdrawal Should a benzodiazepine be needed, diazepam (Valium) or chlordiazepoxide (Librium) may be the preferred agents in the lowest dose possible for the shortest period of time Women should not stop taking their medication without working with their provider Women who are pregnant, psychologically stable, and prefer to continue taking their medication may be able to do so after consulting with their therapist and Ob/Gyn provider Women who are pregnant and have severe anxiety should remain on medication, as they are at high risk for relapse Children Substance Abuse Anxiety disorders, especially social anxiety disorder can present in children from preschool to elementary school age Children often exhibit more somatic symptoms If the disorders are not appropriately treatment, anxiety can persist into adulthood and increase the risk of depression and substance abuse Cognitive behavioral therapy and social skills training are effective nonpharmacologic therapies in children Antidepressants are first-line choices, but children and adolescents must be monitored closely for an increased risk of suicidal ideation Benzodiazepines should be reserved as last-line agents for children Patients with a substance abuse issue pose special consideration in the choice of an anxiolytic Patients often misuse alcohol, cannabis, or other substance to self- treat the anxiety It is often to know the difference between the symptoms of an anxiety disorder, such as GAD and withdrawal symptoms Benzodiazepines should be avoided in this population Buspirone is often an effective agent for patients with anxiety and a history of substance abuse 14

15 Pearls for Treatment Take Home Points The long-term goals for anxiety disorders is remission with minimal or no anxiety symptoms along with no functional impairment Treatment must be individualized Antidepressants are the agents of choice, although the anti-anxiety effects may have a lag time of 2 to 4 weeks Patients should be closely monitored for potential side effects and suicidal ideation Patients should be given an adequate time of about 8 to 12 weeks when assessing effectiveness The optimal duration of treatment is not known but will depend on several factors, including the severity of the disorder Panic disorder and social anxiety disorder usually requires longer treatments If a benzodiazepine is used, the lowest dose possible for the shortest period of time should be followed Patients taking benzodiazepines should be closely monitored for side effects and potential misuse, abuse, or dependence Mother s Little Helper And though she s not really ill There s a little yellow pill She goes running for the shelter of a mother s little helper And it helps her on her way, gets her through her busy day Melinda C. Joyce, Pharm.D., FAPhA, FACHE mbjoyce@chc.net Keith Richards and Mick Jagger 15