February 2nd, 2015 CDM 4 Hayley EvansGeneralized Anxiety Disorder1.Identify medication-responsive symptoms of generalized anxiety disorder.DSM-5 Criteria of GAD1. Excessive anxiety/worry lasting for >6 months with difficulty controlling theworry2. Presence of 3 or more of the following symptoms-restlessness-feeling “keyed up”-easily fatigued-difficulty concentrating-irritability-muscle tension-sleep disturbance 3. anxiety/worry results in significant distress or functional impairment 4. symptoms not caused by a substance, general medical condition, other psychiatric disorder Pathophysiology-Locus ceruleus- overactive in eliciting fear response-Amygdala- overactive in anxiety/fear response-Anterior cingulated cortex- overactive in anxiety/fear-Hippocampus- consolidation of traumatic memory and contextual fear conditioning-Hypothalamus-integrates neuroendocrine and autonomic responses to a threat *Neurotransmitter involvement-Noradrenergic model-ANS are hypersensitive and overreact to various stimuli via LC-Drugs with anxiolytic effects decrease LC firing and decrease NE activity -GABA receptor model-GABA is a major inhibitory NT in the CNS-Specific role of GABA receptors in anxiety disorders not established-Drugs that decrease anxiety and cause sedation target GABA-A receptors -Serotonergic model -Serotonin 5-HT is an inhibitory NT released by neurons in the raphe nuclei of the brain stem; these neurons project widely throughout the brain-Postulated that increased 5-HT activity decreases NE activity in the LC leading to inhibition defense/escape responses leading to decreased CRF release by the hypothalamus EtiologyFebruary 2nd, 2015 CDM 4 Hayley Evans-Medical illnesses -CV, endocrine/metabolic, neurologic, respiratory, -Psychiatric illnesses-Mood disorders e.g. depression, bipolar disorder, psychotic disorders e.g. schizophrenia, dementia, substance use disorders -Drugs associated with anxiety symptoms-Anticonvulsants, antidepressants, antihypertensives, antibiotics, bronchodilators, corticosteroids, dopamine agonists, herbals, illicit substances, NSAIDs, stimulants, sympathomimetics, thyroid hormones, toxicity/overdose situations Onset-Avg age of onset is ~21 years, but there appears to be a bimodal distribution-Onset occurs earlier when GAD is primary; later when GAD is secondary-GAD can be exacerbated or precipitated in later life (often between ages 35 and 45 years) by significant psychosocial stressors Duration-Course of the illness is chronic -High percentage of relapse and low rates of recovery-Likelihood of remission at 2 years is 25%-Pts report sig interference with their lives  high probability of seeking treatment-Lifetime co-morbidity with another psychiatric disorder occurs in 90% of patients with GAD, depression found in >60%Screening*Self rated scales-GAD Assessment-7-Beck Anxiety Inventory-Penn State Worry Questionnaire-Zung Self rated Anxiety ScaleTreatment Approach-First line therapy options: SSRIs, SNRIs-If symptoms persist after an adequate trial (4-6 wks at adequate dose) -Switch to an alternate SSRI or SNRI-As an alt, augmenting with an alternative mechanism antidepressant, an atypical antipsychotic, BZD, antihistamine, buspirone, or pregabalin may be appropriate -If response (50% reduction in symptoms) has occurred after 4-6 weeks of trial-Continue antidepressant at an optimal dose and re-evaluate at 12 weeks intotherapy-GOAL: remission (absence of symptoms)February 2nd, 2015 CDM 4 Hayley EvansNon-pharm-Psychotherapy: cognitive behavioral therapy, supportive psychotherapy-Relaxation training-Meditation exercises 2.Recall proposed mechanisms of action, side effect profiles, and drug interactions of available anxiolytics.Benzodiazepines-Most frequently used for ACUTE treatment-Provide rapid relief of anxiety symptoms-Short term use: can be used for 2-3 weeks max as bridge therapy until 1st line agent becomes therapeutic-long term use is not recommended MOA: bind to the gamma subunit of the GABA-A receptor, causing an allosteric modification of the receptor that results in an increase in GABA-A receptor activity Drug Brand nameApproved dosagerange (mg/day)Max dose for geri-atric pts (mg/day)Approx equivalent dose (mg)CommentsalprazolamXanax 0.75-4 (IR)1-10 (XR)2 0.5 Assoc. w/ significantrebound anxietyclonazepamKlonopin 1-4 3 0.25-0.5clorazepateTranxene 7.5-60 30 7.5diazepam Valium 2-40 20 5lorazepamAtivan 0.5-10 3 1 Preferred in elderlyoxazepam Serax 30-120 60 30 Preferred in elderlyDrug Time to peak plasma level (hours)Elimina-tion half-life, parent(hours)Metabolic pathwayClinically significant interactionsProtein binding (%)alprazolam 1-2 12-15 oxidation no 80clonazepam 1-4 5-30 N-dealkyl-ation, oxidationno 85clorazepate 1-2 prodrug oxidation yes 97February 2nd, 2015 CDM 4 Hayley Evansdiazepam 0.5-2 20-80 oxidation yes 98lorazepam 2-4 10-20 conjugation no 85Adverse Effects Adverse drug reactionMonitoring parameterMedication education pointsDrowsiness, fatigue Patient interview Avoid operating large machinery; tolerance to sedation develops after repeated dosingAnterograde amnesia,memory impairmentPatient interview Risk of anterograde amnesia worsened with concomitant alcoholWithdrawal symptoms Physical exam; patient interviewTaper doses on discontinuationDependence Patient interview; prescription monitoring program(Monitor for early refills or escalation of dosage)Respiratory depressionRespiratory rate Avoid taking with other CNS depressantsPsychomotor impairmentPhysical exam(↑ risk of falls)Paradoxical disinhibitionPhysical exam; family report(↑ in anxiety, irritability, or agitation may be seenin the elderly or children)Discontinuation-Common symptoms of BZD withdrawal include: anxiety, insomnia, restlessness, muscle tension, irritability-Withdrawal seizures can occur with d/c of BZDs with a short elimination half- life , usually within 3 days of d/c drug, high BZD doses, long duration of therapy, and concurrent use of drugs that lower seizure threshold are risk factors-25% per week reduction in dose until 50% of the dose is reached, followed by dosage reduction by 12.5% every 4-7 days -long term use of BZDs requires a 2-4 month slow taperPharmacodynamic-Alcohol + BZD= additive CNS depressant effects-Other CNS depressants e.g. opioids, antipsychotics, antihistamines + BZD = potentiation of adverse sedative effectsFebruary 2nd, 2015 CDM 4 Hayley EvansPharmacokinetic-Concurrent use of CYP3A4 inhibitors: may increase blood levels