NOTHING TO WORRY ABOUT: TREATMENT REFRACTORY ANXIETY DISORDERS - PowerPoint PPT Presentation

NOTHING TO WORRY ABOUT: TREATMENT REFRACTORY ANXIETY DISORDERS

Learning Objectives • Explore factors that guide antidepressant selection and dosing • Discuss the evidence of “next-line” interventions in treatment- resistant anxiety disorders • Review the evidence for selective GABAergic interventions and benzodiazepines in treatment-resistant anxiety

Disclosures of Potential Conflicts Source Consultant Royalties Speakers’ Research Material Support Bureau Support Myriad X X FDA X Otsuka X Allergan X Lundbeck X National Institutes of X Health Springer Publishing X CMEology X Neuronetics X

Learning Objectives • Explore factors that guide antidepressant selection and dosing • Discuss the evidence of “next-line” interventions in treatment- resistant anxiety disorders • Review the evidence for selective GABAergic interventions and benzodiazepines in treatment-resistant anxiety

Off-Label Medication Use Dr. Strawn does intend to discuss the use of off-label/unapproved use of drugs.

What is Treatment-Resistant Anxiety? • Failed at least one first-line NRT treatment, SSRI/SNRI SNRI SERT SSRI SERT • Failed psychotherapeutic treatment • At least one first-line psychotherapeutic treatment (e.g., CBT) • Current symptoms in the moderate range + impairment Bookma et al. Aligning the many definitions of treatment resistance in anxiety disorders: a systematic review. Depression & Anxiety 2019;36(9):801-12.

How Common is Treatment- Resistant Anxiety

Prevalence of Treatment-Resistant Anxiety Acute Response in Clinical Trials • 50–60% of patients respond to initial treatment • Remission rates are generally between 25–35% Probability of Recurrence Relapse • Half of initial responders experience recurrence Time Spent Ill • GAD 74% • Social anxiety 80% • Panic disorder 41% Time Since Recovery (years) Cowley et al. J Clin Psychiatry 1997;58:554-561. Ramsawh.J Affect Disord 2011;132:260-4. Bruce et al. Am J Psychiatry 2005;162:1179-87.

Approaching Treatment-Resistant Anxiety

Treatment Resistance Comorbidity and other factors • Unrecognized substance use • Over-the-counter medications • Situational or interpersonal context • Comorbid • Personality disorders • ADHD • Trauma, abuse, posttraumatic stress symptoms

Treatment Resistance Medical Factors & Concurrent Medications/Substances • Tachyarrhythmias • Concurrent medications • Routine screening EKG, high false • Caffeine negatives • What does the evidence actually show? • Thyroid disease • Sympathomimetics • AM TSH with exam consistent with hyperthyroidism, irregular menses, • Corticosteroids recent weight change • Concurrent marijuana use • Age >35 • Next slide • Family history of thyroid disease • Prior history of abnormal TSH • Concurrent medications that affect thyroid function (e.g., amiodarone, benzodiazepines?)

vs. THC Cannabidiol isomer of THC NOT psychoactive Psychoactive anxiolytic anxiogenic anticonvulsant Greydanus DE et al. Disease Month 2015;61:118-75. Iseger TA, Bossong MG. Schizophr Res 2015;162:153-61. Mammen et al. J Clin Psychiatry 2018;79:17r11839.

THC vs. Cannabidiol: Different Binding Properties central and peripheral neuron terminals immune cells CB1 CB1 CB2 CB2 THC: partial agonist THC: partial agonist CBD: unclear binding at CB receptors; (low affinity?) may interact with 5HT receptors

THC vs. CBD: Psychiatric Effects Cannabis w/ Cannabis w/ CBD alone Low CBD Content High CBD Content Psychosis symptoms Higher risk of Lower risk of hallucinations Possible antipsychotic hallucinations and and delusions effects delusions Psychotic disorder Earlier age of onset Later age of onset Cognition Higher risk of acute Lower risk of acute memory impairment memory impairment Anxiety Anxiogenic; Anxiolytic; Increased amygdalar Reduced amygdalar activity activity Iseger TA, Bossong MG. Schizophr Res 2016;162:153-61.

Treatment Resistance Diagnostic Re-evaluation Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Treatment Resistance Diagnostic Re-evaluation Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus Difficult to control anxiety Intermittent panic, anxiety, or avoidance about multiple things Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Treatment Resistance Diagnostic Re-evaluation Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus Difficult to control anxiety Intermittent panic, anxiety, or avoidance about multiple things Fear of Some uncued, Fear of specific embarrassment and spontaneous objects/situations social scrutiny episodes of anxiety Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Treatment Resistance Diagnostic Re-evaluation Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus Difficult to control anxiety Intermittent panic, anxiety, or avoidance about multiple things Fear of Some uncued, Fear of specific embarrassment and spontaneous objects/situations social scrutiny episodes of anxiety Evaluate for Evaluate for Evaluate for Evaluate for social anxiety specific panic disorder agoraphobia disorder phobia Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Treatment Resistance Diagnostic Re-evaluation Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus Difficult to control anxiety Intermittent panic, anxiety, or avoidance about multiple things Fear of Some uncued, Fear of specific embarrassment and spontaneous objects/situations social scrutiny episodes of anxiety Evaluate for Evaluate for Evaluate for Evaluate for social anxiety Evaluate for GAD specific panic disorder agoraphobia disorder phobia Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Treatment Resistance Dose and Prior Trials

Considering Mechanism of Action in Treatment-Resistant Anxiety

Treatment Resistance and Mechanisms of Action Transporters 5-HT NE Dopamine G-Protein 5-HT 1A 5-HT 1B 5-HT 1D 5-HT 2C 5-HT 7 alpha 2 Receptors- linked receptors Ion 5-HT 3 GABA Channel- linked receptors Monoamine Enzymes Oxidase

SSRIs in Anxiety Disorders: Beyond the Basics

Citalopram & Escitalopram Metabolism Amine 2C19 oxidase 2D6 3A4 r-desmethyl- r-didesmethyl- R-Citalopram citalopram citalopram 2D6 2D6 Citalopram N-oxide Amine 2C19 oxidase 2D6 3A4 s-desmethyl- s-didesmethyl- S-Citalopram 2D6 citalopram citalopram

2C19 Polymorphisms and Therapeutic Failure Jukic et al. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: a retrospective study based on 2,087 patients. American Journal of Psychiatry 2018;175(2):463-70.

SSRI Dosing in Anxiety Disorders Jakubovski et al. Systematic review and meta ‐ analysis: Dose–response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety 2019;36(3):198-212.

SSRI + CBT Augmentation in GAD • Outpatients with GAD, >60 years of age, N=73 Escitalopram Placebo • Open-label + CBT Escitalopram + CBT escitalopram then without CBT randomized to: • 16 wks of escitalopram + CBT, then escitalopram maintenance (28 wk); Placebo • escitalopram, then maintenance Relapse Prevention in without CBT escitalopram; Social Anxiety Disorder • escitalopram + CBT, then placebo; • escitalopram, followed by placebo. Wetherell et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am. J. Psychiatry 2013;170(7):782-9.

SNRIs in Anxiety Disorders: Beyond the Basics

Treatment Resistance and Mechanisms of Action Transporters 5-HT NE Dopamine G-Protein 5-HT 1A 5-HT 1B 5-HT 1D 5-HT 2C 5-HT 7 alpha 2 Receptors- linked receptors Ion 5-HT 3 GABA Channel- linked receptors Monoamine Enzymes Oxidase

Treatment Resistance and Mechanisms of Action Transporters 5-HT NE Dopamine G-Protein 5-HT 1A 5-HT 1B 5-HT 1D 5-HT 2A 5-HT 7 alpha 2 Receptors- linked receptors Ion 5-HT 3 GABA Channel- linked receptors Monoamine Enzymes Oxidase

Noradrenergic Reuptake Inhibition in PFC Norepinephrine Transporter Norepinephrine Dopamine

Venlafaxine • FDA-approved for GAD, MDD, panic disorder, and social anxiety disorder • o -desmethyl-venlafaxine • inhibits 5-HT and NE reuptake transporters • greater potency at the NE transporter • Dose-related increases in BP

VENLAFAXINE > DESVENLAFAXINE DESVENLAFAXINE > VENLAFAXINE Haslemo et al. Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. Br J Clin Pharmacol 2019;85(1):194–201.

SNRI Dosing in Anxiety Disorders Week of Treatment 0 4 8 12 0 -0.1 Difference in Anxiety Standardized Mean -0.2 imipramine 100 mg -0.3 imipramine 200 mg imipramine 400 mg -0.4 -0.5 -0.6 -0.7 Jakubovski et al. Depress Anxiety 2019;36(3):198-212.