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’ Bureau Research Support Material Support Myriad X X FDA X Otsuka X Allergan X Lundbeck X National Institutes of Health X 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

treatment, SSRI/SNRI

• Failed psychotherapeutic treatment
• At least one first-line psychotherapeutic

treatment (e.g., CBT)

• Current symptoms in the moderate

range + impairment

SERT

SSRI

Bookma et al. Aligning the many definitions of treatment resistance in anxiety disorders: a systematic review. Depression & Anxiety 2019;36(9):801-12.

NRT SERT

SNRI

How Common is Treatment- Resistant Anxiety

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.

Acute Response in Clinical Trials

• 50–60% of patients respond to

initial treatment

• Remission rates are generally

between 25–35% Relapse

• Half of initial responders

experience recurrence Time Spent Ill

• GAD 74%
• Social anxiety 80%
• Panic disorder 41%

Prevalence of Treatment-Resistant Anxiety

Probability of Recurrence Time Since Recovery (years)

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
• Routine screening EKG, high false

negatives

• Thyroid disease
• AM TSH with exam consistent with

hyperthyroidism, irregular menses, recent weight change

• Age >35
• Family history of thyroid disease
• Prior history of abnormal TSH
• Concurrent medications that affect

thyroid function (e.g., amiodarone, benzodiazepines?)

• Concurrent medications
• Caffeine
• What does the evidence actually

show?

• Sympathomimetics
• Corticosteroids
• Concurrent marijuana use
• Next slide

THC Cannabidiol vs.

Psychoactive anxiogenic NOT psychoactive anxiolytic anticonvulsant isomer

• f THC

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

CB1 CB1

central and peripheral neuron terminals immune cells

CB2 CB2

THC: partial agonist THC: partial agonist (low affinity?) CBD: unclear binding at CB receptors; may interact with 5HT receptors

Psychosis symptoms Higher risk of hallucinations and delusions Lower risk of hallucinations and delusions Possible antipsychotic effects Psychotic disorder Earlier age of onset Later age of onset Cognition Higher risk of acute memory impairment Lower risk of acute memory impairment Anxiety Anxiogenic; Increased amygdalar activity Anxiolytic; Reduced amygdalar activity

THC vs. CBD: Psychiatric Effects

Cannabis w/ Low CBD Content Cannabis w/ High CBD Content CBD alone

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 Intermittent panic, anxiety, or avoidance Difficult to control anxiety 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

Fear of embarrassment and social scrutiny Fear of specific

• bjects/situations

Some uncued, spontaneous episodes of anxiety

Intermittent panic, anxiety, or avoidance Difficult to control anxiety about multiple things

Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus

Evaluate for social anxiety disorder Evaluate for panic disorder Evaluate for agoraphobia Evaluate for specific phobia Fear of embarrassment and social scrutiny Fear of specific

• bjects/situations

Some uncued, spontaneous episodes of anxiety

Intermittent panic, anxiety, or avoidance Difficult to control anxiety about multiple things

Treatment Resistance Diagnostic Re-evaluation

Adapted from Baldwin et al. J Psychopharmacol 2005;19:567-96.

Significant anxiety-related symptoms and impaired function Evaluate comorbidity Prominent symptom focus

Evaluate for GAD Evaluate for social anxiety disorder Evaluate for panic disorder Evaluate for agoraphobia Evaluate for specific phobia Fear of embarrassment and social scrutiny Fear of specific

• bjects/situations

Some uncued, spontaneous episodes of anxiety

Intermittent panic, anxiety, or avoidance Difficult to control anxiety about multiple things

Treatment Resistance Diagnostic Re-evaluation

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

Transporters G-Protein Receptors- linked receptors Ion Channel- linked receptors 5-HT1A 5-HT1B 5-HT2C 5-HT1D 5-HT7 alpha2 5-HT3 GABA Monoamine Oxidase Enzymes 5-HT NE Dopamine

Treatment Resistance and Mechanisms of Action

SSRIs in Anxiety Disorders: Beyond the Basics

Citalopram N-oxide s-didesmethyl- citalopram r-didesmethyl- citalopram

2C19 3A4 2D6

r-desmethyl- citalopram s-desmethyl- citalopram

2C19 3A4 2D6 2D6

Amine

• xidase

Amine

• xidase

S-Citalopram R-Citalopram 2D6 2D6

Citalopram & Escitalopram Metabolism

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.

2C19 Polymorphisms and Therapeutic Failure

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 Dosing in Anxiety Disorders

SSRI + CBT Augmentation in GAD

• Outpatients with GAD,

>60 years of age, N=73

• Open-label

escitalopram then randomized to:

• 16 wks of

escitalopram + CBT, then escitalopram maintenance (28 wk);

• escitalopram, then

maintenance escitalopram;

• escitalopram + CBT,

then placebo;

• escitalopram,

followed by placebo.

Wetherell et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in

• lder adults. Am. J. Psychiatry 2013;170(7):782-9.

Relapse Prevention in Social Anxiety Disorder

Escitalopram without CBT Escitalopram + CBT Placebo without CBT Placebo + CBT

SNRIs in Anxiety Disorders: Beyond the Basics

Treatment Resistance and Mechanisms of Action

Transporters G-Protein Receptors- linked receptors Ion Channel- linked receptors 5-HT1A 5-HT1B 5-HT2C 5-HT1D 5-HT7 alpha2 5-HT3 GABA Monoamine Oxidase Enzymes 5-HT NE Dopamine

Treatment Resistance and Mechanisms of Action

Transporters G-Protein Receptors- linked receptors Ion Channel- linked receptors 5-HT NE Dopamine Enzymes 5-HT1A 5-HT1B 5-HT2A 5-HT1D 5-HT7 alpha2 5-HT3 GABA Monoamine Oxidase

Noradrenergic Reuptake Inhibition in PFC

Norepinephrine Transporter Dopamine Norepinephrine

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

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.

VENLAFAXINE > DESVENLAFAXINE DESVENLAFAXINE > VENLAFAXINE

SNRI Dosing in Anxiety Disorders

Jakubovski et al. Depress Anxiety 2019;36(3):198-212.

• 0.7
• 0.6
• 0.5
• 0.4
• 0.3
• 0.2
• 0.1

4 8 12 imipramine 100 mg imipramine 200 mg imipramine 400 mg Week of Treatment Standardized Mean Difference in Anxiety

How long to treat?

Rickels et al. Time to Relapse After 6 and 12 Months’ Treatment of Generalized Anxiety Disorder With Venlafaxine Extended

• Release. Arch Gen Psychiatry 2010;67(12):1274-81.

Half the rate

• f relapse

compared to 6 months

• f treatment

6 months 12 months

5-HT1A Modulators in Treatment- Resistant Anxiety

Mechanisms of Action

Transporters G-Protein Receptors- linked receptors Ion Channel- linked receptors Enzymes 5-HT NE Dopamine 5-HT1A 5-HT1B 5-HT2A 5-HT1D 5-HT7 alpha2 5-HT3 GABA Monoamine Oxidase

Buspirone in GAD

• Cochrane (κ=36) in adult GAD
• efficacy and tolerability
• more effective in patients who have

not been previously treated with benzodiazepines

• Pediatric GAD
• well-tolerated in youth
• RCTs were underpowered to detect

small effect sizes (Cohen’s d <0.15) (Strawn et al, 2018)

• Age 6 to 17 years, N=559
• Dose: 15-60 mg/day

GSK, Package Insert, accessed 2014.

5-HT1a receptor

Mixed Agents in Treatment- Resistant Anxiety

Treatment Resistance and Mechanisms of Action

Transporters G-Protein Receptors- linked receptors Ion Channel- linked receptors 5-HT1A 5-HT1B 5-HT2C 5-HT2A 5-HT7 alpha2 Enzymes 5-HT3 GABA Monoamine Oxidase 5-HT NE Dopamine

Quetiapine in GAD

• Remission
• 150 mg quetiapine XR 42.6%
• paroxetine 39%
• placebo 27%
• AEs
• Quetiapine
• dry mouth,

somnolence, fatigue dizziness, and headache

• Paroxetine
• nausea, headache,

dizziness Week

Bandelow et al. Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder. Data from a randomized, double-blind, placebo- and active-controlled study. International Journal of Neuropsychopharmacology 2010;13(3):305–20. Maneeton et al. Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials. Drug Design, Development, and Therapy 2016;10:259-76.

• Inhibition of excitatory neurotransmission
• rapid onset (typically ≤1 week)
• Reduces psychic and somatic GAD sx.
• In long-term studies, maintained improvements

and delayed relapse compared with placebo

• AEs: dizziness, somnolence, and weight gain.
• SSRI/SNRI augmentation with pregabalin >

placebo.

Strawn and Geractioti. The treatment of generalized anxiety disorder with pregabalin, an atypical

• anxiolytic. Neuropsychiatr Dis Treat 2007;3(2):237–43.

Baldwin et al. Efficacy and safety of pregabalin in generalised anxiety disorder: A critical review of the literature.J Psychopharmacol 2015;29(10):1047-60.

calcium

Pregabalin

Pregabalin in Treatment-Resistant Anxiety

• 10
• 8
• 6
• 4
• 2

Rickela et al. Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI

• treatment. International Clinical Psychopharmacology 2012;27(3):142–50.
• Adjunctive pregabalin

(150–600 mg/day, n=180) or placebo (n=176)

• HAM-A responder rates >

for pregabalin (48%) vs. placebo (35%; p=0.015)

• Time-to-sustained

response favors pregabalin (p=0.014)

• Discontinuation similar

for pregabalin (4.4%) and placebo (2.3%)

• Pregabalin should be

tapered rather than discontinued abruptly

Baseline WK 1 WK 2 WK 3 WK 4 WK 5 WK 6 WK 7 WK 8

Change avg over 8 weeks

* LS mean change HAM-A score ** * *

* P<0.05; **P=0.01 Treatment-by-week interaction P=0.81 Pregabalin Placebo

Supplements in Treatment- Resistant Anxiety

Lavender Oil: Silexan

• No affinity for targets of other anxiolytics:
• 5-HT, NE, dopamine transporters
• MAO-A
• GABAA
• Lavender oils associated with sex-

steroid signaling disruption  unopposed estrogen action  producing gynecomastia in pre-pubertal youth.

Strawn et al. Expert Opin Pharmacother 2018;19(10):1057-70. Schuwald et al. PLoS ONE 2013;8(4): e59998.

calcium

Lavender Oil: Silexan

• Lorazepam vs. silexan
• comparable improvements
• Double-blind, double-dummy,

paroxetine-referenced trial (N = 539)

• silexan (160 or 80 mg/day) > placebo (p<0.01);

paroxetine trended toward significance (p=0.10)

• silexan well-tolerated and had fewer adverse

events than paroxetine

• Meta-analysis (K = 5)
• greater improvement with 160 mg dose
• side effects were generally mild and include

headache, nausea/diarrhea, eructation

• Woelk. Phytomedicine 2010;17:94–9; Kasper et al. Int. J. Neuropsychopharmacol 2014;17:859–69.

Generoso et al. J Clin Psychopharmacol 2017;37(1):115-7. Yap et al. Efficacy and safety of lavender essential oil (Silexan) capsules among patients suffering from anxiety disorders: A network meta-

• analysis. Sci Rep 2019;9:18042.

Week

• 16
• 14
• 12
• 10
• 8
• 6
• 4
• 2

2 4 6 8 10 Silexan (160 mg) Silexan (80 mg) Paroxetine Placebo

Change in HAM-A score

• Several, but not all RCTs suggest

efficacy

• Banned in several European

countries in the early 2000s secondary to ~100 reports of hepatotoxicity

• Recently reintroduced
• Routine transaminase

monitoring

Pittler et al. Kava extract versus placebo for treating anxiety. Cochrane Database Syst Rev 2003;(1):CD003383. Connor et al. A placebo-controlled study of Kava kava in generalized anxiety disorder. Int Clin Psychopharmacol 2002;17:185–8.

• Ernst. A re-evaluation of kava (Piper methysticum). Br J Clin Pharmacol 2007;415–7.

Strawn et al. Expert Opin Pharmacother 2018;19(10):1057-70.

Monitor LFTs

Kava (Piper methysticum)

Benzodiazepine Augmentation in Treatment-Resistant Anxiety

Augmentation in Tx-Resistant Anxiety

• 24-week RCT of patients with panic disorder:
• Phase 1: 6-week lead-in with open-label sertraline (or escitalopram) to

prospectively define treatment refractoriness (lack of remission)

• Phase 2: 6-week double-blind RCT of (1) increased SSRI dose versus

(2) continued SSRI plus placebo

• Phase 3: 12-week RCT of added CBT compared to “medication-
• ptimization” with SSRI plus clonazepam
• CBT or clonazepam augmentation in non-remitted panic after 12

weeks of an SSRI did not differ

Simon et al. Next-Step Strategies for Panic Disorder Refractory to Initial Pharmacotherapy. J Clin Psychiatry 2009;70(11):1563–70.

Pollack et al. A Double-Blind Randomized Controlled Trial of Augmentation and Switch Strategies for Refractory Social Anxiety Disorder. Am J Psychiatry 2014;171:44-53.

Augmentation in Tx-Resistant Anxiety

Greenblatt et al. Archives of General Psychiatry 1993;50:715.

Patients with Remission, %

10 20 30 40 50 <20 20-39 40-59 >60

Plasma Alprazolam Concentration, ng/mL n=25 n=47 n=56 n=64

Benzodiazepine Exposure in Panic Disorder

Benzodiazepine Tapering

5 10 15 20

Alprazolam Diazepam Mean Hamilton Anxiety Rating Scale Score TAPER NO DRUG 1 2 3 4 5 WEEK END OF STUDY BASELINE

Noyes et al. American J Psychiatry 1991;148(4):517-23.

• Pharmacologic factors
• Higher daily dose
• Shorter half-life
• Longer duration of

therapy

• More rapid taper
• Clinical factors
• Panic disorder or

higher pre-taper anxiety or depression

• Personality

psychopathology

• Concomitant

substance abuse/use

Noyes et al. American J Psychiatry 1991;148(4):517-23.

Predictors of Benzodiazepine Withdrawal

Selective GABAergic Agents in Treatment-Resistant Anxiety

Adjunctive Eszopiclone

• Escitalopram + eszopiclone (n=294) or placebo (n=301) x 10 weeks
• Eszopiclone + escitalopram improved sleep and daytime

functioning (p<0.05)

• No tolerance
• Eszopiclone + escitalopram  greater improvement in anxiety

Pollack et al. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety

• disorder. Arch Gen Psychiatry 2008;65:551–62.

GABA GABA GABA GABA GABA chloride

Gabapentin

Gabapentin in Anxiety Disorders

• 1 positive RCT
• 1 negative RCT
• 1 positive

equivalence- based RCT

Pande et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacology 1999;19(4):341-8. Pande et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clinical

• Psychopharmacology. 2000;20(4):467–71.

Social Anxiety Symptom Score Week

TCAs

Tricyclic Antidepressants

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013. M1 NRI SRI H1 1

sodium channel blocker

NA+

imipramine trimipramine

M1 NRI H1 1

sodium channel blocker

NA+

desipramine lofepramine maprotiline protriptyline

M1

5HT2C

SRI H1 1

sodium channel blocker

NA+

5HT2A NRI

amitriptyline amoxapine (minimal SRI) clomipramine doxepin nortriptyline (minimal SRI)

TCAs: Pharmacokinetics Tips and Pearls

Substrates Inhibitors amitriptyline → nortriptyline imipramine → desipramine clomipramine → desmethylclomipramine doxepin fluvoxamine Inducers tobacco smoking Substrates Inhibitors All TCAs duloxetine fluoxetine paroxetine bupropion duloxetine Inducers none

Spina E et al. Clin Ther 2008;30(7):1206-27. Dubovsky SL. Expert Opinion Drug Metab Toxicol 2015;11(3):369-79.

MAO Inhibitors

Blanco et al. A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder. Arch Gen Psychiatry 2010;67(3):286-95.

Phenelzine, CBT, or Combination Therapy in Social Anxiety Disorder

Patients (Percent) Response Remission (CGI) Combined Combined Phenelzine Phenelzine CBT group Placebo CBT group

Benzo MAOI SSRI AED RIMOA-A Drug Class 1.12 1.0 0.68 0.46 0.42 Effect Size

How do MAOIs stack up?

MAOI Dosing

Thase ME. J Clin Psychiatry 2012;73(suppl 1):10-6.

Starting Dose (mg/day) Titration (mg/day) Initial Target Dose (mg/day) Maximum Daily Dose (mg/day) Isocarboxazid 10–20 None 30–60 30–60 Moclobemide 150 None 300 600 Phenelzine 15–45 15 every 2–3 weeks 15–60 90 Selegiline transdermal 6 3 no less than every 2 weeks 6 6–12 Tranylcypromine 10–30 10 every 2–3 weeks 30–40 60

Beyond “First-Line” Treatments for Anxiety Disorders

Strawn et al. Expert Opin Pharmacother 2018;19(10):1057-70.

First-line

SSRI/SNRI + Psychotherapy Change to different SSRI/SNRI

TCA Quetiapine MAOI Buspirone Long-acting benzo Pregabalin Buspirone Long-acting benzo Pregabalin

Yes No

Response? Continue treatment Partial response? Response? Augmentation

Continue pharmacotherapy for 12 months

Response after 8 weeks?

Yes No Yes Yes No

Partial response? Augmentation

Yes

Summary: Beyond “First-Line” Treatments for Anxiety Disorders

• Non-response
• Consider unrecognized substance use, OTC medications, context-

related anxiety, comorbidity (e.g., personality disorders, ADHD, trauma)

• General medical factors
• Augmentation for partial SSRI response:
• BZDs, eszopiclone, and CBT
• SSRIs and SNRIs are treatment mainstays for anxiety disorders;

however, multiple RCTs support the efficacy of pregabalin, quetiapine, and gabapentin raising the possibility that these agents might be tried in patients who failed to respond to first-line treatment

Posttest 1

A 32-year-old Caucasian ophthalmologist with generalized anxiety disorder is treated with escitalopram 10 mg qAM and has partial improvement in anxiety over 3 months of

• treatment. He has had a 30% reduction in his GAD-7 score. Which is the next best

intervention? 1. Begin cross-titration to duloxetine 2. Begin a cross-titration to citalopram 3. Titrate escitalopram to 20 mg daily 4. Add quetiapine 50 mg qHS

Posttest 2

A 50-year-old preschool teacher with generalized anxiety disorder has a past medical history remarkable for diabetes mellitus which is controlled with metformin 1000 mg BID has been treated with venlafaxine ER 150 mg. She wishes to “not be on an antidepressant anymore.” Which of the following is true regarding the optimal length of treatment prior to discontinuing venlafaxine? 1. Risk of recurrence is lowest when patients have been treated for 3 months 2. Risk of recurrence is lowest when patients have been treated for 6 months 3. Risk of recurrence is lowest when patients have been treated for 12 months 4. Risk of recurrence is unrelated to duration of treatment

Posttest 3

When treating patients with kava (Piper methysticum), which of the following laboratory studies should be monitored? 1. Transaminases (i.e., AST and ALT) 2. Renal function (i.e., creatinine clearance) 3. Thyroid stimulating hormone (TSH) 4. Absolute neutrophil count (ANC)

Posttest 4

Pregabalin: 1. Produces improvement in anxiety symptoms within 1 week 2. Is associated with weight loss 3. Allosterically binds to the GABAA receptor 4. May produce treatment-emergent hypertension