Clinical Significance of Anxiety in Depressed Patients Selecting an Antidepressant

The Clinical Significance of Anxiety Disorders and the DSM-5 Anxious Distress Specifier in Depressed Patients Clinical Significance of Anxiety in Depressed Patients Selecting an Antidepressant Rhode Island Factors Associated with Antidepressant Choice Study (FAACS) Mark Zimmerman, MD Director of Outpatient Psychiatry Director of the Partial Hospital Program Rhode Island Hospital Professor of Psychiatry Brown Medical School Providence, Rhode Island Rhode Island FAACS Study 10 psychiatrists (7 male; 3 female) AD medication prescribed for depression as part of routine clinical practice 43-item Yes/No questionnaire completed immediately after medication prescribed 1137 questionnaires completed 730 initial visit; 297 follow-up visit; 110 missing 669 initiation of treatment; 302 switch; 102 augmentation; 64 missing Factors Influencing Choice of AD Medication Concern of drug interaction 5.6% Avoid discontinuation syndrome 0.4% Half-life 1.9% Insurance considerations 0.3% Medication cost 1.0% Availability of samples 9.7% Once per day dosing 15.1% No need to titrate 0.2% Concern about suicidality 4.1% AD = antidepressant. Factors Influencing Choice of AD Medication (cont d) Comorbid Conditions Influencing AD Choice Prior positive response 17.0% Familial positive response 4.0% Patient expressed interest 5.2% Bad public relations 1.1% Prior failure with medication 25.9% Presence of comorbid disorder 45.6% Presence of specific symptom 52.3% Avoid specific side effects 48.7% Panic disorder 12.3% GAD 16.3% OCD 4.2% OCD spectrum 0.4% ADHD 2.8% Social phobia 3.6% Impulse control d/o 1.4% Bulimia 1.1% PTSD 5.1% ADHD = attention-deficit/hyperactivity disorder; GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder.

Specific Symptoms Influencing AD Choice Clinical Significance of Anxiety in Depressed Patients Insomnia 18.2% Hypersomnia 7.1% Reduced appetite 5.4% Increased appetite 7.2% Fatigue 14.2% High anxiety 19.9% Anger/irritability 8.1% Atypical features 1.3% Melancholic features 2.4% Impaired functioning Increased suicidality Poorer response to acute treatment Increased risk of relapse Reduced rate of remission Andreescu C, et al. Br J Psychiatry. 2007;190:344-349. Fava M, et al. Psychol Med. 2004;34(7):1299-1308. Kessler RC, et al. Epidemiol Psychiatr Serv. 2015;24(3):210-226. Melartin TK, et al. J Clin Psychiatry. 2004;65(6):810-819. Pfeiffer PN, et al. Depress Anxiety. 2009;26(8):752-757. Sherbourne CD, et al. J Affect Disord. 1997;43(3):245-250. Schaffer A, et al. Can J Psychiatry. 2000;45(9):822-826. Seo HJ, et al. J Nerv Ment Dis. 2011;199(1):42-48. Simon NM, et al. J Psychiatr Res. 2007;41(3-4):255-264. Different Approaches Towards Identifying Anxiety in Depressed Patients How Frequent is Anxiety in Depressed Patients? DSM anxiety disorder diagnosis Hamilton Rating Scale for Depression Anxiety/Somatization Factor Hamilton Rating Scale for Depression anxiety items Montgomery-Åsberg Depression Rating Scale anxiety item Hamilton Anxiety Rating Scale DSM-5 Anxious Distress Specifier Frequency of Anxiety Disorders in Depressed Patients Depends on broadness of definition Current vs lifetime Full criteria vs Full + partial remission NOS diagnoses Findings from the Rhode Island MIDAS project 373 MDD outpatients Full criteria 57.4% Full + partial remission 60.6% Full + partial + NOS diagnoses 67.6% Frequency of Current Anxiety Disorders in 373 Depressed Outpatients Anxiety Disorder Current Full Partial Remission NOS Panic disorder 17.1% 2.4% 2.1% Agoraphobia without panic 1.1% 0.0% 0.0% Specific phobia 13.7% 0.3% 0.5% Social phobia 33.0% 0.0% 0.8% OCD 9.9% 0.0% 0.5% PTSD 13.4% 8.3% 9.4% GAD 15.0% 0.0% 1.6% MIDAS = Methods to Improve Diagnostic Assessment and Services; MDD = major depressive disorder; NOS = not otherwise specified. Zimmerman M, et al. Am J Psychiatry. 2000;157(8):1337-1340. Zimmerman M, et al. Am J Psychiatry. 2000;157(8):1337-1340.

Other Studies on the Prevalence of Anxiety Disorders in Depressed Patients Anxiety Disorder MIDAS (n = 373) Melartin (n = 269) Fava (n = 255) Kessler (n = 1530) Any anxiety disorder 57.4% 57% 44.7% 57.5% Panic disorder 17.1% 17% 8.2% Agoraphobia without 1.1% 12% 5.1% panic Specific phobia 13.7% 25% 14.9% Social phobia 33.0% 20% 26.2% OCD 9.9% 7% 4.7% PTSD 13.4% 1% --- GAD 15.0% 14% 10.2% Fava M, et al. Compr Psychiatry. 2000;41(2):97-102. Kessler RC, et al. JAMA. 2003;289(23):3095-3105. Melartin TK, et al. J Clin Psychiatry. 2002;63(2):126-134. Are Comorbid Anxiety Disorders Underrecognized in Depressed Patients? Frequency of current DSM-IV disorders compared in 2 independent cohorts: 300 depressed outpatients interviewed with the SCID 610 depressed outpatients interviewed by psychiatrist s unstructured clinical interview (ie, usual care) The 2 samples were similar in demographic characteristics and scores on a self-report symptom scale. SCID = Structured Clinical Interview for DSM. Zimmerman M, et al. J Psychiatr Res. 2003;37(4):325-333. Frequency of Current Anxiety Disorders in Depressed Patients Desire for Treatment for Comorbid Anxiety Disorders in Depressed Patients nonscid SCID Odds (n = 610) (n = 300) Ratio Panic disorder 8.1% 15.7% 2.1 Social phobia 2.1% 32.7% 22.3 Specific phobia 0.8% 12.3% 17.0 PTSD 7.7% 11.3% 1.5 GAD 6.7% 20.0% 3.5 OCD 3.3% 8.7% 2.8 Any anxiety disorder 23.6% 57.3% 4.3 n Treatment Desired Panic disorder 47 97.9% Social phobia 98 73.5% Specific phobia 37 56.8% PTSD 34 88.2% GAD 60 91.7% OCD 26 80.8% Any anxiety disorder 172 86.6% Zimmerman M, et al. J Psychiatr Res. 2003;37(4):325-333. Zimmerman M, et al. J Psychiatr Res. 2003;37(4):325-333. Improving Detection Semi-structured interviews Screening questionnaires Screening Measures General distress Global anxiety Anxiety disorders Single disorders Multiple disorders Screen for Adult Anxiety Related Disorders (SCAARED) Augmented Provisional Diagnostic Interview (PDI) Psychiatric Diagnostic Screening Questionnaire (PDSQ) Angulo M, et al. Psychiatry Res. 2017;253:84-90. Houston JP, et al. Postgrad Med. 2011;123(5):89-95. Zimmerman M, et al. Arch Gen Psychiatry. 2001;58(8):787-794.

A Brief Review of Principles of Screening Screening and Diagnosis: A 2-Stage Process 2-stage process Deriving a cutoff score Statistics of Screening Cutoff Score Selection Cutoff score is not an invariant component of the test Depends on purpose of test Impact of Lowering the Cutoff Score Impact of Raising the Cutoff Score

Cutoff Score Selection for Screening Screening for Anxiety Disorders in Depressed Patients High sensitivity Cast broad net High negative predictive value Rule out the disorder Zimmerman M, et al. J Psychiatr Res. 2006;40(3):267-272. Treatment: Study Designs Key Question 1. Efficacy in treating anxiety in depressed patients Open-label Active vs active Placebo-controlled: active vs placebo Placebo-controlled: active vs active vs placebo Is there evidence of differential treatment response? 2. Efficacy in treating depression (and anxiety) in anxious depressed patients Open-label Active vs active Placebo-controlled: active vs placebo Placebo-controlled: active vs active vs placebo STAR*D Level 1 STAR*D Level 2 Level 1 treatment citalopram 2876 patients Anxious depression: > 7 on HAMD Anxiety/Somatization Factor 53% with anxious depression Results 1. Anxious depression associated with poorer outcome Remission rate: 22.2% vs 33.4%, P <.001 Response rate: 41.7% vs 52.8%, P <.001 2. Anxious depression associated with slower response HAMD = Hamilton Rating Scale for Depression Scale; STAR*D = Sequenced Treatment Alternatives to Relieve Depression. Fava M, et al. Am J Psychiatry. 2008;165(3):342-351. Level 2 treatment Switch: Bupropion vs sertraline vs venlafaxine XR Augment citalopram: bupropion vs buspirone Results (remission rates) 1. Switch arm: Anxious vs nonanxious groups Bupropion: 10.2% vs 33.9% Sertraline: 8.3% vs 28.5% Venlafaxine XR: 12.1% vs 36.4% 2. Augmentation of citalopram arm Bupropion: 17.9% vs 36.7% Buspirone: 9.2% vs 39.2% XR = extended release. Fava M, et al. Am J Psychiatry. 2008;165(3):342-351.

CO-MED 665 patients randomized to 3 treatment groups Escitalopram + placebo Escitalopram + bupropion SR Venlafaxine XR + mirtazapine Anxious depression: > 7 on HAMD Anxiety/Somatization Factor 75% with anxious depression Results 1. Presence of anxious features was not associated with: Outcome in any medication group Difference in outcome between medication groups SR = sustained release. Chan HN, et al. Intl J Neuropsychopharmacol. 2012;15(10):1387-1399. Meta- and Pooled Analyses of Efficacy in Anxious Depressed Patients: Placebo-Controlled Studies Baldwin Vortioxetine 10 studies HAMA > 20 Davidson Venlafaxine 5 studies HAMD psychic anxiety > 3 Delini-Stula Imipramine 5 studies various Fawcett Mirtazapine 8 studies HAMD anxiety items Kornstein Desvenlafaxine 7 studies HAMD A/S factor > 7 Nelson Duloxetine 11 studies HAMD A/S factor > 7 Papakostas Escitalopram 13 studies HAMD A/S factor > 7 Thase Quetiapine 2 studies HAMD A/S factor > 7 Thase Vilazodone 2 studies HAMD A/S factor > 7 Tollefson Fluoxetine 19 studies HAMD A/S factor > 7 HAMA = Hamilton Anxiety Rating Scale; A/S = anxiety/somatization. Baldwin DS, et al. J Affect Disord. 2016;206:140-150. Davidson JR, et al. Depress Anxiety. 2002;16(1):4-13. Delini-Stula A, et al. Int J Psychiatry Clin Pract. 2000:4(2):111-117. Fawcett J, et al. J Clin Psychiatry. 1998;59(3):123-127. Kornstein SG, et al. Hum Psychopharmacol. 2014;29(5):492-501. Nelson JC. Depress Anxiety. 2010;27(1):12-18. Papakostas GI, et al. Eur Arch Psychiatry Clin Neurosci. 2011;261(3):147-156. Thase ME, et al. Depress Anxiety. 2012;29(7):574-586. Thase ME, et al. Intl Clin Psychopharmacol. 2014;29(6):351-356. Tollefson GD, et al. J Clin Psychiatry. 1994;55(2):50-59. Meta- and Pooled Analyses of Efficacy in Anxious Depressed Patients: Head-to-Head Comparisons Davidson Venlafaxine vs fluoxetine (5) HAMD psychic anxiety >3 Delini-Stula Moclobemide vs imipramine (5) various Fawcett Mirtazapine vs amitriptyline (4) HAMD anxiety items Papakostas Escitalopram vs SSRIs (7) HAMD A/S factor > 7 Escitalopram vs SNRIs (4) HAMD A/S factor > 7 Papakostas Bupropion vs SSRIs (10) HAMD A/S factor > 7 Tollefson Fluoxetine vs TCAs (14) HAMD A/S factor > 7 SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant. Davidson JR, et al. Depress Anxiety. 2002;16(1):4-13. Delini-Stula A, et al. Int J Psychiatry Clin Pract. 2000:4(2):111-117. Fawcett J, et al. J Clin Psychiatry. 1998;59(3):123-127. Papakostas GI, et al. Eur Arch Psychiatry Clin Neurosci. 2011;261(3):147-156. Papakostas GI, et al. J Clin Psychiatry. 2008;69(8):1287-1292. Tollefson GD, et al. J Clin Psychiatry. 1994;55(2):50-59. Literature Review Review of 31 studies of dimensional anxious depression 71% used HAMD Anxiety/Somatization Factor Score Conclusions 1. SSRIs, SNRIs, and TCAs are effective in treating anxious depression 2. Patients with anxious depression have poorer outcome than patients without anxiety 3. Anxious depression associated with greater rate of side effects 4. Patients with anxious depression often do not experience sustained response or remission following initial treatment success Ionescu DF, et al. Prim Care Companion CNS Disord. 2014;16(3). National Institute of Health and Clinical Excellence (NICE) (2009) Official Treatment Guidelines NICE clinical guideline 90 Depression: The Treatment and Management of Depression in Adults 1.6.1.1 Do not routinely vary the treatment strategies for depression described in this guideline by depression subtype as there is no convincing evidence to support such action. NICE. Depression in Adults: Recognition and Management. www.nice.org.uk/guidance/cg90/chapter/1- guidance. Accessed June 2, 2017.

Canadian Network for Mood and Anxiety Treatments (CANMAT) (2009) Comorbid anxiety and substance use disorders are frequently associated with MDD, although there is also substantial overlap with eating disorders and attention deficit hyperactivity disorder. While these comorbidities do not substantially alter treatment selection, in general, there are lower rates of response and remission in patients with comorbid conditions. American Psychiatric Association (2010) Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition SSRIs are beneficial for patients with co-occurring depression and social anxiety disorder and co-occurring depression and PTSD. Bupropion is comparable to SSRIs in the treatment of patients with MDD and low to moderate levels of anxiety. Clomipramine and SSRIs have demonstrated efficacy in managing obsessive-compulsive symptoms in addition to treating depression. Lam RW, et al. J Affect Disord. 2009;117 Suppl 1:S26-S43. American Psychiatric Association Work Group on Major Depressive Disorder. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed June 2, 2017. British Association for Psychopharmacology (2015) Evidence-based Guidelines for Treating Depressive Disorders with Antidepressants If anxiety does impair outcomes of antidepressant treatment, there are few indications that one type of antidepressant is notably more effective than another, and the NNTs of those differences found are of small clinical relevance in most circumstances Canadian Network for Mood and Anxiety Treatments (CANMAT) (2016) Use an antidepressant with efficacy in generalized anxiety disorder (Level 4 ie, Clinical Consensus) No differences in efficacy between SSRIs, SNRIs, and bupropion (Level 2) NNT = number needed to treat. Cleare A, et al. J Psychopharmacol. 2015;29(5):459-525. Kennedy SH, et al. Can J Psychiatry. 2016;61(9):540-569. Influence of Insomnia on AD Selection What is the Bupropion Story? No Insomnia Insomnia (n = 202) Fluoxetine (8.3%) 10.2% 0.5% Sertraline (12.3%) 14.8% 2.5% Venlafaxine (12.3%) 14.7% 3.0% Bupropion (17.4%) 21.6% 0.5% Paroxetine (7.3%) 6.9% 9.9% Citalopram (23.4%) 25.5% 15.8% Nefazodone (4.8%) 2.9% 14.4% Mirtazapine (9.4%) 1.6% 45.5% TCA (2.9%) 1.6% 7.9%

Influence of Anxiety on AD Selection No Anxiety Anxious (n = 202) Bupropion (17.4%) 21.8% 1.4% Fluoxetine (8.3%) 9.7% 3.2% TCA (2.9%) 2.5% 4.5% Sertraline (12.3%) 12.4% 13.1% Paroxetine (7.3%) 7.1% 9.0% Citalopram (23.4%) 22.9% 27.1% Mirtazapine (9.4%) 9.2% 11.3% Venlafaxine (12.3%) 10.6% 20.4% Nefazodone (4.8%) 3.7% 10.0% Papakostas Meta-Analysis #1 Efficacy of bupropion and SSRIs in treating anxiety symptoms in depressed patients 10 studies Anxiety symptoms measured by HAMA and HAMD A/S factor No difference between bupropion and SSRIs in reducing anxiety symptoms Conclusion: Contrary to clinician impression, there does not appear to be any difference in the anxiolytic efficacy of bupropion and the SSRIs when use to treat MDD. Papakostas GI, et al. J Psychiatr Res. 2008;42(2):134-140. Papakostas Meta-Analysis #2 A Major Limitation: Subject Selection Efficacy of bupropion and SSRIs in treating depressed patients with high levels of anxiety 10 studies High anxiety: HAMD A/S factor > 7 Response rate significantly greater with SSRIs for anxious patients on HAMD (65.4% vs 59.4%) and HAMA (61.5% vs 54.5%). No difference between bupropion and SSRIs in nonanxious patients Conclusion: There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Papakostas GI, et al. J Clin Psychiatry. 2008;69(8):1287-1292. Zimmerman M, et al. Mayo Clin Proc. 2015;90(9):1180-1186. An Alternative Approach: DSM-5 Anxious Distress Specifier Criteria Presence of at least 2 of the following symptoms during the majority of days of the episode: Feeling keyed up or tense Feeling unusually restless Difficulty concentrating because of worry Fear that something awful may happen Feeling that the individual might lose control of himself or herself Empirical Support for the DSM-5 Anxious Distress Specifier Criteria American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

Studies of the DADS Some studies have used proxies of the DADS from measures developed before the specifier was defined One study assessed 3 criteria (but still required at least 2) Another study assessed 4 criteria (and required at least 2) DADS = DSM-5 Anxious Distress Specifier. McIntyre RS, et al. Ther Adv Chronic Dis. 2016;7(3):153-159. McIntyre RS, et al. J Affect Disord. 2016;201:116-123. Measures of the DADS Clinically Useful Depression Outcome Scale Anxious Distress Specifier Subscale (CUDOS-A) A self-report scale 5 items rated on 5-point ordinal scale I felt keyed up or on edge because I was worried about things. I felt very fidgety, making it difficult to sit still. I had difficulty concentrating because my mind was on my worries. I worried a lot that something bad might happen. When I was extremely anxious, I was afraid I would lose control. Zimmerman M, et al. J Clin Psychiatry. 2014;75(6):601-607. Reliability and Validity of the CUDOS-A Sample 793 depressed outpatients Reliability and Validity of the CUDOS-A: Association with Anxiety Disorder Diagnosis Reliability Internal consistency Cronbach s alpha =.79 Test-retest reliability =.89 Discriminant and convergent validity Correlation with SADS anxiety =.47 Correlation with SADS depression =.16 SADS = Schedule for Affective Disorders and Schizophrenia. Zimmerman M, et al. J Clin Psychiatry. 2014;75(6):601-607. Zimmerman M, et al. J Clin Psychiatry. 2014;75(6):601-607. Reliability and Validity of the CUDOS-A: Association with Impairment in Functioning Interview Measure: DSM-5 Anxious Distress Specifier Interview (DADSI) Sample: 173 partial hospital patients in major depressive episode Reliability (n = 23) Joint interview interrater reliability Subtyping: kappa = 1.0 Dimensional score: intraclass correlation coefficient =.93 Test-retest interrater reliability Subtyping: kappa=.60 Dimensional score: intraclass correlation coefficient =.80 Zimmerman M, et al. J Clin Psychiatry. 2014;75(6):601-607. Zimmerman M, et al. Compr Psychiatry. 2017;76:11-17.

DADSI Discriminant and Convergent Validity DADSI: Sensitivity to Change Discriminant and convergent validity Correlation with SADS anxiety/depression =.54/.28 Correlation with CUXOS/CUDOS =.49/.30 Correlation with HAMA/HAMD =.59/.45 Correlation with HAMD anx/melan subscales =.49/.30 CUXOS = Clinically Useful Anxiety Outcome Scale. Zimmerman M, et al. Compr Psychiatry. 2017;76:11-17. Zimmerman M, et al. Compr Psychiatry. 2017;76:11-17. Association between DADSI and HAMD Anxiety/Somatization Factor Sample: 202 depressed patients in partial hospital Measures: DADSI HAMD Results 1. Frequency of anxious subtype DADSI 78.2% HAMD 67.3% 2. Correlation between dimensional scores: r =.50 3. Categorical agreement in subtyping: k =.21 Questions for Future Research on the DADS Clinical significance of the DADS Comparative validity to other indicators of anxiety Is the DADS a simpler, more clinically useful, way of assessing anxiety in depressed patients? Definition of the DADS Which symptoms What cutoff Cross-sectional vs entire episode Zimmerman M, et al. J Psychiatr Res. 2017; In press. Conclusions How frequent are anxiety disorders in depressed patients? About 50% of depressed patients have an anxiety disorder Most overlooked disorder social anxiety disorder Screening scales can improve detection What is the clinical significance of comorbid anxiety? Patients want anxiety treated Greater psychosocial impairment Poorer response to treatment Psychiatrists prescribing practice is influenced Is there a best antidepressant for highly anxious depressed patients? Clinical guidelines say no Conclusions (cont d) Is there a worst antidepressant for highly anxious depressed patients? Clinical guidelines say no What advantages does the DSM-5 anxious distress specifier offer? Simpler and less time consuming to assess