Obsessive-Compulsive Disorder Lisa Zakhary, MD PhD Medical Director,

Obsessive-Compulsive Disorder Lisa Zakhary, MD PhD Medical Director,

Obsessive-Compulsive Disorder Lisa Zakhary, MD PhD Medical Director, OCD and Related Disorders Program Director of Psychopharmacology, Excoriation Clinic and Research Unit Massachusetts General Hospital 10/13/2019 www.mghcme.org Disclosures Research Support: Promentis Pharmaceuticals, Inc. www.mghcme.org www.mghcme.org Wellcome Library (1950) Watts-Freeman lobotomy instruments. [Photo] from https://commons.wikimedia.org/wiki/File:Watts-Freeman_lobotomy_instruments._Wellcome_L0026980.jpg Treatment of OCD Cognitive Behavioral Therapy (CBT)

+ Selective Serotonin Reuptake Inhibitors (SSRIs) www.mghcme.org OCD >2% prevalence, 10th leading cause of disability by WHO Obsessions: repetitive unwanted intrusive thoughts which cause anxiety or distress Compulsions: repetitive behaviors or mental acts performed to neutralize obsessions or reduce anxiety Diagnosis in DSM-5 Presence of obsessions, compulsions, or both Obsessions/compulsions >1h/day or cause distress or impairment Variable insight, may be delusional Ruscio. Molecular Psychiatry 2010; Murray. The Global Burden of Disease 1996; Copyright 2017 by Graham Waters via CartoonStock - www.cartoonstock.com/cartoonview.asp?catref=gwan71 www.mghcme.org

By acting on unwanted (egodystonic) impulse to harm oneself or others Blurting out insults Harm by carelessness (fire, driving) Egodystonic sexual thoughts

Contamination Symmetry/exactness Losing control Compulsions Obsessions Perverse Orientation Religious (scrupulosity) Superstitious (color, numbers) Fear of losing things Many more Cleaning/washing Ordering/arranging Checking (including seeking reassurance)

Repeating Rereading, rewriting Activities (going through door) Body movements (touch, tap, rub) Done in multiples or until it feels right Mental Reviewing, praying, counting, undoing Others Urge to confess Excessive list-making Eating rituals

Superstitious rituals Adapted from https://iocdf.org/about-ocd/ www.mghcme.org Lesser known OCD Losing control By acting on unwanted (egodystonic) impulse to harm oneself or others Blurting out insults or obscenities Harm by carelessness/driving variant Sexual OCD Sexual orientation Perverse (pedophilia, incest, etc.) Postpartum OCD Fear of harming ones infant either by carelessness or by losing control OCD Eating Disorders www.mghcme.org SRIs for OCD Serotonin reuptake inhibitors (SRIs) effective

Clomipramine, 4 RCTs Fluvoxamine, 6 RCTs Fluoxetine, 3 RCTs Sertraline, 6 RCTs Escitalopram, 2 RCTs Citalopram, 1 RCT Paroxetine, 4 RCTs Comparative studies limited, SRIs thought to be equally effective Because high doses often required, SRIs with lower side effect profiles typically trialed first Reviewed in Bandelow. World J Biol Psychiatry. 2008; Reviewed in Fineberg. Int J Neuropsychopharmacol. 2005; Mundo. J Clin Psychopharmacol. 1997; Bergeron R. J Clin Psychopharmacol, 2001; Hollander. J Clin Psychiatry 2003; Montgomery. Eur Neuropsychopharmacol 1993; Romano. J Clin Psychopharmacol 2001; Stein. Curr Med Res Opin 2007; Zohar. British Journal of Psychiatry 1996 www.mghcme.org Which SRI?

Drug Name Target Dose Advantag es Escitalopra m 20 mg/d Well-tolerated Sertraline 200 mg/ d Well-tolerated Fluoxetine 80 mg/d

Well-tolerated, long half-life activating Drug interactions Citalopram 40 mg/d Well-tolerated Potential QTc Reduced max dose may not be sufficient in OCD Paroxetine 60 mg/d Sedation, weight gain, short half-life Fluvoxamin

e 300 mg/ d Sedation Clomiprami ne 250 mg/ d SSRIs Effective Disadvantages Sedation, constipation, urinary retention, HoTN, QTc, seizures, drug interactions, weight gain www.mghcme.org

For the reluctant patient Patience (may take years) Propose micro doses Address w/ therapy Pharmacogenomic testing (e.g.Genesight) www.mghcme.org SSRI trial in OCD High doses (max or >max) often required Response delayed (4-6 wks for initial effect, 10-12 wks for full effect) Rapid titration recommended Trial length: 12 wks (4-6 wks at the maximum tolerable dose) Duration of treatment 1-2 years recommended Consider dose reduction after 1-2 years if mostly asymptomatic Many studies found that lower doses just as effective in maintenance phase When ready to taper, taper no more than 10%25% q12mo to prevent relapse Relapse risk lessened with CBT

Reviewed in Koran. Am J Psychiatry. 2007 www.mghcme.org Typical response to SSRIs SSRI NO RESPONSE PARTIAL RESPONSE www.mghcme.org Treatment approach to OCD PARTIAL RESPONSE TO SSRI INCREASE SSRI DOSE >MAX AUGMENTATION www.mghcme.org First-line augmenting agents for OCD

Risperidone Blockade of dopamine D2 receptor (and serotonin 5-HT2A) 3 positive RCTs, most often used augmenting agent, ~1-2 mg/d Other antipsychotics used but studies limited or mixed Aripiprazole, 2 positive RCTs, least risk of metabolic syndrome, ~10-15 mg/d Haloperidone, 2 positive RCTs, useful in pts with tics, ~2-6 mg/d (beware of tardive dyskinesia) Quetiapine, 5 RCTs, mixed results (2/5 positive), ~300 mg/d Olanzapine, 2 RCTs, mixed results (1/2 positive), ~11 mg/d Meta-analysis (multiple):Risperidone >>>placebo while quetiapine and olanzapine are not Memantine Blocks glutamate receptors 2 positive RCTs, ~10 mg PO BID 5mg PO QHS x7d, then 5mg PO BID x7d, then 10mg PO BID Reviewed in Arumugham. Expert Rev Neurother. 2013; Veale. BMC Psychiatry. 2014; Bloch. Mol Psychiatry. 2006; Dold. Int J Neuropsychopharmacol. 2013; Stewart. J Clin Psychopharmacol. 2010; Ghaleiha. J Psychiatr Res. 2013; Haghighi. Psychopharmacology 2013 www.mghcme.org Second-line augmenting agents for OCD Clomipramine Several positive open-label studies and 1 positive RCT

Study doses varied, ~55-150mg/d (typically 50-75mg) SSRIs can unpredictably increase clomipramine levels, start low dose (25 mg PO QHS) and monitor QTc before and QTc/clomipramine level while titrating Other glutamatergic drugs Lamotrigine, 1 positive RCT, ~100 mg/d Risk of Steven-Johnson Syndrome, standard dosing initiation Check for drug interactions Topiramate, 2 positive RCTs, ~180 mg/d AE (cognitive, sedation, appetite suppression) may be dose-limiting Start 25mg PO QHS, increase by 25mg qweek, reevaluate at 100mg PO QHS N-acetylcysteine (NAC), 2 RCT, ~2400 TDD OTC glutamatergic modulator Addiction, gambling, OCD, schizophrenia, BPAD 600mg PO BID x2 weeks, then 1200mg PO BID (Jarrow or Swanson brand) Pallanti. Eur Psychiatry 1999; Ravizza. Psychopharmacol Bull 1996; Diniz. J Clin Psychopharmacol 2011; Bruno. J Psychopharmacol. 2012; Mowla. CNS Spectr. 2012; Afshar. J Clin Psychopharmacol. 2012; Paydary. J Clin Pharm Ther. 2016 www.mghcme.org A note on anxiolytics Benzodiazepines not proven to be helpful for OCD Clonazepam ineffective in 2 RCTs Interferes with exposure response prevention therapy

Sometimes though used when comorbid GAD or panic disorder present Gabapentin, 900mg TDD, accelerates response to SSRI in open-label study Onder. Eur Arch Psychiatry Clin Neurosci. 2008; Hollander. World J Biol Psychiatry. 2003; Crockett. Ann Clin Psychiatry. 2004 www.mghcme.org Treatment approach to OCD PARTIAL RESPONSE TO SSRI INCREASE SSRI DOSE >MAX AUGMENTATION www.mghcme.org Higher than max SSRI dosing Drug Escitalopram Sertraline Fluoxetine Paroxetine My >max

dosing Notes Check EKG FDA Max Dose Published OCD >max dosing 20 mg/d Up to 60 mg/d 30 mg/d 200 mg/d Up to 400mg/d 300mg/d 80 mg/d Up to 120 mg/d

120 mg/d 60 mg/d Up to 100 mg/d 80 mg/d Fluvoxamin 300 mg/d e Up to 400 mg/ d Clomiprami ne Up to 300mg/ d Not recommended due to seizure risk

Up to 120 mg/ d High dosing controversial given QTc prolongation risk, I consider only with EKG monitoring, pt consent, and h/o failed medication trials Citalopram 250 mg/d 40mg 60 mg/d No guidelines on above maximum dosing in OCD exist doses circled are generally well-tolerated in my practice Koran. Am J Psychiatry. 2007; Ninan. J Clin Psychiatry. 2006; Dougherty. Int Clin Psychopharmacol. 2009 www.mghcme.org Limited alternative to SSRIs Clomipramine, 4 beneficial RCTs, very effective but second-line due to AE

SNRIs Venlafaxine Beneficial in 3 open-label studies Venlafaxine ~265mg/d as effective as clomipramine in comparator RCT, no placebo Venlafaxine ~300mg/d as effective as paxil in comparator RCT, no placebo No sig effect in 1 small placebo-controlled RCT but trial too short (8 wks) Limited studies but may effectively treat OCD, larger placebo-controlled RCTs needed Duloxetine No RCTs Beneficial in case series in 3/4 patients, ~120mg/d Beneficial in single open-label study ~120mg/day Limited studies, but mostly positive, RCTs needed

Option for pts with pain Buspirone, 60mg TDD, 1/3 positive RCTs Mirtazepine, 30-60mg PO QHS, positive open-label study Rauch. J Clin Psychopharmacol. 1996; Sevincok. Aust N Z J Psychiatry. 2002; Hollander. J Clin Psychiatry. 2003; Albert. J Clin Psychiatry. 2002; Denys. J Clin Psychopharmacol. 2003; Yaryura-Tobias. Arch Gen Psychiatry. 1996; Dell'osso. J Psychopharmacol. 2008; Dougherty. Int J Neuropsychopharmacol. 2015; Koran. J Clin Psychiatry. 2005; Grady, Am J Psychiatry. 1993 www.mghcme.org Suggested medication approach to OCD INCREASE SSRI UNTIL SX RESOLVE OR TO MAXIMUM DOSE/ HIGHEST TOLERABLE DOSE FOR 12WKS NO RESPONSE TO SSRI SWITCH TO DIFFERENT SSRI (at least 2) SWITCH TO DIFFERENT CLASS Clomipramine Venlafaxine Duloxetine PARTIAL RESPONSE TO SSRI

INCREASE SSRI>MAX AUGMENT Escitalopram, 30 mg/d Risperidone/Aripiprazole Sertraline, 300 mg/d Memantine Fluoxetine, 120 mg/d CBT Clomipramine Topiramate Lamotrigine NAC www.mghcme.org Treatment of pts with OCD and BPAD 11-25% pts with bipolar disorder have OCD SSRIs can induce mania

Not well-studied although a few principles have emerged Mood stabilization alone may treat OCD sx MULTIPLE mood stabilizers/antipsychotics may be required for OCD remission SSRIs should only be considered for severe cases AND with mood stabilizer CBT should be prioritized Think outside the SSRI box Topiramate, beneficial for mania and OCD when added to mood stabilizer in RCT, (~180mg/d) Memantine, beneficial for pts w/ mania when added to mood stabilizer (10-30 mg TDD), also beneficial in OCD when added to SSRI (10mg PO BID) Lamotrigine, helpful in BPAD depression and OCD NAC, beneficial in BPAD depression/mania (1000mg PO BID) and OCD (~1200mg PO BID) Psychosurgery/ECT Reviewed in Kazhungil. Indian J Psychiatry. 2016; Perugi. J Clin Psychiatry. 2002. Amerio. J Affect Disord. 2014; Sahraian. J Affect Disord. 2014; Koukopoulos. J Affect Disord. 2012; Koukopoulos. Bipolar Disord. 2010; Berk. Biol Psychiatry. 2008. Magalhes. Aust N Z J Psychiatry. 2013; Afshar. J Clin Psychopharmacol. 2012. www.mghcme.org Treatment of pts with severe OCD Triple threat: SSRI + memantine + antipsychotic (e.g. risperidone) CBT (again but different) Consider residential treatment McLean OCDI Institute, www.mcleanhospital.org/programs/ocd-institute-ocdi

Rogers OCD Center, rogersbh.org/what-we-treat/ocd-anxiety/ocd-and-anxiety-residentialservices Houston OCD Program, houstonocdprogram.org/residential-support-program/ Many others TMS Psychosurgery (cingulotomy, capsulotomy, DBS) www.mghcme.org Additional OCD Resources Imp of the Mind by Lee Baer (comprehensive overview for pts, families, and clinicians) APA Practice Guideline for the Treatment Of Patients With Obsessive-compulsive Disorder by Lorrin Koran et al. Finding specialists: International OCD Foundation, www.iocdf.org Koran. Am J Psychiatry. 2007 www.mghcme.org

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