MEDICATION STRATEGIES FOR RESISTANT OCD Stimulants Opiates Glutamate

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MEDICATION STRATEGIES FOR RESISTANT OCD Stimulants, Opiates, Glutamate Antagonists Lorrin Koran, M. D. ,

MEDICATION STRATEGIES FOR RESISTANT OCD Stimulants, Opiates, Glutamate Antagonists Lorrin Koran, M. D. , Professor of Psychiatry, Emeritus, Stanford University Medical Center © 2019 American Psychiatric Association. All rights reserved.

Treatment of OCD American Psychiatric Association Guidline First Line Treatments 1. CBT (Exposure/Response Prevention)

Treatment of OCD American Psychiatric Association Guidline First Line Treatments 1. CBT (Exposure/Response Prevention) • Time intensive, less accessible 2. Medication (an SSRI, e. g. , Prozac) • Side effects, drug interactions • higher doses produce better outcomes 3. Combination of CBT + SSRI

D-amphetamine vs. Caffeine for Treatment-resistant OCD: Background • Two double-blind, single dose studies find

D-amphetamine vs. Caffeine for Treatment-resistant OCD: Background • Two double-blind, single dose studies find d -amphetamine 30 mg effective for OCD 1, 2 • One case report of Adderall alone effective 3 • 4 cases Adderall added to an SSRI is effective 4 1 Insel T, et al. Psychopharmacol 1983; 80: 231 -235 2 Joffee RT, et al. J Clin Psychopharmacol 1991; 11: 237 -241 3 Albucher RC, et al. Am J Psychiatry 2001; 158: 818 -819 4 Owley OT, et al. J Child Adolesc Psychopharmacol 2002; 12: 165 -171

D-amphetamine vs. Caffeine: Methods • Adults aged 18 -55, Y-BOCS ≥ 20 after ≥

D-amphetamine vs. Caffeine: Methods • Adults aged 18 -55, Y-BOCS ≥ 20 after ≥ 12 weeks of SSRI or SNRI • No substance abuse, bipolar, panic, schizophrenia, heart disease, seizures, glaucoma, serious medical disorder • Randomized to d-amphetamine 30 mg/d or caffeine 300 mg/d • Called nightly during week 1 for Y-BOCS rating • If Y-BOCS ≥ 20%, continued 4 more weeks Koran L, et al. J Clin Psychiatry 2009; 70: 1530 -35

D-Amphetamine vs. Caffeine Subjects • N=24, all Caucasian, 11 Female, 13 Male mean age

D-Amphetamine vs. Caffeine Subjects • N=24, all Caucasian, 11 Female, 13 Male mean age = 40 (± 13. 2) • Mean age at OCD onset = 13. 8 (± 9. 3) • Mean baseline Y-BOCS = 27. 8 (± 4. 1) • Comorbidities: MDD = 5, Dysthymia = 7, GAD = 3, Social Anxiety Disorder = 1

D-Amphetamine vs. Caffeine: Groups • 12 d-amphetamine, 12 caffeine • No differences except: more

D-Amphetamine vs. Caffeine: Groups • 12 d-amphetamine, 12 caffeine • No differences except: more caffeine subjects taking a dopamine-blocking drug (5 vs. 3), fewer a benzodiazepine (1 vs. 4) • 6 per group had a prior trial of adding a dopamine-blocking drug • 10 per group had prior SSRI/SNRI trials

D-Amphetamine vs. Caffeine End of Week 1 Results • 6 (50%) d-amphet responders, mean

D-Amphetamine vs. Caffeine End of Week 1 Results • 6 (50%) d-amphet responders, mean Y-BOCS 41% (range 22%-52%). (≥ 35% n = 4) • 7 (58%) caffeine responders, mean Y-BOCS 45% (range 25%-74%). (≥ 35% n = 5) • Drug liking: d-amphet = 4. 3, caffeine = 5. 4 • Drug “high” d-amphet = 1. 8, caffeine = 2. 6 • in Y-BOCS score and in general anxiety and depression scores were not related

D-Amphetamine vs. Caffeine: End of Week 5 Results • 1 d-amphet drop out (inadequate

D-Amphetamine vs. Caffeine: End of Week 5 Results • 1 d-amphet drop out (inadequate response) • Mean Y-BOCS % (final observation) – d-amphetamine: 42% (20%-80%) – Caffeine: 51% (27%-89%) • Blinding successful: investigators guess correctly in 46% at EOW 1, 54% at EOW 5 • Side effects not clinically important

D-Amphetamine vs. Caffeine: Explanations • ? Placebo response to both drugs (Unlikely) – 2

D-Amphetamine vs. Caffeine: Explanations • ? Placebo response to both drugs (Unlikely) – 2 prior positive, placebo-controlled d-amphet trials (placebo was a sugar pill, so blinding may have failed) – Placebo response in adding anti-dopamine to SSRI = 11% • Our response rate = 42% d-amphet, 58% caffeine – Placebo augment response is not Immediate or sustained • D-amphetamine and Caffeine are both effective (Likely) – DA may D 1 receptor stimulation attention regulation and working memory 1 obsessions compulsions – Caffeine DA, serotonin, and glutamate release – Caffeine did attention, mood, energy 1 Arnsten AFT, J Clin Psychiatry 2006; 67(suppl 8): 7 -12.

Glutamate Antagonists: Memantine (1) • Rx-resistant, augment 12 weeks, open-label 1 – N=14 5

Glutamate Antagonists: Memantine (1) • Rx-resistant, augment 12 weeks, open-label 1 – N=14 5 mg/d 20 mg/d at week 4. – Mean baseline Y-BOCS = 27. 4 – 45% respond (Y-BOCS ≥ 25% + GCI-I = 1 or 2) • Rx-resistant, augment, mean = 2 months, case-control 2 – N=22, residential Rx. Mean memantine dose 18 mg/d – Taking SRI: Memantine 60%; controls 70% – Y-BOCS ≥ 50%: memantime 23% vs. controls 5% 1 Aboujaoude E, et al. J Clin Psychopharmacol 2009; 29(1): 51 -55 2 Stewart SE, et al. J Clin Psychopharmacol 2010; 30: 34 -39

Glutamate Antagonists: Memantine (2) • Rx-resistant, 12 -weeks, double-blind 1 – No comorbidity, on

Glutamate Antagonists: Memantine (2) • Rx-resistant, 12 -weeks, double-blind 1 – No comorbidity, on stable SSRI 12 weeks – Add memantine 10 mg bid vs. placebo • N=32. Mean baseline Y-BOCS = 33. 9 and 33. 4 • Y-BOCS ≥ 35% responders – Week 8: None – Week 12: Memantine = 73%, Placebo = 0% 1 Modarresi A, et al. Pharmacopsychiatry 2018; 51: 263 -269

Glutamate Antagonists: Lamotragine • Rx-resistant, augment SSRI, 16 weeks, dbl-blind 1 – N=40 (33

Glutamate Antagonists: Lamotragine • Rx-resistant, augment SSRI, 16 weeks, dbl-blind 1 – N=40 (33 completers, 17 Lam, 16 Pla). No cormorbidity. – Lamotragine 25 mg/d 100 mg/d at week 4 – Mean baseline Y-BOCS = 26. 7 and 25. 7 – Y-BOCS ≥ 25% / 35%: Lam 85% vs. placebo 0% Rx-resistant, augment SRI 16 weeks, chart review 2 – N=22. No comorbidity. Mean baseline Y-BOCS = 28. 9 – Lamotragine 25 mg/d 100 -200 mg/d at week 4 -8 – Y-BOCS ≥ 35%: 91%. Mean = 67% 1 Bruno A, et al. J Psychopharmacol 2012; 26(11): 1456 -1462 2 Hussain A, et al. Indian J Psychol Med 2015; 37(2): 154 -158

 Opiate Treatment Open-Label • Morphine 20 -40 mg once weekly, Rx-resistant – 5

Opiate Treatment Open-Label • Morphine 20 -40 mg once weekly, Rx-resistant – 5 cases, large response, duration 5 -8 days 1 • Tramadol (mean 254 ± 119 mg/d) open-label 6 wks 2 N=6, mean OCD duration 27 years mean failed SSRI trials 2. 9 – Mean Y-BOCS = 25%: from 27. 8 to 20. 7 – 3/6 much improved by end of week 1 1 Warneke L. Can J Psychiatry 1997; 42: 667 -668 2 Shapira NA, et al. Depress Anxiety 1997; 6: 170 -177

Once Weekly Double-blind Oral Morphine for Treatment-Resistant OCD • 23 subjects with OCD >

Once Weekly Double-blind Oral Morphine for Treatment-Resistant OCD • 23 subjects with OCD > 3 years – Failed > 2 adequate SRI trials. Y-BOCS ≥ 21 • Continued concurrent medications – stable doses for at least 8 weeks • Given random order, 2 -week blocks of: – Oral morphine 30 mg (± 15 mg week 2) – Lorazepam 1 mg (± 0. 5 mg week 2) – Placebo 2 capsules (± 1 capsule week 2) Koran L, et al. J Clin Psychiatry 2005; 66: 353 -359

Once-Weekly Oral Morphine Results • Morphine responders (Y-BOCS ≥ 25%) 7/23 – All were

Once-Weekly Oral Morphine Results • Morphine responders (Y-BOCS ≥ 25%) 7/23 – All were taking an SSRI/SNRI – 1/7 (14%) taking a dopamine-blocker responded vs. 6/17 (35%) not taking a dopamine-blocker • Morphine responders: 5/7 Y-BOCS ≥ 40% • Lorazepam responders: 1/4 Y-BOCS ≥ 40% • No placebo responders