Fluvoxamine was 1st SSRI approved for OCD. FLUV has highest affinity for sigma receptor and shortest-half life. The ratio of SERT: NET binding is 100:1. Rates of sexual side effects may be lower than other SSRIs.
12 students & 1 teacher died on April, 1999, 20 more students injured. Following lawsuit, Solvay donates 10K to charity (American Cancer Society).
300 mg is the max daily dose of FLUV. The 4 month wait-list was not completed due to ethical reasons.
Using-anti-depressants refers to currently using anti-depressants at end of 5 year follow-up. No Longer met criteria for OCD according to DSM IV criteria. The large SDs for YBOCS suggests some patients had substantial deteoriation or where at the high-end of the scale.
Interview with patient and family to determine when first symptoms of OCD were present in two samples (N=161). Younger-patients with early onset (<21) onset had higher rates of Tourette’s Disorder. Older onset patients had higher rates of GAD/MDD.
Fluvoxamine is a strong inhibitor of 1A2 and may impair elimination of drugs. “Children aged between 6 and 11 years had higher values for bodyweight-corrected mean Cmax (14.8 vs4.2 μg/L/kg) and area under the plasma concentration-time curve (AUC12h; 155.1 vs 43.9 μg • h/L/kg) than adolescents aged between 12 and 17 years afterfluvoxamine 200 mg/day (given as 100mg twice daily up to steady-state).”
Phenelzine (Nardil) = MAO-I,Ven/Dul = SNRIs. #s above each drug are the Odds Ratio relative to placebo.
Note potential difference in clinically versus statistically significant findings (bottom: paroxetine).
CSA: child sexual abuse
Psychopharmacology of Anxiety: Part II OCD & PTSD
Anxiety II: Agents for PTSD & OCD Brian J. Piper, Ph.D., M.S. firstname.lastname@example.org Office Hours: T/Th 3-4 or by appointment February 1, 2013
Objectives• Pharmacy students should be able to: – List the key characteristics of Post-Traumatic Stress Disorder & Obsessive Compulsive Disorder – Rank the therapeutic options by efficacy and differentiate the pharmacotherapies by MOA and adverse events.
Psychotherapy & Anxiety Disorders • Specific therapies, typically brief ( < 12 weeks) have solid empirical support • Effects are delayed but sustained • Important option for vulnerable populations Anxiety Disorder Importance of Psychotherapy Phobias Systematic desensitization is gold standard. Social Anxiety Disorder >50% of patients show response to CBTD GAD CBT and pharmacotherapy have similar efficacyD Panic Disorder CBT produces improvements in 75% of patientsD Obsessive Compulsive Dis CBT (with or without SSRI) is recommended as first-line txD Post-Traumatic Stress Dis EMDR > fluoxetine in maintaining improvementsDDDiPiro et al. (2012). Pharmacotherapy: A Pathophysiologic Approach, Chapters 79 & 80.
Yale Brown Obsessive Compulsive Scale • Obsessions (5 items) – How much of your time do you occupy with obsessions? None ------ Extreme (8+ hours/day) – How much do your obsession interfere socially or with work? Not at all ----- Extreme (Incapacitating) • Compulsions (5 items) – How much time do you spend performing compulsive behaviors? None ---- 8+ hours/day – How much control do you have over the rituals? Complete Control ---- No control, unable to even delay 7To take test: http://www.psymed.info/psymed/default.aspx?m=Test&id=52&l=3
OCD Options 2nd Line 1st LineModified from Stahl, S. (2008). Essential Psychopharmacology, p. 770.
Fluvoxamine• MOA: SRI• Indications: FDA approved for OCD (adult & pediatric)• Half-Life: 16 hours• Adverse Effects: nausea, vomiting, weight gain, sexual--------------------------- ------------------------------
Paradoxical Aggression? • Animal studies demonstrate inverse relationship between 5-HT & aggression • E.H. receives sertraline, later fluvoxamine • Parents of E.H. sue Solvay • Solvay withdraws fluvoxamine (2002 – 2008) • Aggressive patients -> drug Drug -> Aggressionhttp://www.denverpost.com/golf/ci_5094436 1981 - 1999
OCD: SSRI, CBT, or Both?• OCD patients randomized to Cognitive Behavior Therapy (CBT), CBT & Fluvoxamine (50-300, Mean = 235 mg/day), or a wait-list.• Clinicians completed the Yale-Brown Obsessive Compulsive Scale (0 – 40) – normal = 0-7 – mild = 8-15; moderate = 16 -23 – 24-31 = severe – 32-40 = extreme Baseline Week 8 (Change) Week 16 (Change) Control (Wait List) 26.8 26.4 (-0.4) NA CBT (1-16) 25.3 21.5 (-3.8)* 13.5 (11.8)* FLVX (1-16) + CBT (9-16) 27.2 20.8 (-6.4)* 15.6 (11.6)* *p < .01 versus BaselineVon Balkom et al. (1998). Journal of Nervous & Mental Disease, 186(8), 492-499.
5 Year Follow-Up CBT (N = 32) CBT + Fluvoxamine (N = 39) Current YBOCS (SD) 12.3 (8.9) 14.9 (9.1) YBOCS Improved by >7 78.1% 73.7% Additional CBT 53% 72% Using Anti-depressants 19% 51%* No Longer OCD 62.5% 51.3% *p < .005van Oppen et al. (2005). J of Clinical Psychiatry, 66, 1415-1422.
Early OCD Age of Onset Early Onset Late-onset (N = 141) (N = 20) MDD 36.2% 66.6%* ADHD 31.2% 25.0% Tourette’s 26.9% 0.0%* GAD 11.3% 41.2%* * p < .01Delorme et al. (2005). Psychological Medicine, 35(2), 237-243.General description (Skip Ad, 0 to 2:25): http://www.youtube.com/watch?v=izT40QNFXuM
Fluvoxamine & Age • Max dose – Adults: 300 mg/day – Adolescents: 300 mg/day – Children: 200 mg/day • Efficacy: similar across age • Contraindications: MAO-Is • Other: CYP1A2 • Adverse Effects: similar across age, transient gastrointestinalCheer & Figgitt (2002). CNS Drugs, 16(2), 139-144.http://www.pdr.net/drugpages/concisemonograph.aspx?concise=1452
SRIs & Adolescence • The 5-HT system undergoes dynamic changes during adolescence • Does chronic anti-depressant treatment alter neurobehavioral development? • Oral paroxetine (15 mg/kg), but not fluvoxamine (30 mg/kg), from PD 33-62 temporarily, reduced weight.Jong et al (2006). European Neuropsychopharmacology, 16, 39-48.
SRIs & Adolescence • The 5-HT system undergoes dynamic changes during adolescence • Does chronic anti-depressant treatment alter neurobehavioral development? • After a 23 day drug free period, the rats were tested on the elevated plus maze V P FJong et al (2006). European Neuropsychopharmacology, 16, 39-48.
Common Sexual Effects • Sexual dysfunction (SD) is common among patients with anxiety & depression • Drug-induced SD is under-reported unless patients queried directly • SD = ↓ desire, ↓ arousal, ↓ orgasm Sertraline Venlafaxine Citalopram Paroxetine Fluoxetine Imipramine Phenelzine Duloxetine Escitalopram FluvoamineSerretti et al. (2009). Journal of Clinical Psychopharmacology, 29, 259 – 266.
Males > FemalesSerretti et al. (2009). Journal of Clinical Psychopharmacology, 29, 259 – 266.
Post Traumatic Stress Disorder • A) Exposure to actual or threatened death, serious injury, or sexual violation • B) Intrusion symptom(s): – spontaneous or cued memories – dreams – flashbacks • C) Avoidance of stimuli associated with traumatic event • D) Social or occupational impairmentExample (1st 3 min): http://www.youtube.com/watch?v=7aFs6695VyQSummarized from: http://www.dsm5.org/ProposedRevision/Pages/proposedrevision.aspx?rid=165
Neural Substrate of PTSD? SSRIs increase 5-HT but therapeutic lag SSRIs increases Brain Derived Neurotrophic Factor (BDNF) BDNF increases neurogenesisStahl et al. (2008). Essential Psychopharmacology, p. 748.
PTSD Options (DiPiro/Stahl) * *FDA Approved sertraline paroxetineModified from Stahl, S. (2008). Essential Psychopharmacology, p. 770.
PTSD Treatment Hierarchy Department of Defense/Veterans Affairs 2010 • “Psychotherapy is the preferred treatment option.” • 1st Line Pharmacotherapies: SSRI, SNRI • Not Recommended: Benzos & anti-psychotics as mono-therapy or used adjunctivelyJeffreys et al. (2012). Journal of Rehabilitation Research & Development, 49(5), 703-715.
Rationale For Avoiding Benzos with PTSD The veteran was diagnosed with PTSD and panic disorder by a psychiatrist in the PTSD Clinic. He was started on sertraline and after several months at a dose of 200 mg daily, he reported only modest reductions in PTSD symptoms. The panic disorder improved but he continued to take clonazepam 1 mg 1–3 times per week to prevent panic attacks when leaving his home. He was referred for PE (Prolonged Exposure) therapy. Although the PE went well in the initial weeks, both the patient and his therapist noted that he was relatively unaffected by anxiety in some therapy sessions. A careful review of his medication use found he was taking clonazepam prior to driving from his home to the VA medical center because driving alone was a common trigger for panic attacks. He was encouraged to not use clonazepam within 24 hours of a PE session, and after several more weeks, he completed PE without difficulty. The post-PE score on the PCL was below the cutoff for PTSD diagnosis.Jeffreys et al. (2012). Journal of Rehabilitation Research & Development, 49(5), 703-715.
Summary• Anxiety Disorders are complex psychiatric conditions that require multi-disciplinary treatment.• SSRIs are first-line pharmacotherapies for OCD & PTSD although there are substantial differences among members of this class.