PSYCHOPHARMACOLOGICAL TREATMENT OF SOCIAL PHOBIA (SP) Professor Jiří Raboch, M.D. Psychiatric Department 1st. Medical Faculty Charles University Prague

TREATMENT OPTIONS CBT MONOAMINE OXIDASE INHIBITORS BENZODIAZEPINES BETA-BLOCKERS SSRIs DUAL REUPTAKE INHIBITORS OTHER/NEWER AGENTS

RANDOMIZED CONTROLLED TRIALS RESPONSE RATE clinically significant reduction of symptoms Clinical Global Impression Scale-Improvement (CGI-I) – „very much“ or „much improved“ 50 % drop in the Liebowitz Social Anxiety Scale (LSAS)

MONOAMINE OXIDASE INHIBITORS

PHENELZINE - controlled studies Study Duration (weeks) N Response rate (%) Tyrer et al., 1973 8 40 Gelernter et al., 1991 12 65 63 + Liebowitz et al., 1992 74 64 + Versiani et al., 1992 16 78 96 + Heimberg et al., 1998 133 65 + + stat. sign. better than placebo

MOCLOBEMIDE – controlled studies Study N Duration (weeks) Response rate (%) Versiani et al., 1992 78 16 81 + Int. Mult. St., 1997 578 12 47/41 + Noyes et al., 1997 583 ns Schneier et al., 1998 77 + stat. sign. better than placebo

BENZODIAZEPINES – controlled studies Study N Duration (weeks) Results Gelernter et al., 1991 65 20 Alprazolam 38 % Placebo 20 % (+) Davidson et al., 1993 75 10 Clonazepam 78,3 % + stat. sign. better than placebo

BUSPIRONE – controlled studies Study N Duration (weeks) Response rate (%) van Vliet et al., 1997 30 12 ns

BETA-BLOCKERS – controlled studies Study N Duration (weeks) Response rate (%) Performance anxiety 11 controlled studies In 8 of them more than 50 % response Liebowitz et al., 1992 atenolol 74 16 ns

SSRIs

FLUVOXAMINE – controlled studies Study N Duration (weeks) Response rate (%) Van Vliet et al., 1994 30 12 46 + Stein et al., 1999 86 43 + Davidson et al., 2004 * 279 34 +++ Westenberg et al., 2004 * 300 48 * CR – controlled-release + p=0,05 +++ p=0,001

PAROXETINE – controlled studies Study N Duration (weeks) Response rate (%) Stein et al., 1998 370 12 55 + Allgulander et al., 1999 96 70 + Baldwin et al., 1999 187 66 + Lepola et al., 2004 * 57 +++ * CR – controlled-release + p=0,05 +++ p=0,001

SERTRALINE – controlled studies Study N Duration (weeks) Response rate (%) Van Ameringen et al., 2001 203 20 53 ++ Blomhoff et al., 2001 387 24 40,2 + Liebowitz et al., 2003 211 12 55,6 +++ ++ p=0,01 +++ p=0,001

FLUOXETINE – controlled studies Study N Duration (weeks) Response rate (%) Kobak et al., 2002 60 14 ns Clark et al., 2003 16 Davidson et al., 2004 295 51 + + p=0,05

s-CITALOPRAM – controlled studies Study N Duration (weeks) Response rate (%) Kasper et al., 2002 181 24 54 +++ Lader et al.,2004 167 5 mg 170 20 mg 79 + 88+++ Davidson et al., 2004 315 8 68++ Kasper et al., 2005 358 12 54++ + p=0,05 ++p=0,01 +++ p=0,001

WHAT DOSAGE? Study N Duration (weeks) Response rate (%) Liebowitz et al., 2002 384 20 mg 12 31.4+++ paroxetine 40 mg 24.5+ Drop on LSAS 60 mg 25.2+ Lader et al.,2004 504 5 mg 24 79 + s-citalopram 10 mg 76 % CGI-I 1,2 20 mg 88 +++ + p=0,05 +++ p=0,001

SNRI

VENLAFAXINE ER – controlled studies Study Duration (weeks) N Response rate (%) Rickels et al., 2004 12 272 50++ Allgulander et al., 2004 434 69+ Liebowitz et al., 2005 440 58,6+++ 271 44+ + p=0,05 ++ p=0,01 +++ p=0,001

WHICH IS BETTER? Few methodologically fair head to head comparisons Lader et al., 2004 20 mg s-citalopram better (p=0,01) than 20 mg paroxetine Liebowitz et al., 2005 paroxetine 20-50 mg/d and venlafaxine ER 75-225 mg - similar effects

OTHER DRUGS

ANTIEPILEPTIC DRUGS -controlled studies Study N Duration (weeks) Response rate (%) Pande et al., 1999 Gabapentin 69 14 32 + Pande et al., 2004 Pregabalin 600 mg 135 10 Better than placebo p=0,024 + stat. sign. better than placebo

ATYPICAL ANTIPSYCHOTICS Study N Duration (weeks) Response rate (%) Barnett et al., 2002 olanzapine 12 8 Improvement (p=0,01) Barnet et al., 2003

COMPARISON OF DRUG CLASSES FOR TREATMENT OF SF Efficacy Tolerability Safety Speed of onset Depression MAOIs ++ - RIMAs + SSRIs BZDN Beta-bl. SNRI Adapted from Westenberg, 2004

SP – first choice TREATMENT SSRIs – s-citalopram, fluvoxamine (CR), paroxetine (CR), sertraline, (fluoxetine) SNRI – venlafaxine ER COMBINATION – CBT + ANTIDEPRESSANTS – few data (sequencing)

SP – second choice TREATMENT and future alternatives MAOIs (phenelzine) Moclobemide Clonazepam Performance anxiety – beta-blockers – propranolol, atenolol Anticonvulsants, atypical antipsychotics

CONCLUSION THERE ARE NUMBER OF EMPIRICALLY VALIDATED ACUTE TREATMENTS FOR SOCIAL PHOBIA THE GOAL OF TREATMENT NEEDS TO BE REFOCUSED FROM ACHIEVING RESPONSE TO ACHIEVING REMISSION IN A LONGER PERSPECTIVE (CONTINUATION AND MAINTENANCE PHASES IN THE TREATMENT)

THANK YOU FOR YOUR ATTENTION!

HOW LONG? Stein et al., 2003 112 patients with SAD, improved after 12 weeks treatment with sertraline CR (100 – 300 mg/day) 24 weeks extension phase Subjects continued to improve compared to placebo treated, although changes were smaller

TREATMENT PHASES. acute 6 – 12 (or longer) weeks TREATMENT PHASES acute 6 – 12 (or longer) weeks continuation up to 1 year maintenance

CONTINUATION TREATMENT? Walker et al., 2000 50 patients with generalized social phobia much or very much improved after 20 weeks of treatments with sertraline (50-200 mg/day) Randomly assigned to sertraline or placebo for another 6 months Relapse rate: placebo group 36 %, sertraline group 4 % (p=0,01)

MAINTENANCE TREATMENT? Versiani et al., 1996 58 patients-responders with SF treated 2 years with moclobemide (600-750 mg/day) After 2 years moclobemide was withdrawn Relapse rate 88 %

Pharmacological treatment of SF: a meta-analysis Drug Effect size 95 % CI Phenelzine 1.02 0.52 – 1.52 Clonazepam 0.97 0.49 – 1.45 Gabapentin 0.78 0.29 – 1.27 Brofaromine 0.66 0.38 – 0,94 SSRIs 0.65 0.50 – 0.81 CI – confidence interval Blanco et al., 2003

PREDICTORS OF TREATMENT RESPONSE Alcohol abuse Comorbid personality disorder Earlier age of onset Higher heart rate and blood pressure Elevated baseline measures of anxiety and depression

TREATMENT RESISTENCE Switching – venlafaxine, phenelzine Augmentation – buspirone, pindolol, benzodiazepines (clonazepam), atypical antipsychotics (olanzapine, risperidone), tiababine

TREATMENT RESISTENCE controlled studies Study N Duration Results Clonazepam + paroxetine Seedat and Stein, 2004 28 10 weeks 79 % resp. 43 %, p=0,06 Pindolol + paroxetine Stein et al., 2001 14 4 weeks NS

CONTINUATION TREATMENT? Stein et al., 2002 … patients with SAD improved after 12 weeks treatment with paroxetine (20-50 mg/day) Randomly assigned to paroxetine or placebo for another 6 months Relapse rate: placebo group 40 %, sertraline group 14 % (p=0,0001)

REMISSION CRITERIA No longer satisfying diagnostic criteria CGI-I very much improved LSAS > 70 % reduction, < 30 SDS < 5

COMPARISON OF DRUG CLASSES FOR TREATMENT OF SF Efficacy Tolerability Safety Speed of onset Depression MAOIs ++ - RIMAs + SSRIs BZDN Beta-bl. SNRI Adapted from Westenberg, 2004