- Email: [email protected]
Neurobiology of social anxiety disorder
S. 13 Pharmacothempeutic options in social phobia
range predicted from studies on animals. Lower doses were less effective (4). Improvements were also found in young adult subjects tested for various aspects of memory. Testing was conducted while blood levels were at peak values but relatively low drug concentrations were used in this first experiment using repeated applications. Improvements were obtained on three aspects of memory: recognition of odors after a delay of 45 min or more, 24 hour retention of associations between complex visual cues, and over-days increases in scores on a visuo-spatial maze. Marginally significant increases were reported for immediate recall of card positions but not for cued recall of verbal memory. There were no instances in which memory scores were reduced, or general intellectual functioning disturbed, on days on which the subjects were given the drug (5). Finally, CX516 has been tested for possible effects on schizophrenia using a repeated dosing paradigm. Results from the trial are expected to be available shortly. The above results constitute the tist evidence that positive modulation of excitatory transmission is both feasible and pharmacologically practical. In addition to improving communication, the drugs also had the expected effects of promoting a likely substrate of memory and increasing neurotrophin expression. Extensive preclinical and initial human data point to an influence on cortical functioning and memory. Together these findings encourage the idea that positive modulators will be useful in treating age associated memory disorders and Alzheimer’s. -0 issues likely to have a major impact on clinical applications are: (1) Will the potent and metabolically stable ampakines now available have the same selectivity in human subjects as the somewhat weaker CX5 16? (2) Can ampakine-induced neurotrophin expression be used to reduce slowly developing neuronal atrophy? References [1] Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993). Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43 (1): 192-7. [2] Arai A, Lynch G (1998). The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization Brain Res 799 (2): 230-4. [3] Staubli U, Perez Y, Xu FB, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994). Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Nat1 Acad Sci U S A 91 (23): 1115862. [4] Lynch G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R (1997). Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Exp Neural 145: 89-92. [5] Ingvar M, Ambms-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997). Enhancement by an ampakine of memory encoding in humans. Exp Neural 146: 553-559.
S.13 Pharmacotherapeutic options in social phobia [ml
Neurobiology of social anxiety disorder
J.A. den Boer, F.J. Bosker, B.R. Slaap. University Hosp. Groningen, The Netherlands
Various models have been employed to study the neurobiology of social anxiety disorder including assessment of central neurotransmitter function, response to chemical challenge, neuroendocrine function, and neuro-imaging. Serotonergic Function: The effectiveness of serotonin-selective reuptake inhibitors (SSRIs) in the treatment of patients with social anxiety disorder indicates that serotonergic function has a role in the aetiology of social anxiety disorder. The benzodiazepine, clonazepam, also has demonstrable efficacy in social anxiety disorder, an effect which may be mediated by its effect on 5-HT utilization in the brain, although there is no evidence of efficacy for other benzodiazepines in patients with social anxiety disorder. The specific 5-HTIA agonist, buspirone, and ondansetron, a 5-HT3 antagonist, have not demonstrated efficacy in patients with social anxiety disorder.
S165
The role of serotonergic function in the aetiology of social anxiety disorder has also been studied using pharmacological tools. Fenfluramine, a serotonin releasing agent, produced a significantly greater rise in cortisol in patients with social anxiety disorder compared with control subjects but had no effect on prolactin in patients or controls. However, the results of this small study require replication and conlirmation. Noradrenergic and DopsminergIc Function: The fear response of social anxiety disorder provokes symptoms which may be adrenergically mediated (e.g., sweating, palpitations, tremor). Therefore, Tancer et al (1994) also assessed the noradrenergic, as well as the dopaminergic system, for dysfunction in patients with social anxiety disorder. A blunted growth hormone response to clonidine, an alpha-2 antagonist, but an unchanged prolactin or eye-blink response to levodopa were observed in patients with social anxiety disorder compared with normal subjects. This indicates that a disturbance of noradrenergic, but not dopaminergic, function is present in patients with social anxiety disorder. Response to Chemical Provocation: Adrenaline caused an increase in catecholamine levels in patients with social anxiety disorder but did not increase anxiety; however, as adrenaline does not penetrate the blood-brain barrier these results are open to interpretation. Although lactate induced panic attacks in patients with panic disorder it had no affect in individuals with social anxiety disorder. Caffeine induced panic attacks in patients with panic disorder and in those with social anxiety disorder. Inhalation of 5% CO2 produced panic attacks in 12/31 patients (39%) with panic disorder and agoraphobia but not in patients with social anxiety disorder. However, a higher concentration of CO2 (35%) precipitated panic attacks in a similar proportion of patients with panic disorder or social anxiety disorder. Furthermore, the pentapeptide pentagastrin, an analogue of CCK4, has been shown to induce panic attacks in patients with social anxiety disorder (van Vliet et al, 1997) as well as in patients with obsessive compulsive disorder (de Leeuw et al, 1996) and panic disorder (van Megen et al, 1994). Neuro-imaging: Magnetic resonance spectroscopy revealed that patients with social anxiety disorder demonstrated significantly lower choline (Cho) and creatinine (Cr) signal-to-noise ratios in subcortical, thalamic and caudate areas compared with age- and gender-matched controls. N-acetyl-aspartate (NAA) and the ratio of NAA to other metabolites were significantly lower in cortical and subcortical regions in patients with social anxiety disorder. A recent study found that patients with social anxiety disorder had significantly lower NAAKho and higher Cho/Cr, mI/Cr and mIiNAA amplitudes in cortical grey matter than control subjects (Tupler et al, 1997). Neuro-imaging has also recently been used to implicate a possible dysfunction of the doyaminergic system in patients with social anxiety disorder. Using a I2 I-labelled cocaine analogue &CIT with single photon emission computed tomography (SPECT), Tiihonen et al. (1997) showed that striatal dopamine reuptake site densities were markedly lower in patients with social anxiety disorder than in control subjects. In summary, patients with panic disorder and social anxiety disorder have a common increased sensitivity for caffeine, carbon dioxide and pentagastrin suggesting a biological similarity. However, all of the studies in social anxiety disorder have involved a limited number of patients and there is, as yet, no clearly defined biological dysfunction in patients with social anxiety disorder. References [1] Tancer, M.E., Mailman, R.B., Stein, M.B., Mason, G.A., Carson, S.W. and Golden, R.N. (1994) Neumendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety, 1, 216-223. [2] Tiihonen, J., Kuikka, J., Bergstrom, K., Lepola, U., Koponen, H. and Leinonen, E (1997) Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry, 154, 239-242. [3] van Megen, H.J., Westenberg, H.G., den Boer, J.A., Haigh, J.R. and Traub, M (1994) Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients. Psychopharmacology (Bed), 114, 449-455. [4] Davidson, J.R.T., Boyko, O., Charles, H.C. et al. (1993a) Magnetic resonance spectroscopy in social phobia. J Clin Psychiatry, 54, (12, Suppl), 19-25. [5] Tupler, L.A., Davidson, J.R., Smith, R.D., Lazeyras, F., Charles, H.C. and Krishnan, K.R. (1997) A repeat proton magnetic resonance spectroscopy study in social phobia. Biol Psychiatry, 42, 419424.
S166
S.13 Pharmacothempeutic
[61 de Leeuw, A.S., den Boer, LA., Slaap, B.R. and Westenberg,H.G. (1996) Pentagaatrin has panic-inducing properties in obsessive compulsive disorder. Psvchoobarmacoloav (Berl). 126.339-344. [7] VA Vll’et, LM., Weys;ehberg; H.G:M., Slaap, B.R., den Boer, J.A and Ho Plan, K.L. (1997) Anxiogenic effects of pentagastin in patients with social phobia and healthy controls. Biol. Psychiat. 42, 7678.
options in social phobia
Conclusions: Gabapentin appears to be a safe and effective treatment for social phobia, although its position in the hierarchy of effective treatments remains to be established. The mechanism by which it reduces social anxiety is a subject of speculation, although it does not appear to work through a direct effect on serotonin. References
-1
Gabapentin in social phobia
J.W. Jefferson. Madison Institute ofMedicine, Inc., Madison, Wisconsin, USA
Introduction: Based on data from the National Comorbidity Survey (NCS), social phobia is the third most common psychiatric disorder with a lifetime prevalence of 13.3% and a 12-month prevalence of 7.9% (Kessler, et al., 1994). While greatly underrecognized and undertreated, social phobia causes substantial psychiatric morbidity. A recent survey of 3,862 HMO members in Madison, Wisconsin found an 8.2% prevalence of social phobia (by SCID), but only 0.5% of those had been diagnosed previously. When compared to a control population, those with social phobia had more than twice the reduction in work and home productivity, twice as many work hours missed due to health problems, and 2fold greater overall disability. A direct correlation was found between severity scores on the Liebowitz Social Anxiety Scale (LSAS) and reduced income, lower occupational status, and lessened likelihood of graduating from college (Katzelnick, et al., in press). An early age of onset (childhood and adolescence), substantial comorbidity (mood, anxiety and substance use disorders), and a chronic course further underscore the need for recognition, diagnosis and appropriate treatment of social phobia. Both psychotherapies and pharmacotherapies can be effective treatments for social phobia. Cognitive-behavior therapy (individual or group) is an extremely useful intervention for many individuals. The value of a broad variety of medications has become better established in recent years as the number of controlled studies has increased. Among the effective drug classes are SSRIs, MAOIs (reversible and irreversible), and benzodiazepines (Davidson, 1998). Animal studies suggesting that gabapentin, a novel GABA analog anticonvulsant, might have anxiolytic properties led to a double-blind, placebo-controlled study of social phobia. Method: The 2 center study (Dean Foundation and Duke University Medical Center) enrolled 82 adults with DSM-IV diagnosed social phobia in a 1Cweek double-blind trial that randomized patients to either placebo or gabapentin after a one week single-blind placebo lead-in. Inclusion criteria included an LSAS score of at least 50 and absence of major psychiatric and medical conditions. A flexible dose design was employed in which gabapentin was started at 300 mg bid and increased in increments no greater than 300 mg daily to a maximum daily dose of 3600 mg (given tid). Outcome measures included the LSAS, Fear Questionnaire (FQ), Brief Social Phobia Scale (BSPS), Social Phobia Inventory (SPIN), CGI, Ham-D and Ham-A. Results: Of the 82 patients enrolled, 69 entered double-blind and 39 completed the study (62% on gabapentin, 51% on placebo). The endpoint measurements for all analyses were based on last observation carried forward. Improvement on the LSAS was significantly greater for gabapentin than for placebo (total score -27.3 vs -11.9, (p = 0.008); anxiety subscale -14.1 vs -5.6 (p = 0.005); avoidance subscale -13.2 vs -6.3 (p = 0.02)). Response (detined by at least a 50% reduction in LSAS scores (ITT) occurred in 32% on gabapentin and 14% on placebo (intentto-treat). Similar responses favoring gabapentin over placebo were noted on the other social phobia outcome measures with greater symptom decrements in those with higher baseline scores. For unclear reasons, a greater drug/placebo difference was seen in men than women (due to a higher placebo response in women) and in older patients (135 years). With regard to dosing, 56% on gabapentin received the maximum dose of 3600 mgday and close to 77% received at least 2100 mg/day. While there were no serious adverse events, 21% on gabapentin and 11% on placebo withdrew because of adverse events. Severe adverse events on gabapentin included nausea, dizziness, somnolence, insomnia, nervousness, and facial edema.
[l] Davidson JRT (1998). Pharmacotherapy of social anxiety disorder. J Clin Psychiatry 59 (suppl 17); 47-51. [2] Katzelnick DJ, Kobak KA, Helstad CP, Greist JH, Davidson J, DeLeire T, Schneier F, Stein M (1998). The direct and indirect costs of social phobia in managed care patients. Presented at 37th Annual Meeting of ACNP, December 1418. [3] Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, Kendler KS (1994). Lifetime and 12-month prevalence of DSMIII-R psychiatric disorders in the United States: results from the National Comorbidiw Sorvev 5 1: 8-19. [4] Pande AC, bavi&n JRT, Jefferson Jw, Janney CA, Katzelnick D J, Weisler RH, Greist JH, Sutherland SM. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychophannacol (in press).
Is.1 3.041 RIMA’s and other drugs in social phobia
I.M. van Vliet. University Medical Centre Utrecht, the Netherlands It is only during the last two decades that the psychopharmacology of social phobia has been subject to investigations and a growing body of evidence has come to support that medication might be helpful in this invalidating disorder. In this lecture an overview is given of the studies in social phobia using the so called ‘classic’ monoamine oxidase inhibitors (MAOI’s), selective MAOA inhibitors (RIMA’s), beta adrenergic blocking agents, benzodiazepines, tricyclic antidepressants (TCA’s), newer antidepressants such as venlafaxine and the selective 5HT-IA agonist buspirone. The effects of the selective serotonin re-uptake inhibitors (SSRI’s) are discussed by David Baldwin. MAOI’s: In several studies, beneficial effects of MAOI’s in the treatment of social phobia (is social anxiety disorder) have been reported. Although these most early studies suffered a number of drawbacks (small patient numbers, mixed patients groups and low drug dosages) a reduction in social anxiety has been reported. More recent studies showed that phenelzine (60-90 mg) led to a marked improvement in two-third of patients with social phobia (1). In a study by Gelemter et al (2) four treatment conditions were compared: phenelzine plus instructions for exposure (IE), alprazolam plus IE, placebo plus IE and cognitive behavioural therapy. Results showed that 63% of the phenelzine treated patients were responders whereas the response rate was 39% in the alprazolam treated group, 24% in the cognitive behavioural group and 20% in the placebo group. However, a major drawback with the conventional and irreversible MAOI’s has been the development of hypertensive crises due to potentiation of the tyramine pressor effect (the so called ‘cheese effect’). MAOI’s also have hypotensive properties and increased glucose tolerance, less interfering with the treatment of diabetes mellitus. RIMA’s: Newer selective and reversible MAOA-inhibitors, such as moclobemide, are devoid of this effect. Patient treated with moclobemide do not need to keep any dietarian restrictions in contrast to patients treated with phenelzine who have to keep a tyramine restricted diet. Other studies with this new generation of drugs demonstrated positive effects of brofaromine and moclobemide in social phobia (3). However brofaromine is no longer in development. For clinical use only moclobemide is available. Later and larger studies with this drug failed to tind any significant difference between moclobemide (up to 900 mg) and placebo after 12 weeks. Beta Adrenergic BIockers: The majority of studies with beta blockers have been performed in patients with a subtype of social phobia i.e. performance anxiety. In several controlled studies the use of beta blockers has appeared useful in reducing autonomic symptoms, such as tremors and palpitations. As a secondary effect, anxiety reduction was achieved. Since not all beta blockers crossed the blood brain barrier it has been argued that the efficacy of beta blockers is related to a
range predicted from studies on animals. Lower doses were less effective (4). Improvements were also found in young adult subjects tested for various aspects of memory. Testing was conducted while blood levels were at peak values but relatively low drug concentrations were used in this first experiment using repeated applications. Improvements were obtained on three aspects of memory: recognition of odors after a delay of 45 min or more, 24 hour retention of associations between complex visual cues, and over-days increases in scores on a visuo-spatial maze. Marginally significant increases were reported for immediate recall of card positions but not for cued recall of verbal memory. There were no instances in which memory scores were reduced, or general intellectual functioning disturbed, on days on which the subjects were given the drug (5). Finally, CX516 has been tested for possible effects on schizophrenia using a repeated dosing paradigm. Results from the trial are expected to be available shortly. The above results constitute the tist evidence that positive modulation of excitatory transmission is both feasible and pharmacologically practical. In addition to improving communication, the drugs also had the expected effects of promoting a likely substrate of memory and increasing neurotrophin expression. Extensive preclinical and initial human data point to an influence on cortical functioning and memory. Together these findings encourage the idea that positive modulators will be useful in treating age associated memory disorders and Alzheimer’s. -0 issues likely to have a major impact on clinical applications are: (1) Will the potent and metabolically stable ampakines now available have the same selectivity in human subjects as the somewhat weaker CX5 16? (2) Can ampakine-induced neurotrophin expression be used to reduce slowly developing neuronal atrophy? References [1] Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993). Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43 (1): 192-7. [2] Arai A, Lynch G (1998). The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization Brain Res 799 (2): 230-4. [3] Staubli U, Perez Y, Xu FB, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994). Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Nat1 Acad Sci U S A 91 (23): 1115862. [4] Lynch G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R (1997). Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Exp Neural 145: 89-92. [5] Ingvar M, Ambms-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997). Enhancement by an ampakine of memory encoding in humans. Exp Neural 146: 553-559.
S.13 Pharmacotherapeutic options in social phobia [ml
Neurobiology of social anxiety disorder
J.A. den Boer, F.J. Bosker, B.R. Slaap. University Hosp. Groningen, The Netherlands
Various models have been employed to study the neurobiology of social anxiety disorder including assessment of central neurotransmitter function, response to chemical challenge, neuroendocrine function, and neuro-imaging. Serotonergic Function: The effectiveness of serotonin-selective reuptake inhibitors (SSRIs) in the treatment of patients with social anxiety disorder indicates that serotonergic function has a role in the aetiology of social anxiety disorder. The benzodiazepine, clonazepam, also has demonstrable efficacy in social anxiety disorder, an effect which may be mediated by its effect on 5-HT utilization in the brain, although there is no evidence of efficacy for other benzodiazepines in patients with social anxiety disorder. The specific 5-HTIA agonist, buspirone, and ondansetron, a 5-HT3 antagonist, have not demonstrated efficacy in patients with social anxiety disorder.
S165
The role of serotonergic function in the aetiology of social anxiety disorder has also been studied using pharmacological tools. Fenfluramine, a serotonin releasing agent, produced a significantly greater rise in cortisol in patients with social anxiety disorder compared with control subjects but had no effect on prolactin in patients or controls. However, the results of this small study require replication and conlirmation. Noradrenergic and DopsminergIc Function: The fear response of social anxiety disorder provokes symptoms which may be adrenergically mediated (e.g., sweating, palpitations, tremor). Therefore, Tancer et al (1994) also assessed the noradrenergic, as well as the dopaminergic system, for dysfunction in patients with social anxiety disorder. A blunted growth hormone response to clonidine, an alpha-2 antagonist, but an unchanged prolactin or eye-blink response to levodopa were observed in patients with social anxiety disorder compared with normal subjects. This indicates that a disturbance of noradrenergic, but not dopaminergic, function is present in patients with social anxiety disorder. Response to Chemical Provocation: Adrenaline caused an increase in catecholamine levels in patients with social anxiety disorder but did not increase anxiety; however, as adrenaline does not penetrate the blood-brain barrier these results are open to interpretation. Although lactate induced panic attacks in patients with panic disorder it had no affect in individuals with social anxiety disorder. Caffeine induced panic attacks in patients with panic disorder and in those with social anxiety disorder. Inhalation of 5% CO2 produced panic attacks in 12/31 patients (39%) with panic disorder and agoraphobia but not in patients with social anxiety disorder. However, a higher concentration of CO2 (35%) precipitated panic attacks in a similar proportion of patients with panic disorder or social anxiety disorder. Furthermore, the pentapeptide pentagastrin, an analogue of CCK4, has been shown to induce panic attacks in patients with social anxiety disorder (van Vliet et al, 1997) as well as in patients with obsessive compulsive disorder (de Leeuw et al, 1996) and panic disorder (van Megen et al, 1994). Neuro-imaging: Magnetic resonance spectroscopy revealed that patients with social anxiety disorder demonstrated significantly lower choline (Cho) and creatinine (Cr) signal-to-noise ratios in subcortical, thalamic and caudate areas compared with age- and gender-matched controls. N-acetyl-aspartate (NAA) and the ratio of NAA to other metabolites were significantly lower in cortical and subcortical regions in patients with social anxiety disorder. A recent study found that patients with social anxiety disorder had significantly lower NAAKho and higher Cho/Cr, mI/Cr and mIiNAA amplitudes in cortical grey matter than control subjects (Tupler et al, 1997). Neuro-imaging has also recently been used to implicate a possible dysfunction of the doyaminergic system in patients with social anxiety disorder. Using a I2 I-labelled cocaine analogue &CIT with single photon emission computed tomography (SPECT), Tiihonen et al. (1997) showed that striatal dopamine reuptake site densities were markedly lower in patients with social anxiety disorder than in control subjects. In summary, patients with panic disorder and social anxiety disorder have a common increased sensitivity for caffeine, carbon dioxide and pentagastrin suggesting a biological similarity. However, all of the studies in social anxiety disorder have involved a limited number of patients and there is, as yet, no clearly defined biological dysfunction in patients with social anxiety disorder. References [1] Tancer, M.E., Mailman, R.B., Stein, M.B., Mason, G.A., Carson, S.W. and Golden, R.N. (1994) Neumendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety, 1, 216-223. [2] Tiihonen, J., Kuikka, J., Bergstrom, K., Lepola, U., Koponen, H. and Leinonen, E (1997) Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry, 154, 239-242. [3] van Megen, H.J., Westenberg, H.G., den Boer, J.A., Haigh, J.R. and Traub, M (1994) Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients. Psychopharmacology (Bed), 114, 449-455. [4] Davidson, J.R.T., Boyko, O., Charles, H.C. et al. (1993a) Magnetic resonance spectroscopy in social phobia. J Clin Psychiatry, 54, (12, Suppl), 19-25. [5] Tupler, L.A., Davidson, J.R., Smith, R.D., Lazeyras, F., Charles, H.C. and Krishnan, K.R. (1997) A repeat proton magnetic resonance spectroscopy study in social phobia. Biol Psychiatry, 42, 419424.
S166
S.13 Pharmacothempeutic
[61 de Leeuw, A.S., den Boer, LA., Slaap, B.R. and Westenberg,H.G. (1996) Pentagaatrin has panic-inducing properties in obsessive compulsive disorder. Psvchoobarmacoloav (Berl). 126.339-344. [7] VA Vll’et, LM., Weys;ehberg; H.G:M., Slaap, B.R., den Boer, J.A and Ho Plan, K.L. (1997) Anxiogenic effects of pentagastin in patients with social phobia and healthy controls. Biol. Psychiat. 42, 7678.
options in social phobia
Conclusions: Gabapentin appears to be a safe and effective treatment for social phobia, although its position in the hierarchy of effective treatments remains to be established. The mechanism by which it reduces social anxiety is a subject of speculation, although it does not appear to work through a direct effect on serotonin. References
-1
Gabapentin in social phobia
J.W. Jefferson. Madison Institute ofMedicine, Inc., Madison, Wisconsin, USA
Introduction: Based on data from the National Comorbidity Survey (NCS), social phobia is the third most common psychiatric disorder with a lifetime prevalence of 13.3% and a 12-month prevalence of 7.9% (Kessler, et al., 1994). While greatly underrecognized and undertreated, social phobia causes substantial psychiatric morbidity. A recent survey of 3,862 HMO members in Madison, Wisconsin found an 8.2% prevalence of social phobia (by SCID), but only 0.5% of those had been diagnosed previously. When compared to a control population, those with social phobia had more than twice the reduction in work and home productivity, twice as many work hours missed due to health problems, and 2fold greater overall disability. A direct correlation was found between severity scores on the Liebowitz Social Anxiety Scale (LSAS) and reduced income, lower occupational status, and lessened likelihood of graduating from college (Katzelnick, et al., in press). An early age of onset (childhood and adolescence), substantial comorbidity (mood, anxiety and substance use disorders), and a chronic course further underscore the need for recognition, diagnosis and appropriate treatment of social phobia. Both psychotherapies and pharmacotherapies can be effective treatments for social phobia. Cognitive-behavior therapy (individual or group) is an extremely useful intervention for many individuals. The value of a broad variety of medications has become better established in recent years as the number of controlled studies has increased. Among the effective drug classes are SSRIs, MAOIs (reversible and irreversible), and benzodiazepines (Davidson, 1998). Animal studies suggesting that gabapentin, a novel GABA analog anticonvulsant, might have anxiolytic properties led to a double-blind, placebo-controlled study of social phobia. Method: The 2 center study (Dean Foundation and Duke University Medical Center) enrolled 82 adults with DSM-IV diagnosed social phobia in a 1Cweek double-blind trial that randomized patients to either placebo or gabapentin after a one week single-blind placebo lead-in. Inclusion criteria included an LSAS score of at least 50 and absence of major psychiatric and medical conditions. A flexible dose design was employed in which gabapentin was started at 300 mg bid and increased in increments no greater than 300 mg daily to a maximum daily dose of 3600 mg (given tid). Outcome measures included the LSAS, Fear Questionnaire (FQ), Brief Social Phobia Scale (BSPS), Social Phobia Inventory (SPIN), CGI, Ham-D and Ham-A. Results: Of the 82 patients enrolled, 69 entered double-blind and 39 completed the study (62% on gabapentin, 51% on placebo). The endpoint measurements for all analyses were based on last observation carried forward. Improvement on the LSAS was significantly greater for gabapentin than for placebo (total score -27.3 vs -11.9, (p = 0.008); anxiety subscale -14.1 vs -5.6 (p = 0.005); avoidance subscale -13.2 vs -6.3 (p = 0.02)). Response (detined by at least a 50% reduction in LSAS scores (ITT) occurred in 32% on gabapentin and 14% on placebo (intentto-treat). Similar responses favoring gabapentin over placebo were noted on the other social phobia outcome measures with greater symptom decrements in those with higher baseline scores. For unclear reasons, a greater drug/placebo difference was seen in men than women (due to a higher placebo response in women) and in older patients (135 years). With regard to dosing, 56% on gabapentin received the maximum dose of 3600 mgday and close to 77% received at least 2100 mg/day. While there were no serious adverse events, 21% on gabapentin and 11% on placebo withdrew because of adverse events. Severe adverse events on gabapentin included nausea, dizziness, somnolence, insomnia, nervousness, and facial edema.
[l] Davidson JRT (1998). Pharmacotherapy of social anxiety disorder. J Clin Psychiatry 59 (suppl 17); 47-51. [2] Katzelnick DJ, Kobak KA, Helstad CP, Greist JH, Davidson J, DeLeire T, Schneier F, Stein M (1998). The direct and indirect costs of social phobia in managed care patients. Presented at 37th Annual Meeting of ACNP, December 1418. [3] Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, Kendler KS (1994). Lifetime and 12-month prevalence of DSMIII-R psychiatric disorders in the United States: results from the National Comorbidiw Sorvev 5 1: 8-19. [4] Pande AC, bavi&n JRT, Jefferson Jw, Janney CA, Katzelnick D J, Weisler RH, Greist JH, Sutherland SM. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychophannacol (in press).
Is.1 3.041 RIMA’s and other drugs in social phobia
I.M. van Vliet. University Medical Centre Utrecht, the Netherlands It is only during the last two decades that the psychopharmacology of social phobia has been subject to investigations and a growing body of evidence has come to support that medication might be helpful in this invalidating disorder. In this lecture an overview is given of the studies in social phobia using the so called ‘classic’ monoamine oxidase inhibitors (MAOI’s), selective MAOA inhibitors (RIMA’s), beta adrenergic blocking agents, benzodiazepines, tricyclic antidepressants (TCA’s), newer antidepressants such as venlafaxine and the selective 5HT-IA agonist buspirone. The effects of the selective serotonin re-uptake inhibitors (SSRI’s) are discussed by David Baldwin. MAOI’s: In several studies, beneficial effects of MAOI’s in the treatment of social phobia (is social anxiety disorder) have been reported. Although these most early studies suffered a number of drawbacks (small patient numbers, mixed patients groups and low drug dosages) a reduction in social anxiety has been reported. More recent studies showed that phenelzine (60-90 mg) led to a marked improvement in two-third of patients with social phobia (1). In a study by Gelemter et al (2) four treatment conditions were compared: phenelzine plus instructions for exposure (IE), alprazolam plus IE, placebo plus IE and cognitive behavioural therapy. Results showed that 63% of the phenelzine treated patients were responders whereas the response rate was 39% in the alprazolam treated group, 24% in the cognitive behavioural group and 20% in the placebo group. However, a major drawback with the conventional and irreversible MAOI’s has been the development of hypertensive crises due to potentiation of the tyramine pressor effect (the so called ‘cheese effect’). MAOI’s also have hypotensive properties and increased glucose tolerance, less interfering with the treatment of diabetes mellitus. RIMA’s: Newer selective and reversible MAOA-inhibitors, such as moclobemide, are devoid of this effect. Patient treated with moclobemide do not need to keep any dietarian restrictions in contrast to patients treated with phenelzine who have to keep a tyramine restricted diet. Other studies with this new generation of drugs demonstrated positive effects of brofaromine and moclobemide in social phobia (3). However brofaromine is no longer in development. For clinical use only moclobemide is available. Later and larger studies with this drug failed to tind any significant difference between moclobemide (up to 900 mg) and placebo after 12 weeks. Beta Adrenergic BIockers: The majority of studies with beta blockers have been performed in patients with a subtype of social phobia i.e. performance anxiety. In several controlled studies the use of beta blockers has appeared useful in reducing autonomic symptoms, such as tremors and palpitations. As a secondary effect, anxiety reduction was achieved. Since not all beta blockers crossed the blood brain barrier it has been argued that the efficacy of beta blockers is related to a