Propsal

,921 Social anxiety and PTSD: from stress to avoidance S185

the study established a trend of efficacy, a higher percentage of the treated patients achieving Good Neurological Outcome. Optimal dose of drug, selected based on these experiments will be employed in a pivotal international trial on several hundred patients scheduled to commence soon. Other potential uses of dexanabinol include treatment of Parkinson’s, Alzheimer’s disease and multiple sclerosis. The Sanofi-Synthelabo compound SR- 141716, a non-classical diarylpyrazole type derivative is the tirst selective CBl receptor ligand (Rinaldi-Carmona et al., 1994). Binding studies indicated that SR-1417 16 has nanomolar afhnity to the CBl receptor and only negligible activity at the CB2 site. In vitro, SR-141716 antagonizes the inhibitory effects of the cannabinoid receptor agonists while in vivo antagonizes classical pharmacological and behavioral effects of CBl agonists. SR- 141716 might function as a reverse agonist at the CBl receptor. As a selective, orally active CBl antagonist, SR-141716 has been used in a large number of studies targeting the involvement of CBl in the cannabimimetic activity of various synthetic and endocannabinoids, and opened new possibilities for identification and characterization of cannabinoid-dependent neuroregulations. Administered alone, SR-14 17 16A altered several physiological or behavioral parameters, such as arousal, memory consolida- tion, sucrose intake, incentive learning and nociception, indi- cating that endogenous cannabinoid systems may be tonically active in certain conditions; it might be possible that endogenous cannabinoid systems are implicated in neuronal dysregulation leading to pathological conditions. It was suggested that some schizophrenic symptoms such as perceptual disturbance may be related to a deregulation of the endogenous cannabinoid systems. Clinical reports indicated the occurrence of psychodysleptic ef- fects, included distorted sensory perceptions, impaired judgement and dissociation of ideas following administration of cannabis. These reports and observation that cannabinoid agonists activate dopaminergic systems, determined examination of effects of SR- 141716A on neuronal functioning as compared to antipsychotic drugs. Typical and atypical neuroleptic agents increase the ex- pression of immediate early genes in various brain regions, the effects being sensitive to dopamine Dz-like receptor stimulation. It was demonstrated that SR- 141716 had similar effects, prob- ably resulted from blockade of endogenous cannabinoid tone on CBl receptors. The results suggested that blockade of CBl receptors could have beneficial effects on pathology of schizo- phrenia.

SR-141716A is currently developed as a CNS agent for the potential treatment of schizophrenia and psychosis. A phase II “meta-trial” comparing the relative efficacy of four schizophrenia investigational candidates has been performed. The trial included 420 patients, with 63 receiving each of the four compounds and two groups of 84 patients receiving either placebo or haloperidol. The outcome of the study is not known (Kendal, 2000). L-DOPA is the classical therapeutic treatment for Parkinson’s disease. How- ever, long-term therapy results in several side-effects, including induced dyskinesia. It was reported that co-administration of SR- 1417 16A with L-DOPA in animal models, reduced dyskinesia without affecting the antiparkinsonian efficacy of L-DOPA. This effect is of interest and is further evahtated.

The potential pharmaceutical value of endogenous ligands to cannabinoid receptors, anandamide and 2-AG is also investigated. Of particular interest is the interaction of anandamide and several neuroreceptor systems which includes: enhancement of GABA- ergic neurotransmission, inhibition of motor behavior paralleled by lowering the activity of nigrostriatal dopaminergic neurons, inhibition of the presynaptic glutamate release, and inhibition of

exocytic noradrenaline release. These actions and the possible, currently evaluated role of endooamrabinoids in schizophrenia might have therapeutic potential.

It is expected that the intensive work in the area of cannabinoids will result in important discoveries with valuable therapeutic applications (Pop, 1999).

[1] Brewster, M. E., Pop, E., Foltz, R. L., Reuschel, S., Griffith, W., Amselem, S., and Biegon, A. (1997). Clinical pharmacokinetics of escalating iv doses of dexanabinol (HU-2 1 l), a neuroprotectant agent, in normal volunteers, Int. J. Clin. Pharmacol. 35, 361-365.

[2] Kendall, D. (2000) SR-141716A Sanofi-Synthelabo, Current Opinion CPNS Investigational Drugs 2, 112-122.

[3] Mechoulam, R., Lander, N., Breuer, A. and Zahaika, J. (1990) Syn- thesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative, Tetrahedron: Asymmetry 1, 3 15-3 19.

[4] Pop, E. (1999) Developing camrabinoids as potential central nervous system agents, Current Opinion CPNS Insvestigational Drugs 1, 587- 596.

[5] Rinaldi-Carmona, M., Barth, F., Heaulme, M., Shire, D., Calandra, B., Congy, C., Martinez, S., Maruani, J., nehat, G., Caput, D., Ferrara, E, Soubrie, P., Breliere, J.C. and Le Fur, G. (1994) SR-141716A, a potent and selective antagonist of the brain camrabinoid receptor, FBBS Lett. 350,240-244.

S.21 Social anxiety and PTSD: from stress to avoidance

15.21.011 The epidemiology, natural history, and pharmacoeconomlcs, of Social Anxiety and PTSD

R.C. Kessler. Department of Health Care Policy, Harvard Medical School, 180 Longwood Avenue, Boston, 444 02115, USA

Purpose: To review the literature on the prevalence, course, and societal costs of Social Anxiety Disorder (Social Phobia) and Post- Traumatic Stress Disorder (PTSD)

Method: A literature search of computerized databases for published reports on anxiety, social phobia, trauma, and PTSD

Results: Prevalence: Epidemiologic surveys suggest that Social Anxiety Disorder and PTSD both commonly occur in the general population. The estimated prevalence of Social Anxiety Disorder in general population surveys is as high as 16% lifetime and 8% in a year. The generalized subtype of Social Anxiety Disorder - a subtype found in approximately 50% of lifetime cases and in up to two-thirds of cases in a year - is much more severe and impairing than other cases. As the name implies, strong fear and avoidance of a wide range of social interaction and performance situations characterize this generalized subtype. Evidence from synthetic cohort studies indicates that the prevalence of generalized Social Anxiety Disorder has increased over the past several decades in the United States. Trends in other countries have not been reported.

The estimated prevalence of PTSD in general population sur- veys in western societies is as high as 15% lifetime and 6% in a year. These prevalences vary greatly across countries depending on variation in trauma exposure. Although representative epidemi- ologic studies have not been carried out in countries experiencing prolonged political or ethnic violence, studies of refugees from such countries early show a substantially higher conditional risk of PTSD among people exposed to these types of ongoing horrific trauma than among victims of the traumas more characteristic of developed countries. For example, 65% of a sample of Bosnian refugees resettled in the U.S. were found to suffer from PTSD.

S186 S.21 Social anxiety and PTSD: from stress to avoidance

The conditional risk of PTSD among trauma victims varies greatly depending on the type of trauma. Risk of PTSD is much greater after exposure to a trauma involving assaultive violence than after other forms of trauma. Duration of trauma exposure is also a significant predictor of PTSD.

Natural history: Studies of the natural history of Social Anx- iety Disorder show typical onset in the early teenage years and typically a very chronic course. Social Anxiety Disorder is highly comorbid with other anxiety disorders, mood disorders, and sub- stance use disorders, and is usually temporally primary in these comorbidities. Onset of subsequent secondary disorders is a strong predictor of the chronic&y of social anxiety. We do not know if this is true merely because secondary comorbid disorders are markers of the severity of the primary social anxiety, or if the onset of secondary disorders has some etiologic effects on the chronicity of social anxiety.

Studies of the natural history of PTSD suggest that it often has a duration of many years. One recent study in the U.S. suggests that the active symptoms of a typical person with PTSD last more than two decades. Chronic@ is related to early age of onset and to exposure to complex traumas involving interpersonal violence. As with Social Anxiety Disorder, PTSD is highly comorbid, and comorbidity is related to chronic& Unlike Social Anxiety Disorder, PTSD is often a temporally secondary disorder. This seems to be true for two reasons. First, some earlier disorders, such as alcoholism, are risk factors for trauma exposure. Second, other earlier disorders, such as depression, are risk factors for the development of PTSD among people exposed to trauma.

Professional help-seeking is an important determinant of illness course. The proportion of people with PTSD who seek treatment is quite high. Only a very small proportion of people with Social Anxiety Disorder, in comparison, seeks professional treatment. The explanation of low rate of help-seeking for social anxiety is not clear. One possibility is that the fear of social situations extends to help-seeking situations. Another is that socially anxious people do not detine their anxiety as an illness. The second possibility is indirectly consistent with the increase in help-seeking observed among people with Social Anxiety Disorder after the onset of secondary comorbid disorders.

Societal costs: As noted above, people with Social Anxiety Disorder are at elevated risk of developing later anxiety, mood, and substance disorders. This is also true of people with PTSD, although PTSD is more likely to be secondary to other comorbid disorders. Importantly, the elevated risk of secondary disorders disappears with the remission of social anxiety and PTSD symp- toms. This means that the causal mechanisms associating primary Social Anxiety Disorder and PTSD with the subsequent onset of other disorders are not due to some underlying vulnerability to anxiety, but rather to factors associated with the anxiety itself. Although this fmding does not prove that either Social Anxiety Disorder or PTSD causes secondary disorders, it is consistent with this possibility.

Related research shows that early-onset Social Anxiety Disorder and PTSD both lead to substantial impairments in developmental role trajectories, such as educational attainment, timing and sta- bility of marriage, timing of having a first child, and occupational stability. These effects are especially important for Social Anxiety Disorder due to the very early age of onset of this disorder. Teenage girls with Social Anxiety Disorder are at especially high risk of teenage childbearing. Both boys and girls with Social Anxiety Disorder are less likely than their counterparts with similar family backgrounds to go on to college after graduation from high school. Early-onset PTSD has similar adverse effects,

but fewer public health implications than Social Anxiety Disorder because of the generally later age of onset of PTSD.

Social Anxiety Disorder and PTSD also adversely effect func- tioning in social and work roles. Social Anxiety Disorder, un- derstandably, effects social role functioning more powerfully than PTSD, but PTSD more strongly effects w6rk role functioning. The annual work productivity loss estimates due to PTSD in the U.S. exceed $3 billion. The less powerful effect of Social Anxiety Disorder on work productivity could be due to selection processes; i.e., the early age of onset of social anxiety leading most people with this disorder to select occupations where fear of social situations is not highly impairing.

Conclusion: Social Anxiety Disorder and PTSD are both highly prevalent and impairing disorders that lead to a number of adverse consequences if untreated. Rates of treatment are low for both disorders, but especially for Social Anxiety Disorder. Early and aggressive outreach to treat people with these disorders could reduce their enormous societal costs.

References

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Ballenger, J.C., J.R.T. Davidson, Y. Lecrubier, D.N. Nutt, E.B. Foa, R.C. Kessler, AC. McFarlane, and A.Y. Shalev. Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety. Journal of Clinical Psychiatry, in press. Greenberg, PE., T. Sisitsky, R.C. Kessler, ST. Finkelstein, E.R. Bemdt, J.R.T. Davidson, J.C. Ballenger, and A.J. Fyer. The economic burden of anxiety disorders in the 1990s. Journal of Clinical Psychiatry 60: 427435, 1999. Heimberg, R.G., M.B. Stein, E. Hripi, and R.C. Kessler. Trends in the prevalence of social phobia in the United States: A synthetic cohort analysis of changes over four decades. European Psychiatry, in press. Kessler, R.C. and R.G. Frank. The impact of psychiatric disorders on work loss days. Psychological Medicine 27: 861-873, 1997.

The International Consortium in Psychiatric Epidemiology. Cross- national comparisons of the prevalences and correlates of mental dis- orders: Results from the WHO International Consortium in Psychiatric Epidemiology. Bulletin of the World Health Organization, in press.

IS.21 .O2] Diagnostic dilemmas in social anxiety disorder and posttraumatic stress

D.J. Stem. University of Stellenbosch, MRC Unit on Anxiety Disorders, Cape Town, South Africa

Anxiety disorders characteristically comprise at least two im- portant components; the anxiety itself, and subsequent attempts to avoid this anxiety. These components are emphasized in both neurobiological and behavioral perspectives; each may have distinctive psychobiological underpinnings and require specific interventions. On the one hand, these kinds of similarities across the anxiety disorders raise the possibility of diagnostic confusion between them. On the other hand, though, the nature of the anxiety, the type of avoidance behaviors, and the context of these symptoms differs from disorder to disorder.

In social anxiety disorder (social phobia) (SAD), anxiety occurs in the context of performance and social situations, and there is subsequent avoidance of situations that might provoke fears of embarrassment or humiliation. Indeed, the term “social anxiety disorder” is increasingly being used in place of “social phobia”, partly because the latter term revolves solely around avoidance symptoms.

In posttraumatic stress disorder (PTSD), an important part of the context of the disorder is a preceding traumatic event. Anxiety is subsequently provoked by internal and external cues which are