The International Society for Affective Disorders (ISAD)–2nd Biennial Conference–Cancun, Mexico 5th–10th March 2004

Journal of Affective Disorders 78 (2004) S5 – S27 www.elsevier.com/locate/jad

Symposium Abstracts

The International Society for Affective Disorders (ISAD)–2nd Biennial Conference–Cancun, Mexico 5th–10th March 2004 Saturday, 6th March 2004 Symposium 1 Bipolar Disorders S1.1 The emergence of the bipolar spectrum: Clinical and theoretical significance Hagop S. Akiskal University of California Kraepelin had envisaged a broad concept of manicdepressive illness that included recurrent depressions. The unipolar – bipolar dichotomy restricted the territory of manic-depression to strictly defined bipolar disorder with mania (bipolar I). Research over the past three decades has shown that bipolarity extends into the severe psychotic domain, as well as into the interface between bipolarity and unipolarity. At the severe end of the spectrum, familial-genetic and course parameters support the extension of bipolar disorder into ‘‘schizobipolar’’. At the ‘‘softer end’’, bipolar II is distinguished from bipolar I by excited periods which are non-psychotic and brief, and sometimes adaptive, hypomania as short as 2 days; in bipolar III, hypomania is associated with antidepressant treatment; in bipolar IV, the depression arises from a hyperthymic (trait subthreshold hypomanic) baseline. More recent data on the near normal distribution of hypomanic overactive behavior in bipolar II and unipolar patients is further evidence for the crumbling of boundaries between unipolar and bipolar disorders. The clinical and familial data in support for extending the bipolar spectrum has come from the US and European centers and commudoi:10.1016/j.jad.2003.12.002

nity studies, and argues for oligogenic inheritance. However, the broadened clinical spectrum does not necessarily imply genetic homogeneity. The high population prevalence of bipolarity at the softer end of the spectrum (5– 10%) argues for a role of bipolar traits such as cyclothymia and hyperthymia in human evolution (e.g. mate selection, territoriality, leadership, exploration, creativity). Finally, the broad spectrum has important therapeutic and public health significance in terms of early intervention and extending the benefit of mood stabilizers to conditions that might otherwise be diagnosed ‘‘unipolar’’ or ‘‘impulse control disorders’’. S1.2 Prediction of recovery and recurrence in patients with first episode mania Mauricio Tohena,b, Carlos A. Zarate Jr.c, John Hennenb, Hari-Mandir Kaur Khalsab, Stephen M. Strakowskid, Priscilla Gebre-Medhinb, Paola Salvatoreb,c, Ross J. Baldessarinib a

Lilly Research Laboratories, Indianapolis, IN Consolidated Department of Psychiatry and Neuroscience Program, Harvard Medical School, Boston; and The International Consortium for Bipolar Disorders Research, McLean Hospital, Belmont, MA c Mood Disorders Research Unit, National Institute of Mental Health, Bethesda, MD d Department of Psychiatry, University of Cincinnati, Cincinnati, OH e Psychiatric Institute, Faculty of Medicine, University Medical Center, Parma, Italy b

Objective: Since improved prediction of illness-course early in bipolar disorder (BPD) is required to guide

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treatment-planning, we evaluated recovery and initial new illness following first-hospitalization for mania. Method: DSM-IV bipolar manic/mixed patients (173 entered, 1989 – 96) were followed 2 – 4 years to assess timing and predictors of outcomes defined as: syndromal (DSM-IV), symptomatic (YMRS V 5 and HDRS V 8), and functional recovery (regaining premorbid occupational and residential status); remission (syndromal recovery sustained z 8 weeks), switch (dissimilar new DSM illness before recovery), relapse (new DSM-mania within 8 weeks of recovery), and recurrence (new DSM episode z 8 weeks post-remission). Results: By 2 years, most subjects achieved syndromal (98%) and symptomatic (72%) recovery. Syndromal recovery (50% by 5.4 weeks) was earlier in women, after brief hospitalization, and with low initial depression ratings. Only 43% recovered functionally, more often older patients and after shorter hospitalization. Within 2 years of syndromal recovery, 40% had new mania (20%) or depression (20%), and 19% switched phases without recovery. Predictors of new mania were initial mood-congruent psychosis, lower premorbid occupational status, and initial classicmania; predictors of new depression were higher occupational status, initial mixed presentation, any comorbidity, and higher initial depression ratings. Antidepressant treatment was marginally related to longer recovery and earlier relapse. Conclusions: Within 2 –4 years of first-lifetime hospitalization for mania, all but 2% of patients recovered syndromally, but 28% remained symptomatic, only 43% recovered functionally, and 59% switched or had new episodes. Risks of new manic and depressive episodes were similar but predicted by contrasting factors. Keywords: Bipolar I disorder; Mania; Outcome S1.3 Clinical research in mania and soft bipolarity: Input from the French multi-site studies ‘‘EPIMAN’’ & ‘‘EPIDEP’’

mania and to facilitate the recognition of soft bipolarity in a national sample. In ‘‘EPIMAN’’, 104 DSM-IV hospitalized manic patients were selected in four university centers. The data were helpful to suggest: (1) an optimal definition of mixed depressive mania by the presence of at least two co-existing depressive symptoms (best predictive value for depressed mood, guilt and suicidal thoughts); (2) the complex dimensionality of mania as composed by a nuclear component ‘‘activation-desinhibition’’ (or impulsivity) with other dimensions such as ‘‘glad’’, ‘‘sad’’ and ‘‘bad’’ mood disturbances, and ‘‘mad’’ or psychotic component; (3) the feasibility and utility of self-assessment; (4) the pathoplastic role of affective temperaments where hyperthymic is prevalent in pure mania and cyclothymic and depressive temperaments more frequently observed in mixed mania; (5) finally the course of illness as characterized by high rates of residual symptoms and relapses during the first year of follow-up. ‘‘EPIDEP’’ was conducted by 48 psychiatric clinicians working in 15 different sites. In the global sample of 532 major depressives seeking help in psychiatry, the initial BP-II rate estimated at 20%, was doubled (39%) 1 month after, by systematic search for hypomania. The BP-II depression showed differential phenomenology (PM disturbances, guilt feelings, and suicidal thoughts). Cyclothymic temperament (CT) appeared as central in defining a distinct and more severe and recurrent form within the soft bipolar spectrum (BP-II1/2 sub-entity). Moreover, the category called ‘‘BP-III’’ (cases with hypomania strictly associated with antidepressants) seemed to be a valid soft bipolar sub-entity. Several principal component analyses revealed a double structure factor of hypomania (‘‘Sunny’’ and ‘‘darks’’ factors). Significant correlation was only obtained between ‘‘dark’’ factor of hypomania and cyclothymia. Finally, individual items related to ‘‘Ups/Downs’’ showed significantly correlated with family history of mania. Globally, EPIDEP succeeded to demonstrate the feasibility of screening BP-II disorder, and refining its phenomenology.

Elie-Georges Hantouche References Mood center, Pitie´-Salpeˆtrie`re Hospital, University of Paris VI, 75013 Paris, France ‘‘EPIMAN’’ and ‘‘EPIDEP’’ studies were dedicated, respectively, to capture the clinical heterogeneity of

Akiskal HS, Azorin JM, Hantouche EG. Proposed multidimensional structure of mania: beyond the euphoric-dysphoric dichotomy. J Affect Disord 2003;73:7 – 18.

Symposium Abstracts

Hantouche EG, Angst J, Akiskal HS. Factor structure of hypomania: interrelationships with cyclothymia and soft bipolar disorders. J Affect Disord 2003; 73:39 – 47.

S1.4 Neuroimaging and psychological findings in bipolar disorder I.N. Ferrier School of Neurology, Neurobiology & Psychiatry, University of Newcastle upon Tyne, England. E-mail: [email protected] Numerous studies using magnetic resonance imaging (MRI) have identified neuroanatomical abnormalities in patients with bipolar disorder. Ventricular enlargement, temporal lobe reduction, amygdala enlargement and volumetric abnormalities of the striatum have been reported. Deep white matter lesions (DWML) are highly significantly found more often (particularly in frontal and temporal areas) in bipolar disorder compared with controls and other psychiatric groups. This increased prevalence is found in patients below the age of 60 and in those in whom careful screening has excluded known risk factors for DWML. Evidence is accumulating that approximately 10% of first onset and/ or young bipolar patients have DWML and the prevalence rises to approximately 50% (with a concomitant increased burden and volume) in more elderly patients and in those with poor outcome. There is evidence that white matter lesions in affective disorder are associated with vascular pathology and that vascular changes in the brain occurs in bipolar patients with no identified medical cause. Neuropathological investigations have confirmed that disturbances of brain structure are a feature of mood disorders. Glial cell reduction in the subgenual prefrontal cortex and lamina-specific neuronal loss of the dorsolateral prefrontal cortex (DLPC) has been reported. Expression of calciumdependent protein kinase messenger RNA has been shown to be significantly reduced in the DLPC of bipolar patients.

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A range of neuropsychological deficits has been demonstrated in manic and depressed patients. However, non-specific factors may confound such studies. Neuropsychological assessments of euthymic bipolar patients suggest that deficits persist during remission. The temporal evolution of these neuropsychological deficits is unclear. Deficits have been associated with illness progression but a few recent studies provide evidence of selective neuropsychological abnormalities in high risk groups in bipolar disorder. The nature of the deficits is controversial. There are changes in executive function and attention but also in learning and memory suggesting on-line monitoring of learning and memory is the primary deficit. These studies will be reviewed with the particular focus on methodological issues and whether non-specific factors such as clinical state and medication may have an impact. This converging evidence from neuropsychological neuroimaging and neuropathology studies will be reviewed together with some recent PET and fMRI data. These findings suggest that there is prefrontal cortex disturbance and disruption of fronto-striatal circuits in bipolar disorder. The implications of this and the outstanding controversies will be discussed.

S1.5 Clinical strategies in treating bipolar disorder Heinz Grunze, S. Dittmann, A. Forsthoff Modern treatment strategies of bipolar disorder consist of skilful psychopharmacotherapy, combined with psychoeducation and psychotherapy. The Stanley Foundation Bipolar Network outpatient clinic at Munich was founded in 1999 and was originally part of a research program involving four centres in the US, one centre in Netherlands (Utrecht) and another German centre, Freiburg. Apart from contributing data for the overall network, several sub analyses on demographics and treatment outcome in this German sample have been conducted. As of July 2002, 152 patients were in continuous outpatient care at the SFBN clinic in Germany. 51.7% of patients were female, 48.3% male. The average age was 42.08 F 13.50 years (21 – 80 years), 40.7% reported a history of rapid cycling,

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Symposium Abstracts

almost 40% more than 20 episodes since illness onset. 26.5% of patients were classified as rapid cycling patients during the follow-up period. Axis I co-morbidity was present in 35.8% of patients, with substance abuse, mostly alcohol dominating with 26.3% and 17.8%, respectively. Psychopharmacological treatment was as follows: 60.4% of patients received monotherapy with one mood stabiliser (23.1% lithium, 11.1% valproate, 11.1% lamotrigine 6.8% carbamazepine and 5.6% an atypical antipsychotic. Combinations of two mood stabilisers were needed in 33.3% of patients with the combination of lithium and valproate being the most frequent. 3.6% of patients received three or more mood stabilisers. Even though patients were in a specialized setting with frequent visits, 56% of the patients suffered of a recurrence and another 12.8% perceived subsyndromal symptoms during the followup period (1– 32 months). In conclusion, these data of a bipolar outpatient clinic demonstrate that especially in specialised settings rapid cycling is a frequent characteristic of bipolar disorder and that polypharmacy is rather the rule than the exception. Combining polypharmacy, close monitoring and psychoeducative programs, an overall improvement in the outcome of patients can be achieved.

Symposium 2 New concepts in antidepressants

ual patients vary widely in their response to different antidepressant drugs, and it is still necessary to have at hand a range of medications offering multiple mechanisms of action—tricyclics, MAOIs, SSRIs, SNRIs, NaSSAs and others. Many of the newer agents lack the side effect burden and the lethality in overdosage of the older drugs, but they have not in general offered anything in the way of improved efficacy. However, they are not all born equal and substantial evidence is emerging that dual action SNRIs and NaSSAs, and in particular venlafaxine and mirtazapine, may offer advantages over their modern counterparts the SSRIs in terms of faster onset of action and greater rates of response and remission. The somewhat heretical notion that some antidepressants may work faster and better than others has led to an expansion of interest in the development of new concepts for treating depressive illness. Targets other than monoamines have been identified including Substance P, glutamate systems especially NMDA receptors, sigma receptors and various hormones. Drugs capable of combating HPA axis hyperactivity by blocking the glucocorticoid receptor may be peculiarly effective in rapidly alleviating psychotic and melancholic depression, while CRF antagonists may be more effective in anxiety-related disorders. BDNF may play a vital role in maintaining neural plasticity, is lowered in depressive illness and during stress, and can be manipulated by drug treatment including current antidepressants. New antidepressants are needed and they are on their way.

S2.1 Do we need more antidepressants? S2.2 How to achieve more remission Roger M. Pinder

Michael E. Thase

Medical Affairs, Organon International Inc, Roseland, NJ 07068, USA

University of Pittsburgh Medical Centre, Pittsburgh, PA, USA

Effective antidepressant treatments have been available for almost half a century. Anti-depressant drugs, mood stabilizers, ECT and psychotherapies are, however, symptomatic treatments that may have to be administered for sustained periods to prevent relapse and recurrence. Moreover, individ-

Despite the introduction of a number of new antidepressant medications over the past 15 years, the management of patients with depression remains a therapeutic challenge. Obtaining a response in antidepressant therapy—commonly defined in clinical trials as an improvement of z 50% on baseline total

Symposium Abstracts

score of the Hamilton Rating Scale for Depression (HAM-D)—ensures little beyond a reduction from baseline in signs and symptoms. For example, responders who continue to experience residual symptoms have high levels of psychosocial dysfunction, are at increased risk of relapse and recurrence, and are high users of medical services. First introduced in a report by the MacArthur Foundation Task Force in 1991, the term remission was introduced to describe a more complete or stringent level of improvement. Subsequently, remission (i.e. complete resolution of symptoms and return to premorbid levels of functioning) has increasingly been accepted as the optimal goal of the acute phase of antidepressant treatment. Within this context, the relative benefits of various psychotherapeutic and pharmacologic approaches to treatment will be re-examined, taking into account the issues such as design sensitivity and statistical power. For individuals with more severe, complicated, recurrent, chronic and bipolar forms of depression, there is evidence that the combination of psychotherapy and pharmacotherapy has been shown to yield higher remission rates than either monotherapy. With respect to choices of antidepressants, the findings of metaanalyses of both individual studies and pooled original data sets suggest that antidepressants with potent effects on both serotoninergic and noradrenergic neurotransmission result in significantly higher remission rates than more highly selective compounds, particularly when tolerability is comparable. The evidence base for various strategies used to augment the treatment of partially remitted patients also will be reviewed.

S2.3 Modulators of the HPA axis Alan F. Schatzberga, Charles DeBattistaa, Ben Floresa, Joel Posenerb a

Stanford University School of Medicine, Stanford, CA, 94305-5717, USA b Washington University, St. Louis, MO, USA For many years, activation of the hypothalamic – pituitary– adrenal axis in depression was viewed as being secondary to the depression, or reflecting psy-

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chosocial stressors involved in the pathogenesis of this disorder. However, in the past decade, activation of the axis has been viewed as playing a more primary role in the etiology of specific depressive syndromes or symptoms and the axis has become a target for novel drug development. This talk will review a number of recent studies in this area. First, data on excessive HPA axis activity in depression are reviewed. These data suggest that most depressive patients do not demonstrate elevated cortisol levels. Indeed, some recent studies suggest many major depressives actually demonstrate lower cortisol levels. In contrast, excessive HPA activity is well described in severely ill or delusional depressives. These data suggest antagonists for cortisol receptors may be particularly effective in such patients. Two such antagonists, ORG 34517 and mifepristone, are under study. These drugs block the low affinity glucocorticoid receptor but not the high affinity mineralocorticoid receptor. Thus, they can be used to modulate cortisol in brain and still preserve much intrinsic HPA axis function. However, these drugs also block progesterone receptors such that long-term use presents a number of problems in women. Data on two Phase II studies of 6– 8 weeks of treatment with ORG 34517 suggest a potential effect in some hypercortisolemic depressed patients. Mifepristone has been reported in pilot studies and one Phase III trial to be rapidly effective in some delusionally depressed patients. Possible alternative mechanisms of action are discussed. Another strategy has been to use agents that block CRH-1 receptors. m-RNA for CRH is increased in the hypothalamus and amygdala in response to stress. CRH in the amygdala may be differentially regulated than is CRH in the hypothalamus. Thus, these agents could be effective in patients who do not demonstrate elevated cortisol levels. One such agent, R-121919, has been reported to be effective in an open trial in depressed inpatients. However, development of this drug was discontinued because of potential side reactions. At least one other CRH antagonist has also been recently associated with side reactions. Last, data are presented on the potential use of cortisol infusion in nondelusional patients. Possible mechanisms of action for this are reviewed.

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S2.4 SERMs and gonadal hormones treatments—theory, reality and factors Uriel Halbreich Biobehavior Program, State University of New York at Buffalo, NY, USA. E-mail: [email protected] In theory estrogens effects on the central nervous system (CNS) suggest potent antidepressant and Neuroprotective actions. However, preliminary data suggest antidepressant efficacy only during periods of hormonal instability—the postpartum, perimenstrual and the perimenopausal periods. Current data do not support an antidepressant effect of estrogens during other periods. Recent reports also did not confirm the suggested neuroprotective effects of conjugated estrogen in postmenopausal women. Several lines of recent research promise to improve previous disappointing results. A) The discovery of at least two estrogen receptors (ER) and their differential distribution in the CNS. B) Varied affinities of various estrogens to the different ERs. C) Development of selective estrogen receptors modulators (SERMs) with targeted tissues and ERs estrogen antagonism and agonism. D) The beginning of a diagnostic shift as well as conceptualization of estrogens’ activity in the context of a broader multidimensional field. Similar developments are probably relevant for progestin and androgens.

vocalizations during maternal separation, substance P antagonists (SPAs) have anti-fear activity. In brain, substance P binds preferentially to the NK1 receptor and it is intriguing to note that NK1 receptors are localized in areas of the brain believed to be critical to depression, including amygdala and hippocampus. Furthermore, it has been shown that substance P neurons inhibit serotonergic neurons in the raphe region of the midbrain and that SPAs increase serotonergic activity. One SPA, aprepitant (also known as MK869), was approved in 2003 for the treatment of chemotherapy-induced emesis. In an early study, aprepitant proved to have equal efficacy to the selective serotonin reuptake inhibitor (SSRI) paroxetine in the treatment of depression and both active agents were superior to placebo. Furthermore, despite its effects in stimulating serotonergic neurotransmission, MK869 appeared devoid of most of the adverse side effects associated with SSRI therapy, such as sexual side effects. However, subsequent trials were not as successful and the manufacturer of MK869 has withdrawn it from further testing as an antidepressant. Other pharmaceutical companies have active SPA programs in depression, but it is not clear whether this class of compounds, despite exciting preclinical indications, will have antidepressant effects in humans.

Symposium 3 Neuro-imaging in anxiety and depression S3.1 The potential of TMS in combination with neuroimaging as a research tool for depression Mark S. George

S2.5 Substance P antagonists

Mount Sinai School of Medicine, New York, NY 10029, USA

Center for Advanced Imaging Research (CAIR), Brain Stimulation Laboratory (BSL) Medical University of South Carolina (MUSC), Charleston, SC 29425, USA. E-mail: [email protected]

There has been great excitement in recent years that antagonists of the brain peptide called Substance P, a member of the neurokinin family, may have antidepressant and anxiolytic activity in humans. In animal models of fear, such as the production of ultrasonic

Despite over two decades of human imaging research, the precise brain regions implicated in depression are not well understood. Candidate reasons for the slow progress involve disease heterogeneity (several diseases with different pathophysiologies falling under

Jack Gorman

Symposium Abstracts

the currently defined syndrome of depression), and the confounds of state and trait, concomitant and past medications, and disease progression over time. Additionally, when changes are found in certain brain regions in patients with depression, are the regions causal with respect to depression, or are they mere epiphenomena associated with the behaviours of depression? Imaging techniques that go beyond passive imaging, and non-invasively stimulate circuits while recording brain activity, might prove useful in this area. Methods: With this goal in mind, our group has pioneered and refined the technique of interleaved TMS/fMRI [1 –5]. This technique involves placing a modified figure eight TMS coil within the MRI scanner, and interleaving the TMS pulsing with the MRI scanning sequence [6]. We have also developed an MRI compatible TMS holder, with associated software, that allows one to precisely and repeatedly position the TMS coil over an identified brain region in a subject [7]. Current work involves reducing the fMRI data analysis time to real-time, refining paired pulse TMS [8], and developing user friendly methods of identifying Brodman regions on a given subject’s scan, and then placing the TMS coil over these probabilistic regions. Results: Other groups have now succeeded in using this technique, even at 3 T [9,10]. In the area of depression, we have recently completed a study in 14 adult patients with depression (bipolar 8, unipolar 6) who were scanned in a 1.5 T MR scanner with intermittent interleaved focal rTMS (1 Hz) applied over the left prefrontal cortex for 7.35 min. One Hz TMS over the left prefrontal cortex, compared to rest, was associated with increased blood oxygen level dependent (BOLD) signal at the site of stimulation as well as in connected limbic regions: bilateral dorsolateral prefrontal cortex (L>R), bilateral orbital frontal cortex (R>L), left hippocampus, mediodorsal nucleus (MD) thalamus, bilateral, putamen, pulvinar and insula (z = 3.09, P < 0.001). The right ventromedial frontal cortex was significantly decreased during prefrontal TMS. Conclusions: The TMS/fMRI technique has much potential, and can clearly demonstrate local and distributed changes associated with direct brain stimulation in depressed patients. However, there is still

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much work remaining before it can be fully used to understand the brain regions involved in mood and anxiety regulation in health and disease. Literature Cited [1] Bohning DE, Shastri A, Nahas Z, et al. Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation (TMS). Investigative Radiology 1998;33(6): 336– 40. [2] Bohning DE, Shastri A, McConnell K, et al. A combined TMS/fMRI study of intensity-dependent TMS over motor cortex. Biological Psychiatry 1999;45:385 –94. [3] Bohning DE, Shastri A, Wassermann EM, et al. BOLD-fMRI response to single-pulse transcranial magnetic stimulation (TMS). J MRI 2000;11. [4] Bohning DE, Shastri A, McGavin L, et al. Motor cortex brain activity induced by 1-Hz transcranial magnetic stimulation is similar in location and level to that for volitional movement. Invest Radiol 2000;35(11):676 –83. [5] Bohning DE, Shastri A, Lomarev MP, Lorberbaum JP, Nahas Z, George MS. BOLD-fMRI response versus transcranial magnetic stimulation (TMS) pulse train length: testing for linearity. Journal of Magnetic Resonance Imaging 2003. [6] Bohning DE, Denslow S, Bohning PA, Lomarev MP, George MS. Interleaving fMRI and TMS. EEG Clin Neurophys 2003;Supplement. [7] Bohning DE, Denslow S, Bohning PA, Walker JA, George MS. A TMS coil positioning/holding system for MR image-guided TMS interleaved with fMRI. Clin Neurophysiol 2003;in press. [8] Bohning DE, Walker JA, Mu Q, Li X, Denslow S, George MS. Interleaved paired pulse TMS and BOLD fMRI. Magn Res Med 2003:abstract. [9] Baudewig J, Siebner HR, Bestmann S, et al. Functional MRI of cortical activations induced by transcranial magnetic stimulation (TMS). NeuroReport 2001;12:3543 – 8. [10] Bestmann S, Baudewig J, Siebner HR, Rothwell JC, Frahm J. Is functional magnetic resonance imaging capable of mapping transcranial magnetic cortex stimulation? EEG Clin Neurophys 2003;Supplement.

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S3.2 Recent developments in the neurobiology of depression Helen Mayberg Emory University

Symposium 4 To identify the most appropriate uses of CBT for depression management S4.1 Cognitive behaviour for depression? Choose horses for courses

Abstract unavailable. Parker G. Roy, K. Eyers (2003) S3.3 Recent neuro-imaging findings in anxiety disorders Andrea Malizia University of Bristol Abstract unavailable. S3.4 Neuroimaging in affective disorders Gin S. Malhi Mood Disorders Unit, Mayne Clinical Research Imaging Centre, School of Psychiatry, Prince of Wales Medical Research Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW 2031 Recent advances in functional neuroimaging have greatly facilitated investigation of emotion in both health and disease. Understanding the cognitive and affective processes involved in its generation, maintenance and modulation have enabled the development of useful models: an essential initial step towards appreciating its neural substrates. This talk presents a number of models pertaining to healthy emotions and mood disorders and against this backdrop reviews salient research with particular reference to affective disorders.

American Journal of Psychiatry, 160:825 –34. University of New South Wales, Australia A recently published review of CBT failed to find clear evidence of its advantage over other psychotherapies, while also identifying a number of other challenges to the general CBT theory. This could reflect a reality that CBT is equally efficacious and/ or that its efficacy emanates more from non-specific psychotherapeutic ingredients rather than from any specific CBT component. Equally, it could reflect the limitations of applying standard efficacy trial paradigms to evaluating CBT, where subjects with homogenised depressive disorders (i.e. major depression) are included, thus preventing any specificity between the type of disorder and patient characteristics on a preferential CBT response. An alternative horse for course model is considered, whereby it is postulated that any particular antidepressant treatment (CBT, drug or other) should not be regarded as a universal treatment and should have its target populations defined. This general objective will then allow subsequent symposium papers addressing candidate CBT responders to be considered.

S4.2 What are the indications for cognitive therapy in unipolar depression? Eugene Paykel

S3.5

University of Cambridge

Anthony Cleare

It takes a long time to establish specific indications for a treatment in psychiatry. This requires not only demonstration of efficacy, and of effectiveness in practice, but of comparative efficacy with other available treatments, any specific advantages in

Institute of Psychiatry Abstract unavailable.

Symposium Abstracts

specific groups of patients or situations, and costeffectiveness. This paper will examine these issues in relation to cognitive therapy in unipolar depression. It was developed in the 1970s, but only recently has sufficient evidence accumulated for attempts to formulate specific indications. In acute treatment in milder depressions it is probably as effective as antidepressants, but there is little evidence that it is comparable to these or ECT in more severe depressions. There is growing evidence of a longer term more specific effect in reducing relapse and recurrence, but also is good evidence of efficacy for antidepressants and of lithium. Treatment costs are higher than for medication. It will be argued in this paper that the indications for cognitive therapy in unipolar depression are as follows: (1) In acute treatment of milder depressions which have not responded adequately to antidepressants. (2) In longer term treatment, in situations where there is high risk of relapse or recurrence, as suggested for instance by previous relapses, or residual symptoms after acute depression, in both cases in spite of medication. (3) Cognitive therapy should not be used alone, but always as an add on to medication, except where the patient declines medication, and provided the greater costs can be met. The indication for relapse and recurrence prevention is the newest. The detailed evidence will be presented.

S4.3 Benefits of CBT in individuals with bipolar disorders Jan Scott Institute of Psychiatry, London, UK The increased acceptance of stress-vulnerability models of severe mental disorders and of brief evidence-based psychological therapies in their treatment has finally led to increased interest in the role of psychotherapies in bipolar disorders. This paper reviews the results from randomized controlled trials of psychological therapies, particularly cognitive therapy, as an adjunct to standard medications. The evidence suggests that the addition of a brief package

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of cognitive techniques or a standard course of cognitive therapy may significantly reduce symptoms, enhance social adjustment and functioning, and reduce relapses and hospitalisation rates in patients with bipolar disorder. However, there are some weaknesses in the current data: for example sample sizes and methodological problems in the published randomised controlled trials and the heterogeneity in the outcomes achieved (some therapies reduce manic but not depressive relapses, others have the opposite effect) suggest that not all individuals will benefit from these approaches. With this in mind, this presentation will explore the results and predictors of outcome identified in the Medical Research Council funded multicentre randomized controlled trial and contrast the findings of this effectiveness study with published findings from single centre efficacy studies. The comparisons suggest that further studies are required to fully establish the place of psychological approaches in day-to-day clinical practice.

S4.4 A critical look at the CBT evidence base Rachel Churchill Health Services Research Department, Institute of Psychiatry, London, UK Objectives: (1) To provide a qualitative summary of all controlled trials of cognitive-behavioural treatments compared with other types of therapy for the management of depression people with depression. (2) To critically appraise the evidence for these treatments. (3) To reconsider the apparent efficacy of CBT in view of the quality of the evidence base for these treatments. Methods: A systematic review and meta-analysis was undertaken. Included were RCTs and CCTs comparing CBT other types of psychological treatment for adults with depression. Data sources were electronic bibliographic databases, specialist journals and study bibliographies. Authors were contacted for further information. Trials were critically appraised and quality rated. Results: Fifty-nine of 76 potentially eligible studies were included. Trials were generally of low overall quality and the critical appraisal identified

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flaws likely to have an influence on outcome. These, along with inconsistencies in the available data, cast doubt on the validity of some of the evidence in this field, limiting the interpretation of findings from trials of CBT. Conclusion: Synthesis of the data from these trials indicated the apparent efficacy of CBT compared with other types of therapy. However, much of the primary research in this field was of poor quality, providing, at this stage, only limited guidance for the use of CBT in the management of depression. A critical look at the sources of these data indicates the need for a more cautious interpretation of these data.

Symposium 5 Chronobiological treatments for major depression S5.1 Chronobiological treatments of bipolar depression Francesco Benedetti, Cristina Colombo, Alessandro Bernasconi, Barbara Barbini, Mara Cigala Fulgosi, Adriana Pontiggia, Enrico Smeraldi Department of Psychiatry, Universita` Vita-Salute, San Raffaele Institute, Via Stamira D’Ancona 20, 20127 Milan, Italy. E-mail: [email protected] An early hope of research on biological rhythms was that chronobiological interventions could become a benign alternative to more radical treatments of depression. The clinical usefulness of sleep – wake rhythm manipulations was, however, questioned by the short duration of their antidepressant effects. In the last 10 years, clinical research at our center was aimed at finding strategies to improve usefulness of chronobiological treatments of bipolar depression. Combined treatments with lithium salts, low-dose antidepressant drugs, and chronobiological interventions such as single or repeated total sleep deprivation (TSD), sleep phase advance (SPA), and morning light therapy (LT), allowed to reach response rates of 60 – 70% and could successfully prevent relapse, thus providing clinical psychiatrists with new instruments

to achieve rapid and sustained antidepressant response in bipolar depressed patients. In bipolar patients the high susceptibility to the clinical effects of chronobiological treatments was confirmed by the clinical efficacy of low-intensity LT. When combined with repeated TSD, morning LT given at the intensity of 150 lx was more effective than ambient light, and less than 2500 lx light. In a retrospective chart review study, the availability of direct sunlight in the morning—but not in the evening— was found to speed up response to common antidepressant treatments in bipolar depressed patients, thus suggesting that exposure to natural sunlight in the morning could be an underestimated and uncontrolled therapy for bipolar depression. Selective serotonin reuptake inhibitors are effective in approximately 70% of patients with a major depressive episode, but therapeutic changes usually require 2 weeks of administration to become clinically relevant. The combination of morning low-intensity LT to citalopram in patients affected by a major depressive episode without psychotic features was found more effective than the combination of placebo. With an optimized timing of administration, LT significantly hastened and potentiated the effect of citalopram, thus providing the clinical psychiatrists with an augmenting strategy which was found effective and devoid of side effects. Finally, the last year’s data from genetic research allowed to partially explain the mechanism of action of chronobiological treatments. The influence of a functional polymorphism in the transcriptional control region upstream of the coding sequence of the 5hydroxytryptamine transporter (5-HTTLPR) on response to TSD was found to be similar to that observed on response to serotonergic drug treatments. Patients treated with TSD followed by light treatment showed the same influence of 5-HTTLPR, thus contributing to explain the synergistic effect of the two treatments. Moreover, recent observations about clock genes and their role in the regulation of mammalian circadian rhythmicity raised interest about the possible role of genetic mechanisms in influencing the circadian rhythms abnormalities that characterize major depressive episodes: preliminary results show that variants of genes pertaining to the molecular clock (CLOCK and GSK3-h), such as age at onset, recurrence of illness, and disorders of the sleep – wake cycle.

Symposium Abstracts

S5.2 Sleep phase advance as a fast-acting antidepressive strategy Mathias Berger Department of Psychiatry and Psychotherapy, University of Freiburg, Hauptstrasse 5, 79104 Freiburg, Germany. E-mail: [email protected] Neither pharmacological nor psychotherapeutic strategies in the treatment of depression have solved the problem of the time lag of at least a few weeks until a significant effect of the treatment occurs. Additional application of sleep deprivation is not helpful to accelerate onset of treatment, since most patients exhibit a relapse into depression during the so-called recovery night. In a series of studies we could show that a 5-day, stepwise sleep advance strategy following successful total sleep deprivation can prevent this relapse in about two third of these responders. In a randomized controlled study this was significantly more effective than a phase delay procedure. To shorten the procedure, we then carried out a first open trial with a 3-day sleep phase advance procedure, which also led to comparable results. Therefore, this therapy seems to be a chance for closing the gap between the onset of pharmaco-/ psychotherapy in depression and treatment response. It also seems to be a suitable approach in therapy resistant depressions.

S5.3 Chronobiological augmentation of sleep deprivation as an antidepressant intervention Joseph Wu University of California, Irvine Sleep deprivation has been shown to have an antidepressant effect. However, the antidepressant effect of conventional sleep deprivation therapy has the limitation of having a short duration. Chronobiological augmentation using light therapy and phase advance of sleep has been used to maintain the antidepressant effect of sleep deprivation.

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Method: Seven women and six men, ages 22 –55, with major depressive disorder (both unipolar and bipolar type) were assigned to medication only versus chronobiological augmentation of sleep deprivation (with light therapy and phase advance of sleep). Patients were followed for 6 weeks. The Structured Interview Guide for the Hamilton Depression Rating Scale was used to assess response. Results: The preliminary impression is that the sleep deprivation responders appeared to show an earlier and sustained response compared to medication only. Conclusions: These preliminary impressions are tentative and further data collection and statistical analysis need to be done to confirm these impressions. [Research supported by Stanley foundation and UCI GCRC.]

S5.4 Light and negative air ion treatment for chronic depression Michael Terman Columbia University, New York, NY, USA Bright light and high-density negative air ion exposure have shown treatment success for the winter depression of seasonal affective disorder (SAD). These nonpharmacologic treatments have fewer side effects and contraindications than antidepressant drugs, and often produce improvement more rapidly. They may also benefit nonseasonally depressed patients who cannot tolerate and must discontinue medication, or who experience relapse after initial response or fail to respond to medication. Method: Twenty-four women and eight men, ages 22– 65, with major depressive disorder (single episode, chronic z 2 years) were randomly assigned to bright light (10,000 lx; n = 10), high-density negative ions (4.5  1014 ions per s; n = 12) or a lowdensity ion placebo (1.7  1011 ions per s; n = 10). High- versus low-density ions forms a true doubleblind comparison, while light versus ions forms a single-blind comparison. Treatment was taken daily for 5 weeks (1 h duration starting V 10 min after waking). The Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affec-

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tive Disorder Version (SIGH-SAD) and Clinical Global Impressions were used to assess weekly response. SIGH-SAD scores at entry were z 20; remission was defined as a score reduction to V 8. Results: Baseline depression severity was similar across groups. All groups showed significant score improvement; however, improvement was far greater under light and high-density ions than under placebo. Remission rate was 50% for both active treatments, and 0% for placebo. Conclusions: In this preliminary study of patients with chronic depression, bright light and high-density negative ions both produced significantly greater clinical improvement than low-density ions. The success rate was similar to that seen for SAD. [Research supported by NIH grant MH42931.]

S5.5 Adjunctive bright light in non-seasonal major depression Klaus Martiny, Marianne Lunde, Mogens Unde´n, Henrik Dam, Per Bech Psychiatric Research Unit, Frederiksborg General Hospital, Denmark. E-mail: [email protected] Objective: To test the effect of adjunctive bright light treatment in patients with non-seasonal major depression in a double-blind clinical trial. Method: Patients with a DSM-IV diagnosis of major depression, but not fulfilling the seasonal pattern specifier, were randomised to 5 weeks of treatment with either 1 h of bright light with 10,000 lx or 1/2 h of dim red light with 50 lx in the morning. All patients were treated with 50 mg sertraline per day. Light intensity for dim light treatment was reduced by use of a red film behind the screen and electronic dampening. The external appearance of the lamp was, apart from the colour of the screen, identical with the bright light lamp. The patients were seen at weekly visits. Depression severity was assessed by use of the Hamilton Depression Scale (HAM-D17), the Hamilton subscale (HAM-D6), the Melancholia Scale, and the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders Version (SIGH-SAD). Seasonality was assessed by use of

the Seasonal Pattern Assessment Questionnaire (SPAQ). Side effects were assessed by a rating scale including both side effects to specific selective serotonin reuptake inhibitors and to light therapy. Results: In total, 102 patients were included in the study. Mean age was 44.6 years, 31% were males. The seven atypical items from the SIGH-SAD (except ‘reverse diurnal’) had a baseline score of 6.5. The SPAQ global seasonality score (GSS) was 9.4. On all four outcome scales the bright light group had a faster reduction of depression scores ( P V 0.05). Response and remission rates were higher for the bright light group ( P V 0.05). Thus, after 5 weeks of therapy, the response rate (50% reduction on HAM-D17) was 66.7% in the bright light group compared to 40.7% in the dim light group. The remission rates (a score of less than 8 on the HAM-D17) were 41.7% in the bright light group and 14.8% in the dim light group. At the end of the study, the patients were asked to evaluate, in %, the perceived benefit from the various treatment elements (psychosocial support, drug, light treatment and others). The benefit of light treatment was rated 22.25% in the bright light group and 16.9% in the dim light group. The benefit of drug treatment was rated 41.7% in the bright light group and 46.5% in the dim light group. We interpret this as an expression of an acceptable blinding of light treatment conditions. Conclusion: This study confirms the additive effects of adjunctive bright light treatment in nonseasonal depression. The post-study evaluation shows a sufficient blinding of light treatment conditions.

Symposium 6 Bipolar Disorders S6.1 A systematic review of the association between obstetric complications and the development of bipolar affective disorder Jan Scott Institute of Psychiatry, London, UK Background: Magnetic resonance imaging studies in bipolar disorders (BP) reveal structural abnormalities that have sometimes been interpreted as evidence

Symposium Abstracts

that obstetric complications (OC) may impair early brain development and increase vulnerability to the development of Bipolar disorders. Aims: This paper comprises a systematic review of studies comparing the obstetric histories of (1) BP cases and non-psychiatric controls and (2) BP cases and cases with other mental disorders, particularly schizophrenia. Method: Publications were identified by computer searches of seven databases (including MEDLINE and PsychLIT), hand searches of reference lists and from grey literature received as personal communications. Result: Only a third of the studies identified were accepted for analysis. There were trends that reached significance in some studies for individuals who developed bipolar disorders to report fewer or less severe OC than individuals who developed schizophrenia, but more OC than healthy unaffected siblings. However, there were no specific OC specifically associated with the development of bipolar disorders. Conclusion: There is no consistent evidence that OC are implicated in the aetiology of bipolar disorders. However, the methodological inadequacies of the majority of studies make definitive conclusions difficult.

S6.2 Atypical depression bipolar II connection

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We attempt to provide empirically-based answers to the difficulty of separating the shifting affective symptomology of those patients from their long-term temperamental and characterologic attributes. In a large sample of major depressive patients with atypical features, as defined by DSM IV, we observed that a large proportion (about 70%) met criteria for bipolar II and related soft bipolar disorders; nearly 60% had antecedent cyclothymic or hyperthymic temperaments. In our atypical depressive patients, lifetime comorbidity with anxiety disorders, body dysmorphic disorder, eating disorders (mainly bulimia) and both cluster C (anxious) and cluster B (dramatic) personality disorders is the rule rather than the exception. In particular, 43% of the patients met DSM-IV criteria for borderline personality disorder (BPD). The presence of cyclothymic temperament explains much of the relationship between atypical depression and BPD. Avoidant and dependent traits also appear relevant to the diagnosis of BPD as well as in predicting several diagnostic criteria such as unstable and intense interpersonal relationships, identity disturbance, and efforts to avoid real or imagined abandonment. These findings suggest that ‘‘atypicality’’ of depression is favoured by affective temperamental dysregulation and anxiety comorbidity, clinically manifesting in a mood disorder subtype which is preponderantly in the realm of the soft bipolar spectrum.

Giulio Perugi S6.3 Depressive mixed states Department of Psychiatry, University of Pisa, Via Roma 67, 56100 Pisa, Italy. Tel.: + 39-050-835-414; fax: + 39-050-21581. E-mail: [email protected] The rubric ‘‘atypical depression’’ defines a large subset of depressive states, in which mood and anxiety disorders are commonly coexisting, characterized by reactive mood, a pattern of stable interpersonal sensitivity (exaggerated vulnerability to feeling hurt by criticism or rejection), and reverse vegetative symptoms such as increased appetite, hypersomnia, and diurnal variation with evening worsening. Previous literature suggests considerable commonality in both the clinical symptoms and the long-term traits of patients with atypical features, bipolar II and related cychothymic depressions, and borderline personality.

Franco Benazzi University of California at San Diego (USA) Collaborating Center in Ravenna (Italy), and Department of Psychiatry, National Health Service, Forli, Italy. E-mail: [email protected] Depressive mixed states (DMX), reported by Falret (1854), Kahlbaum (1882), and Hecker (1898), were clearly described by Weygandt (1899) and Kraepelin (1913) in mood disorders corresponding to DSM-IV bipolar-I (BP-I), bipolar-II (BP-II) and major depressive disorder (MDD). DMX were defined as depression plus some concurrent excitement (hypo-manic) symptoms of mood, thought, and be-

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havior. Hecker best described BP-II DMX, viewed as a marker of ‘‘cyclothymia’’ (BP-II). Recent studies on DMX were by Perugi et al. (1997, 2001) in BP-I, Akiskal and Benazzi and Benazzi (2000 – 2003) in BP-II (replicated by Sato et al., 2003, Judd et al., 2003). BP-II DMX was defined by Akiskal and Benazzi as major depressive episode (MDE) plus three or more intra-episode hypomanic symptoms (onset during MDE, duration at least 1 week). This dimensional definition and its validation were the result of clinical, family history, and psychometric studies, showing strong associations with many bipolar validators like bipolar family history, and a hypomanic factor in depression (replicating Hecker’s observation of DMX as marker of BP-II). The definition of BP-II DMX was based on its diagnostic utility (Kendell, 2003), like predicting BP-II and treatment impact. BP-II DMX studies were done in more representative non-tertiary care (private practice) outpatients. Frequency of BP-II versus MDD was 55% in a 600 sample (replicating the 1:1 ratio found by Angst et al., 2003 in a community sample). Probing for history of hypomania focusing more on overactivity than mood change, using the DSM-IV SCID-CV as modified by Benazzi and Akiskal (2003), increased BP-II diagnoses. Frequency of DMX was 60% in BP-II, 30% in MDD. Hypomanic symptoms were assessed by the Hypomania Interview Guide during index MDE (off psychoactive drugs). Most common intra-episode hypomanic symptoms were irritability, racing/crowded thoughts, distractibility, psychomotor agitation, more talkativeness. DMX, versus bipolar validators (young onset, many recurrences, atypical depression, bipolar family history) had the best combination of sensitivity and specificity for predicting BP-II (60%, 68%), while family history had the highest specificity (80%) but it is more difficult to get (especially BP-II). DMX may be a cross-sectional marker suggesting the BP-II nature of depression, then requiring skilful probing for history of hypomania (not always simple to get, as patients usually see it as a period of well being). DMX in MDD had onset and family history similar to BP-II, suggesting a continuity between BP-II and MDD. Continuity was also supported by distribution curves of hypomanic symptoms (and atypical symptoms), showing lack of bi-modality in the entire sample. A DMX dimensional definition was also supported

versus a categorical definition and versus combinations of specific symptoms. Bipolar validators were not significantly different between MDE plus full hypomania versus DMX, and versus BP-II MDE, not supporting a DMX definition like DSM-IV BP-I mixed. DMX was more common in females, in young onset BP-II, in younger age BP-II. Depression plus racing thoughts was associated with suicide ideas. Temperamental frequent mood swings may facilitate DMX onset. Clinicians observed that DMX may worsen using only antidepressants, and that hypomanic symptoms should be first controlled by mood stabilisers or antipsychotics before using antidepressants. DMX in BP-II and MDD may be underdiagnosed if not systematically assessed, as it is the case for BP-II. Acknowledgements These studies would not have been possible without the inspiration, close collaboration, and support by Hagop S. Akiskal.

S6.4 Advances in the last decade for bipolar disorder Joseph F. Goldberg Recent years have witnessed unprecedented strides in our understanding of bipolar disorder, bearing on refinement of its diagnosis, biological and clinical correlates, therapeutics, and psychosocial impact. The historical underrecognition of cyclity has begun to challenge older epidemiologic assumptions, alerting the field to finer-grained unipolar versus bipolar distinctions. Many follow-up studies have by now observed the persistent and sub-threshold mood symptoms, extensive comorbidity, illness complexity, and phenotypic heterogeneity inherent to bipolar disorder, supporting the concept of a bipolar spectrum—that is, mood and cognitive or behavioral symptom constellations that probably reflect incomplete penetrance. Research interests have increasingly become redirected to studying well-characterized clinical subgroups, such as those with bipolar I versus II disorder, rapid cycling, pediatric and early onset, or comorbid features.

Symposium Abstracts

Molecular linkage studies have pointed to susceptibility loci apparently unique among bipolar kindreds, as well as markers potentially shared with schizophrenia. Neuroimaging studies have identified both functional/metabolic and anatomic distinctions in patients with bipolar disorder that may differ across multi-episode patients. Finally, pharmacotherapeutic advances have challenged traditional definitions of ‘‘mood stabilizers’’ and transformed therapeutics on multiple levels, amid the growing array of major drug classes used in bipolar disorder, including lithium, anticonvulsants, atypical antipsychotics, and antidepressants. Controlled ‘‘efficacy’’ trials as well as realworld ‘‘effectiveness’’ studies demonstrate varied within- and between-class tolerabilities as well as outcomes for target symptoms (e.g. mania versus depression, anti-suicide properties, utility for comorbid features). The rise of combination drug therapy— modeled after traditional complex disease management – offers prospects for pharmacodynamic synergies, although evidence-based studies remain far outpaced by anecdotal impressions. Evidence also has begun to accrue for the distinct benefits for diagnosis-specific psychotherapies added to medications. While the likelihood for an all-inclusive unifying disease theory seems increasingly remote, future advances are likely to come from pluralistic models that build on current foundations.

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and the health care system. This presentation will summarize recent developments in psychoeducation, cognitive-behavioral therapy, interpersonal therapy, and family therapy in bipolar disorder, and further identify provider-targeted measures to improve treatment, together with broader health services research findings. In addition, these treatments and pharmacotherapy together will be blended into a recently articulated ‘‘hierarchy of treatment needs’’ model for planning delivery of care that will be evidence-based, comprehensive, and pragmatic.

Symposium 7 Positive advocacy by patients in affective disorders Symposium 8 From epidemiology to intervention: Strategies to reduce the burden of depression S8.1 The burden of affective disorders in Mexico Marı´a Elena Medina-Mora, Guilherme Borges, Carmen Lara National Institute on Psychiatry

S6.5 Psychosocial interventions for bipolar disorder Sagar Parikh University of Toronto Pharmacotherapy is essential as the basis for successful treatment of bipolar disorder and has been clarified through numerous studies. No clear standards for psychosocial interventions for bipolar disorder have been established, even though it is clear that pharmacotherapy alone is insufficient. A key dimension of treatment success, either in pharmacotherapy or in psychotherapy, lies in the organization and coordinated delivery of both treatments. Using the broadest definition of psychosocial interventions, therapeutic efforts may be seen to act at the level of patient, of the provider,

The presentation will describe prevalence of affective disorders, socio demographic correlates, service utilization, type and quality of treatment received and impairment, in the Mexican urban population between 18 and 65 years of age. The information comes from the Mexican data from the WHO 2000 initiative on Mental Health. The sample design was probabilistic, stratified and multistage; one individual per household was selected. The target population was non-institutionalized inhabitants of households in urban localities of more than 2500 inhabitants, which represents 72% of the national population. A total of 5826 completed interviews were achieved, the response rate was 76.6%. The instrument is a computer assisted version of the Composite International Diagnostic Interview (CIDI certified version 15; World Health Organization, 2001), a structured diagnostic interview, installed on a

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laptop and administered face to face by a lay interviewer, impairment was assessed through the WHODAS, that was previously validated in the country among patients suffering from depression. The translation of the instrument into Spanish was carried out according to WHO recommendations. The information was collected by interviewers with previous experience in systematic data collection and extensively trained and supervised during field work. Fifty-four percent were females, 40% were between 18 and 29 years of age, 66% had completed, 68% had completed 6 years of schooling and 12% had a university degree, 67% were married or living with someone, 58% were employed. Using algorithms for producing ICD 10 diagnosis, prevalence of affective disorders in life time was estimated in 9.1%, in the last 12 months in 4.5% and in the last 30 days in 1.9%. Rates were higher among females (11.2% life time prevalence) than among males (6.7%). Prevalence of major depression was estimated in 4.5 in life time for females and 2% for males. Analysis of periods of onset showed three ages where the initiation of major depressive episodes was more common, around 17 years of age, at 32 and after 60. Results from the study show that affective disorders initiate along all ages of life span. Service utilization was low; impairment due to mental disorders was higher than the one reported for other physical chronic conditions. Post traumatic stress disorders and depression showed the highest levels of impairment in all areas of life and depression showed the highest rate of days out of role. Implications for policy are discussed.

S8.2 The burden of medically unexplained symptoms Christopher Dowrick University of Liverpool The burden of medically unexplained symptoms should be understood in several different ways: in terms of its complex epidemiology; its uncertain epistemology; the distress experienced both by patients and their doctors; and the extent to which it may be exacerbated by dysfunctional encounters between doctors and patients.

Epidemiology: About one in five patients attending family doctors in the UK have medically unexplained symptoms, a proportion similar to that found in community surveys in France, Nigeria and Italy. Medically unexplained symptoms frequently coexist with mood or anxiety disorder, both cross-sectionally and longitudinally: however, in the WHO primary care study, the proportion varied dramatically around the world, from 45% to 90%. The economic burden is also high. In the US patients with high levels of somatisation or health anxiety accounted for up to 50% more visits to primary care doctors, up to 50% greater out-patient costs, and one third more hospitalizations. Epistemology: There is considerable debate as to how medically unexplained symptoms should properly be conceptualised. Are they simply a manifestation of psychiatric disorder, as DSM-4 and ICD-10 would have us believe with their various categories of somatisation and somatoform disorders? Within this perspective, there are those who take a wide definition and others who take a narrow definition of the disorder, which goes some way to explaining apparent variations in prevalence. Are variations in prevalence across the world the result of differing cultural perceptions of health and illness, including the issue of whether mind and body should properly be seen as distinct? Or do they relate to differences in health care systems, in particular the presence or absence of personal medical lists, and how doctors and patients communicate? Experience: Patients are usually distressed by the experience of their medically unexplained symptoms, and may feel frustrated by the failure of their doctors to help them. Family doctors express lower satisfaction with care for these patients than patients with psychological problems. They often find these patients burdensome: partly because of the frequency with which they attend, and partly because they present a fundamental challenge to their sense of professional expertise and competence. Encounters: Effective interventions can reduce the burden of medically unexplained symptoms both for patients and health care systems. These include systematic approaches using either antidepressant medication or problem solving treatment; and there are indications of success in training family doctors to use reattribution techniques. But it is important

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to be aware that doctors themselves may be part of the problem. In a qualitative study of audio taped consultations between patients with unexplained symptoms and UK family doctors, we found that most patients presented psychological cues [1]. However, the doctors commonly ignored these cues and attempted to normalise the problems, which had the counter-productive effect of increasing the range and severity of symptoms presented [2]. The burden of medically unexplained symptoms may therefore sometimes be the product, not the cause, of unsuccessful encounters between patients and their doctors. [1] P. Salmon, C. Dowrick, A. Ring, G. Humphris, Voiced but unheard agendas: psychosocial cues in patients with unexplained symptoms, British Journal of General Practice, in press. [2] C. Dowrick, A. Ring, G. Humphris, P. Salmon, Normalisation of unexplained symptoms by general practitioners: towards a functional typology, British Journal of General Practice, in press.

S8.3 Avertable burden of affective disorders: A global cost-effectiveness analysis Dan Chisholm Global Programme on Evidence for Policy, World Health Organisation, Geneva, Switzerland Context: Despite the availability of effective treatment, bipolar affective disorder and (unipolar) depression continue to impose an immense epidemiological, social and economic burden on societies throughout the world. In order to stimulate new investment into its appropriate management, there is a need to demonstrate that interventions are not only effective and sustainable, but also affordable and sustainable. Aim: To estimate the population-level cost-effectiveness of evidence-based interventions for reducing the current burden of bipolar disorder and depression in different regions of the world. Method: WHO has embarked on a new initiative to assemble databases on the cost-effectiveness of key health interventions in 14 epidemiological subregions. WHO-CHOICE advocates a ‘generalised’

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form of cost-effectiveness analysis, in which costs and effects of both current and new interventions are compared to the starting point of ‘doing nothing’. Accordingly the costs and effectiveness of pharmacological (older and newer anti-depressants, mood stabilisers) and psychosocial interventions provided in primary care or outpatient settings were compared in a population model to an epidemiological situation representing the untreated natural history of these disorders. Effectiveness was expressed in terms of DALYs averted (i.e. reduced burden) and costs were expressed in international dollars. Results: Implemented at a coverage level of 50%, total DALYs averted annually by the first-line treatment of bipolar disorder with lithium or valproic acid (with and without psychosocial care) amounted to 200– 350 per one million total population, at a cost ranging from less than I$ 10,000 per DALY averted in high-mortality developing sub regions to more than I$ 30,000 in developed sub regions. For averting the burden of depression, pharmacotherapy with TCAs or generic SSRIs, particularly when accompanied by proactive collaborative care, were the most cost-effective strategies (cost per DALY averted: < I$ 1500, high-mortality developing sub regions; < I$ 2500, low-mortality developing regions; < I$ 10,000, developed sub regions). Conclusion: Using a threshold value of each averted DALY being worth at least average per capita income in a given region, results indicate that cost-effective interventions exist for reducing the burden of affective disorders. However, a substantial investment of resources will be needed if the existing burden of these disorders is to be significantly dented.

S8.4 Reducing the burden of affective disorders: Barriers and opportunities Jose L. Ayuso-Mateos Department of Psychiatry, Universidad Auto´noma de Madrid, SPAIN. E-mail: [email protected] Affective disorders constitute a significant public health burden as a result of its high prevalence and

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chronicity. Recent epidemiological research has demonstrated the considerable (and previously underestimated) burden that affective disorders impose on individuals, communities, and health services throughout the world. In the final report of the Global Burden of Disease (GBD) study carried out by WHO and the World Bank, the proportion of GBD caused by affective disorders was estimated at 4.2%. The latest estimates for the year 2000 show that depression is already the largest single cause of disability and fourth largest cause of burden world-wide, ranging from 4.7% to 3.5% in less developed regions like South East Asia and the Eastern Mediterranean to a proportion exceeding 8% in developed regions. The burden imposed by these disorders is projected to increase by the year 2020, largely as a result of better control of communicable diseases and consequent survival into older age. Even in developed countries, despite advances in treatment and services delivery, the substantial burden of affective disorders remains unchecked because available management strategies are not used or not used effectively. The recent development of community and public policy interventions that prevent illness, increase recognition, promotes access to care and improve treatment adherence suggest that a reduction in the burden is potentially achievable. Barriers to reduction of this high burden include factors that increase the risk for these disorders, worsen their outcome or lead to inefficient use of the health care system. Effective reduction of this barrier will require interventions at multiple levels: individual, families, communities and health care systems.

S8.5 A comprehensive strategy to decrease the burden of depression: PAHO experience in Latin America Jose Miquel Caldas de Almeida Epidemiological studies have shown a high prevalence of depression in Latin America (the mean life time prevalence rate of depressive disorders across community based surveys in several Latin American countries is 14.3%). In these countries, unipolar depressive disorders are first in the rank of causes of the burden of disease (6.7% of the burden of

disease). Yet, despite the magnitude and impact of depressive disorders, most of the people affected do not have access to any treatment: less than 20% of people identified as patients with a depressive disorder in the community survey developed in Mexico in 2001 – 2002 had used health services in the previous 12 months, and there is no reason to believe that the situation in other Latin American countries is significantly better. In order to raise awareness on the magnitude of depression related problems and to reduce the untreated depression prevalence, the Pan American Health Organization (PAHO/WHO) designed and tested a comprehensive program ‘‘Know Depression and Face it’’ with the following objectives: (a) increase the general knowledge on depression, its symptoms, consequences and available treatments; (b) dispel the misconceptions that interfere with the adequate use of mental health services and promote the attitudes that facilitate an effective referral to these services; (c) strengthening capacities of health professionals to recognize and treat depressive disorders. The program, based on a concentric-circle targeted intervention model, includes interventions at the levels of the individuals, families, community, health system, mass media and political authorities. Three main strategies were used: (1) Production of specific educational materials; (2) Dissemination of information on the recognition and treatment of depression using the natural existing networks; (3) Training of professionals and key community members in the detection and management of depression. Training modules for general practitioners and nurses were developed and tested. Specific materials to strengthen the capacities of key members of the community (religious leaders, women groups and hairdressers) in the detection and referral of depression were also tested. Other components of the program include raising awareness campaigns for the general population, workplaces, and public institutions. Training modules for nurses and community members showed to be effective in the improvement of detection and referral of depressed patients to general practitioners. Although it was not possible to measure changes in stigma and utilization of services by depressive patients, the first results of this program suggest that it can promote changes in the negative attitudes towards depression and improve the utiliza-

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tion of health services. The work developed in Panama can provide interesting methodological approaches for the prevention and treatment of depression. However, it has some limitations, mainly the ones resulting from having been developed just in one country. The next phase of the project includes the review of the materials developed in Panama, the elaboration of a package to be used in the development of national programs against depression and the test of this package in three countries of Latin America.

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S9.3 Can brain imaging help to untangle the anxiety-depression knot? Sanjaya Saxena UCLA Neuro-psychiatric Institute Abstract unavailable.

S9.4 New neuroimaging findings in panic disorder

Symposium 9 Anxiety and depression: A Gordian knot S9.1 Depression in PTSD and OCD: From theoretical considerations to practical interventions Joseph Zohar Chaim Sheba Medical Centre Abstract unavailable.

S9.2 Analysis and depression: A cognitive behaviour perspective

Johan A. den Boer, M.L. Boshuisen, G.J. ter Horst Department of Biological Psychiatry, Academic Hospital Groningen, P.O. Box 30001, 9700RB Groningen, The Netherlands In the last two decades a large number of brain imaging studies have been conducted investigating both structural and functional aspects of the brain in patients suffering from panic disorder (PD).The aim of the research reported here was to further characterize the neurobiological substrate of panic disorder (PD), and to characterize the effects of treatment on the recovery of the affected circuitry. We used H215O PET scanning and pharmacological challenge with the CCK-B receptor agonist pentagastrin in PD patients and healthy control subjects.

Emanuel Maidenberg UCLA

Study I

The complex question of commonality may be examined on different levels of analysis: brain functions, genetic vulnerability, personality factors, thoughts, and behaviours, to name a few. An assumption that different mood states lead to moodspecific perceptions and responses underlies the Cognitive-Behaviour approach to psychology and Cognitive-Behaviour Therapy (CBT). This presentation will examine commonalities and differences in current Cognitive-Behaviour conceptualization of anxiety and depression. Generally, more similarities than differences become apparent on closer examination suggesting, a need for additional treatments aimed at mixed anxiety/depression.

Methods: Seventeen PD patients and 21 healthy control subjects were studied with H215O PET scan, before and after a pentagastrin challenge. Results: During anticipatory anxiety we found diminished activity in the precentral gyrus, the inferior frontal gyrus, the right amygdala and the anterior insula in PD patients compared to controls. Hyperactivity in patients compared to controls was observed in the parahippocampal gyrus, the superior temporal lobe, the hypothalamus, the anterior cingulate gyrus and the midbrain. After the challenge, the patients showed decreases compared to the control subjects in the precentral gyrus, the inferior frontal gyrus and the anterior insula. Regions of increased

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activity in the patients compared to the controls were the parahippocampal gyrus, the superior temporal lobe, the anterior cingulate gyrus and the midbrain. We also found remarkable similarities in the patterns of brain activity during anxious arousal, anxiety, and full-blown panic attacks induced by pentagastrin in the PD patients compared to the healthy control subjects. During the procedure five panic disorder patients experienced a spontaneous panic attack while being scanned during what was supposed to be a resting scan. We compared the pattern of brain activity during spontaneous panic attacks with the pattern generated by pentagastrin induced panic attacks. No rCBF differences could be observed between the spontaneous and the pentagastrin induced panic attacks.

Study II Six patients were studied twice with H215O PET scan, once before and once after 12 weeks of successful treatment with the SSRI sertraline. Four H215O PET scans were made, all immediately after injection of pentagastrin (once) and saline (three times). The data were compared with other pre- and post-treatment data of patients who only participated in the neuroimaging study once, either before or after treatment. Results: Before treatment all patients experienced a panic attack after pentagastrin injection, while after successful treatment only two of the six patients panicked. After treatment we observed increases in the rCBF in the parahippocampal gyrus, the midbrain, the thalamus and the hypothalamus as compared to the situation before treatment, in rest as well as after pentagastrin injection. In the prefrontal cortex and the orbitofrontal cortex posttreatment, a decrease was seen during rest, while an increase was noticed during pentagastrin challenge as compared to the pretreatment situation. In conclusion, the data do not support the hypothesis that there is increased activity of the amygdala in either anticipatory anxiety, or during panic. The finding that spontaneous panic leads to the same pattern of activation in the brain support the notion that pentagastrin is a reliable method for the induction of panic.

The results of this study also suggest that after successful sertraline treatment of PD patients there are still changes in rCBF during pentagastrin challenge, but these changes are comparable to the changes seen in healthy control subjects, and thus more related to a normal reaction on pentagastrin. This confirms our hypothesis of partial normalization of rCBF patterns in PD patients after successful pharmacological treatment.

S9.5 Future directions in the research of anxiety and depression Jack Gorman Mount Sinai School of Medicine Abstract unavailable.

Symposium 10 Affective disorders across the life span S10.1 Developmental influences on the onset of first episode major depression in adolescence Ian M. Goodyer University of Cambridge First episode major depression is associated with abnormal levels of cortisol and DHEA in around 40 –50% of cases. Prospective studies have shown that high levels of both of these hormones are associated with the onset of major depression in adolescents at high risk for affective disorders that is not explained by recent life events and difficulties nor the temperamental style of the adolescent. The psychological and behavioural consequences of these hormone changes remain unclear but it is increasingly apparent that a high cortisol/DHEA ratio may be a physiological index of persistent disorder in adolescents at high risk for psychopathology. Recent findings from a new set of clinical and community based studies will be used to illustrate the complex-

Symposium Abstracts

ities that exist at the level of measurement, the potential effect of developmental change and of gender over the adolescent period on the associations between cortisol, DHEA and depression.

S10.2 Puberty and psychiatric disorders: A multidimensional developmental approach Adrian Angold Duke University Adolescence is a period of life when adult patterns of several psychiatric disorders (such as the female preponderance in unipolar depression) become established. Using data from the community-based Great Smoky Mountains Study I present evidence that quite different aspects of adolescence and puberty are related to different sorts of psychopathology, and that these effects are strongly sex-differentiated. For instance, increases in sex steroids are associated with rising prevalence of depression in girls, while FSH and LH (but not sex steroids) are associated with increasing levels of generalized anxiety disorder, and early pubertal timing (rather than hormones) is associated with conduct disorder. Data on family psychopathology and functioning, and life stress will then be used to develop an epigenetic model of the emergence of the adult sex ratio in unipolar depression.

S10.3 Juvenile versus adult onset depression: Multiple differences imply different pathways Jonathan Hill University of Liverpool Background: Several sources of heterogeneity in major depression have been identified. These include age of onset, presence of comorbid disorders, and history of childhood sexual abuse. This study examined these factors in the context of the contrast between onset of depression in young women before and after age 16. Method: Sampling was carried out in two phases. In the first, questionnaires were sent to women aged

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25– 36 in five primary care practices. Second phase subjects for interview (N = 197) were drawn from three strata defined on the basis of childhood adversities. Interviews conducted and rated independently assessed (a) recalled childhood experiences, psychopathology and parental psychiatric disorder, and (b) adult personality functioning and adult lifetime psychopathology. Frequencies of predictor and response variables, effect estimates and their confidence intervals were weighted back to the general population questionnaire sample. Results: Compared to adult onset depression, juvenile onset adult depression was associated with comorbid childhood psychopathology and peer problems, poor parental care and child sexual abuse involving actual or attempted intercourse; those with juvenile onset depression were more likely to have a teenage pregnancy, and as adults they had higher levels of comorbid psychiatric disorders, and personality dysfunction. The adult onset depression group was characterised by a history of contact child sexual abuse without actual or attempted intercourse, and to a lesser extent, poor parental care. Juvenile onset depression was associated with a parental history of alcohol problems, and adult onset with a history of depression in parents. Conclusions: Although the childhood data in this study were based on retrospective reports, they were consistent with findings from prospective studies. They add to the evidence that juvenile and adult onset depression in adult life probably arise from different developmental pathways and causal processes. Juvenile onset depression appears to be a component of a broad set of emotional and behavioural problems, and social impairment starting in early childhood, in which the causal processes involve an interaction between inherited vulnerabilities and adverse family environments. Adult onset depression occurs in women who appear to have functioned well during childhood and adolescence, and come from families with few psychosocial risks. We propose that the strong association of adult onset depression with a history of contact child sexual abuse without intercourse, implies that the subjects had used coping strategies that were adaptive in childhood but confer vulnerability in adult life. In addition there may be a further adult onset group in which depression arises from an inherited vulnerability without significant environmental risk factors.

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Symposium Abstracts

S10.4 Depression in adolescence, early adulthood and mid-life: Developmental variations in risk Barbara Maughan MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London Vulnerability to depression follows a distinct ageprofile across the life-course. From low rates in childhood risks rise sharply in adolescence, peaking in the late teens/early 20s for women, and rather later for men; in both sexes levels then decline gradually over the following decades. These marked age-trends raise the possibility that risks for depression also vary by developmental stage. This paper examines developmental change in two aspects of environmental risk: (i) age-trends in the impact of childhood adversities, and (ii) age-trends in the nature of precipitating stressors at different stages in adult life. The data are drawn from the Isle of Wight Follow-up Study, a prospective study of epidemiologically-defined samples first assessed in adolescence (ages 14/15 years) and re-contacted at mid-life (44/45 years). Excluding deaths during the follow-up period, 92% of adolescent study members were relocated in adulthood, and 70% (n = 355) re-interviewed at mid-life. Interviews with parents and adolescents provided diagnoses of DSMIV minor depression in adolescence, and data on childhood risk and vulnerability factors. Adult lifetime diagnoses of DSM-IV major depressive disorder, age at onset of first adult episode, exposure to physical and sexual abuse in childhood, and key precipitating stressors in adulthood were assessed at the mid-life follow-up. (i) Childhood adversity: In cross-sectional studies, childhood adversity has been widely examined as a vulnerability factor for depression throughout the adult years. Recent prospective data from the Dunedin longitudinal study suggest, however, that (with the exception of child sexual abuse) the impact of adverse childhood experiences and other early vulnerabilities is largely confined to cases with first onset in adolescence. The Isle of Wight study findings confirmed that view. Individuals rated as depressed at ages 14/15 years (7.3% of the sample) showed significantly depressed IQ scores by contrast with both neverdepressed and later-depressed members of the sample;

higher rates of comorbid anxiety disorders, irritability and poor peer relationships in adolescence; and increased risks of childhood and adolescent exposure to parental discord and divorce and to both physical and sexual abuse. First onsets of depression in the late teens and 20s showed only minor elevations in these risks, and onsets in the 30s and 40s were unassociated with adverse childhood experiences. (ii) Adult stressors: Experiences of loss, humiliation and entrapment show strong links with risk for depression across the main years of adulthood, while health-related disability is among the most common precursors of first onset in older age. The Isle of Wight findings showed that loss and humiliation associated with marital problems were as powerful precipitants of depression in middle adulthood as in the 20s and 30s. By contrast, work-related stressors, multiple bereavements or other events closely following bereavement, and health problems (especially those that compromised the ability to work) became increasingly salient as risks for first onset depression in the middle adult years. Health-related disabilities were more important precursors of depression in men at mid-life, daily hassles more salient for women.

S10.5 Neurobiological changes in late life depression: Cause or consequence? John O’Brien Department of Psychiatry, Institute for Ageing and Health, University of Newcastle upon Tyne Depression in later life is associated with a high prevalence of cognitive impairments, which persist despite recovery, and structural brain changes on neuroimaging, including white matter lesions and atrophy. Depression has emerged as a risk factor for dementia and is now clearly established as a risk factor for the future development of vascular disease. The relationships between these features are not well understood, but it has been suggested that changes, which occur during depression, such as hypercortisolaemia or immune activation, may be implicated. Raised cortisol levels, for example, are known to be associated with hippocampal damage in animals and in Cushing’s syndrome are associated with both hippocampal atro-

Symposium Abstracts

phy on MRI and cognitive impairments. The current study tested the hypothesis that biological changes during depression, particularly hypercortisoaemia, were aetiologically related to brain atrophy and persisting cognitive impairments. Elderly (age>60) subjects with DSM-IV major depression (n = 43) and age-matched controls (n = 40) underwent a 1.0 T volumetric MRI scan, cognitive testing and salivary cortisol measurement. Depressed subjects showed deficits in multiple cognitive domains compared to controls, including impairments in attention, verbal and non-verbal memory, spatial working memory and executive function. They also exhibited significant hypercortisolaemia (mean AUC: depressed = 144.2 F 66.8 nmol/l; controls = 95.8 F 28.4 nmol/l, P < 001). However, there were no significant correlations be-

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tween cognitive test measures and cortisol levels. Structural brain changes (hippocampal atrophy, frontal atrophy) were present only in those with late-onset depression and were related to persisting cognitive impairments. Volumetric analysis of white matter lesions showed an increase in volume in depressed subjects, especially in left frontal lobes. Such lesions have previously been shown to predict poor outcome and our previous autopsy studies have demonstrated that they are part of a spectrum of vascular changes that can be demonstrated in frontal cortex, consistent with the notion of a ‘‘vascular depression’’. Results do not support the hypothesis that being depressed itself causes brain changes but instead suggests neurobiological, especially vascular, changes as important aetiological factors in late-life depression.