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

Journal of Affective Disorders 78 (2004) S29 – S38 www.elsevier.com/locate/jad

Symposium Abstracts

The International Society for Affective Disorders (ISAD)—2nd Biennial Conference, Cancun, Mexico 5th–10th March 2004 Sunday, 7th of March 2004 Symposium 11 Cochrane reviews: Advancing the design of clinical trials and guiding practice S11.1 Fluoxetine and amitriptyline: First-line treatments or reference compounds? Corrado Barbui, Andrea Cipriani Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Italy In recent years fluoxetine and amitriptyline have been extensively studied in meta-analyses of clinical trials comparing new and old antidepressive (AD) agents in subjects with depression. However, many clinical and research questions remain unsolved. We performed a re-analysis of amitriptyline clinical trials to assess whether amitriptyline still has a place in the pharmacological treatment of depression, and a reanalysis of fluoxetine clinical trials to investigate whether the design of fluoxetine trials has been biased by the common belief that new drugs under evaluation are better than reference ones (wish bias). To address the first issue, we investigated the contribution of study setting on outcome in clinical trials comparing amitriptyline with any other AD. A systematic review and meta-regression analysis of amitriptyline randomised clinical trials was carried out. The electronic search yielded 181 randomised clinical trials, 47% enrolling inpatients and 53% outdoi:10.1016/j.jad.2003.12.003

patients with depression. Both on a dichotomous and continuous outcome amitriptyline resulted more effective than control agents in inpatients (Peto odds ratio (OR) 1.22, 95%, Confidence Interval (CI) 1.04, 1.42; Standardised Mean Difference (SMD) 0.28, 95% CI 0.08, 0.46), but not in outpatients (Peto OR 1.01, 95% CI 0.88, 1.17; SMD 0.10, 95% CI 0.02, 0.23). Among inpatients amitriptyline was significantly more effective than tricyclics (TCAs) and nonsignificantly more effective than the selective serotonin re-uptake inhibitors (SSRIs). Among outpatients no statistically significant differences emerged between amitriptyline and TCAs and between amitriptyline and the SSRIs. Amitriptyline was less well tolerated than control agents in outpatients (Peto OR 0.90, 95% CI 0.81, 0.99), but not in inpatients (Peto OR 1.09, 95% CI 0.95, 1.25). These data suggest that a reasonable approach could be the first-line prescribing of newer agents in the routine outpatient care of depressive subjects, and the use of amitriptyline in inpatients with depression. To address the second issue, we compared fluoxetine dose and outcome in trials where fluoxetine was the experimental drug with trials where it was the comparator. A systematic review of randomised controlled trials comparing fluoxetine with any other antidepressant in depressive patients was carried out. Studies were allocated to one of the following two groups: group 1, fluoxetine was the experimental drug; group 2, fluoxetine was the control drug. The systematic search yielded 103 randomised trials. Studies where fluoxetine was the experimental drug adopted a higher dose regimen than group 2 studies. In the efficacy analysis, the weighted rate of fluoxetine responders was 70.1% (95% CI 67.4%, 72.8%) in

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group 1 studies and 57.9% (95% CI 57.2%, 58.7%) in group 2 studies. The weighted rate of fluoxetine dropouts was significantly higher in group 1 studies. A meta-regression analysis indicated that, after adjusting for possible confounders (year and country of publication, sample size, weeks of follow-up, setting, diagnostic criteria), studies where fluoxetine was the experimental agent were positively associated with treatment effect, indicating a significant advantage for fluoxetine. The evidence that the outcome of fluoxetine trials varied according to whether this drug was used as a new compound or a reference one suggests the presence of bias. Systematic reviews and metaanalyses represent an invaluable tool to highlight pitfalls in the design of clinical trials and to guide everyday practice. Conflict of interest: none. S11.2 Low dosage TCA for depression: What have psychopharmacologists been doing for 50 years Toshi Furukawa Department of Psychiatry, Nagoya City University Medical School, Nagoya, Japan Background: Tricyclic antidepressants are still prescribed as often as selective serotonin reuptake inhibitors and other newer antidepressants in the world. Experts have often claimed that clinicians prescribe tricyclic antidepressants at less than adequate dosages. In order to determine how low dosage tricyclic antidepressants compare with placebo and with standard dosage tricyclics in acute phase treatment of depression in terms of effects and side effects, we conducted a systematic review (Furukawa et al., 2003) of randomised trials comparing low dosage tricyclics (100 mg/day or less) with placebo or standard dosage tricyclics in adults with depression. Methods: We performed electronic search of the Cochrane Collaboration Depression, Anxiety and Neurosis Group Controlled Trials Register (which incorporates group searches of MEDLINE, EMBASE, CINAHL, PsycINFO, PSYNDEX and LILACS, and group hand searches), conducted SciSearch and reference search of included studies, and contacted significant authors. Two independent reviewers assessed eligibility and quality of the

studies and extracted data. Main outcome measures included random effects model relative risk of response in depression, according to the original authors’ definition but usually defined as 50% or greater reduction in depressive severity. Relative risks of overall dropouts and dropouts due to side effects were also examined. Results: We identified 35 studies (2013 participants) comparing low dosage tricyclics against placebo and six studies (551 participants) comparing low against standard dosage tricyclics. Low dosage tricyclics, mostly between 75 and 100 mg/day, were 1.65 (95% confidence interval: 1.36– 2.0) and 1.47 (1.12 – 1.94) times more likely than placebo to bring about response at 4 weeks and 6– 8 weeks. Several sensitivity analyses confirmed these findings. On the other hand, standard dosage tricyclics failed to bring about more response but produced more dropouts due to side effects than low dosage tricyclics. Conclusions: The evidence suggests that administration of low dose tricyclic is a defensible practice. Tricyclic antidepressants at dosages below the heretofore recommended range are more effective than placebo. They may or may not be as effective as but certainly cause fewer dropouts due to side effects than standard dosage tricyclics. A very similar relationship between response and tolerability has been shown for SSRIs as well (Bollini et al., 1999): dosages of 21– 40 mg/day of fluoxetine or equivalent showed a greater response rate and an even greater adverse event rate than dosages below 20 mg/day. Professionals need remind themselves that, after 50 years of usage, they have not been able to establish the minimum effective dosage and the effective dosage ranges for antidepressants—a simple set of numbers that every practising physician and patient would want to know. 1) Furukawa, T., McGuire, H., Barbui, C., 2003. Low dosage TCA for major depression (Cochrane review). The Cochrane Library, Issue 3. Update Software, Oxford. 2) Bollini, P., Pampallona, S., Tabaldi, G., Kupelnick, B., Munizza, C., 1999. Effectiveness of antidepressants: meta-analysis of dose – effect relationships in randomized clinical trials. Br. J. Psychiatry 173, 297 – 303.

Symposium Abstracts

S11.3 Psychological debriefing for PTSD: What have we really done? Simon Wessely Institute of Psychiatry If asked most people will probably believe that what is called ‘‘psychological debriefing’’ is helpful in the immediate aftermath of disaster. Talking about what has happening, explaining what we know about psychological reactions, and allowing people to ventilate their feelings, is a ‘‘good’’ thing. And indeed single session psychological debriefing has become exceptionally popular, a social movement. But does it work? We carried out the first ever systematic review and meta-analysis of RCTs in this area. The results showed that there was no evidence that psychological debriefing did what it is supposed to do—reduce the rate of subsequent psychiatric disorders, such as post-traumatic stress disorder. And the two best and longest trials showed something unexpected—an increase in the rate of psychiatric disorder in those who had received the intervention. I shall discuss the possible reasons for these unexpected findings, and also how the Cochrane review has been used and abused by both the proponents and the opponents of debriefing, counseling and psychological treatments in general. Vast quantities of bathwaters have been ejected, but quite a few babies as well. S11.4 Psychological treatments for depression: What should we be doing? Rachel Churchill 1 , V. Hunot, M. McGuire, S. Wessely

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brief therapy; (iii) that there would be clinical and methodological heterogeneity between trials and observed effects would be modified by pre-specified clinical and methodological characteristics. Methods: A systematic review and meta-analysis was performed. Data sources were electronic bibliographic databases, specialist journals and study bibliographies. Authors were contacted for further information. Included were RCTs and CCTs of brief psychological treatments compared with treatment as usual or another type of psychological treatment for adults with depression. Trials were quality rated. Results: Sixty-three of 76 potentially eligible studies were included. Trials were generally of low overall quality. Hypothesis (i) was supported by all the data. Hypothesis (ii) was supported by the recovery data, but the mean change and mean difference data demonstrated non-significant differences only. Considerable heterogeneity between studies was identified, providing support for hypothesis (iii). Meta-regression analyses suggested that much of the variability might be due to type of comparison in trials used in the analyses for hypothesis (i), and to baseline severity and number of sessions in trials used in analyses for hypothesis (ii). Conclusion: Brief psychological therapy appears to be effective in the treatment of depression. CBT might be more effective than other types of therapy, particularly in less severely depressed patients and where fewer sessions can be offered. However, much of the primary research in this field is of poor quality, providing only limited guidance for clinical decision-making.

Symposium 12 Suicide and affective disorders

Health Services Research Department, Institute of Psychiatry, London, UK

S12.1 Suicide, depression and the vulnerability for suicidal behaviour

Objectives: (1) To provide a qualitative summary of all controlled trials of brief psychological therapy for people with depression. (2) To provide a quantitative synthesis of a proportion of trials, testing three hypotheses: (i) that brief psychological treatments would demonstrate greater efficacy than treatment as usual; (ii) that efficacy of brief cognitive-behavioural treatments would be greater than for other types of

Kees van Heeringen

1

University Hospital Gent Three levels of risk factors associated with suicidal behaviour can be described. First, psychological autopsy studies have demonstrated that nearly all suicides occur within the context of a psychiatric disorder. Axis-

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Symposium Abstracts

I disorders with a particularly increased risk include mood disorder, schizophrenia, and alcohol dependence. The risk in association with the latter two disorders is strongly increased in case of a co-morbid mood disorder. Secondly, a number of factors have been identified as influencing the threshold for acting on suicidal impulses, including exposure to suicide among peers or in the media, availability and acceptability of mental health care, and social support. Thirdly, it has become clear that these (mainly state-dependent) characteristics are not sufficient to explain why some but not all depressed individuals commit suicide. There is now increasing insight in an underlying and trait-dependent predisposition or vulnerability to suicidal behaviour. This presentation will focus on biological and cognitive psychological aspects of this predisposition to suicide. Biological research has mainly focused on two aspects, i.e. a hyper-reactivity of the stress-system and an impaired function of the serotonine neurotransmission system. These characteristics appear to be interrelated, as the stress hormone cortisol has been shown to have cytotoxic effects on the serotonergic system. Studies in the cognitive psychological area have identified three core characteristics, which distinguish depressed suicidal from depressed non-suicidal individuals. These psychological characteristics include tendencies (1) to perceive oneself as a loser when confronted with psychosocial adversity, (2) to perceive no escape from this situation (leading to feelings of entrapment and related to deficient problem solving), and (3) to perceive no rescue (leading to the development of feelings of hopelessness). Recent research suggests that the results from biological and psychological approaches converge to a considerable extent. Particularly for the first and third characteristic, as mentioned above, a comprehensive psychobiological can be described. With regard to the first characteristic, the extent of activation of the stresssystem, as measured by 24-h cortisol production, correlates with a personality characteristic that determines the sensitivity to social or interpersonal stimuli. From neuro-anatomical, neuropsychological and neurobiological points of view this characteristic is related to frontotemporal/hippocampal functioning, attentional biases, and the serotonine (5-HT1a) and noradrenaline neurotransmission systems, as demonstrated by functional neuro-imaging and neuropsychological investigations. Regarding the third characteristic, func-

tional neuro-imaging studies have shown that the development of feelings of hopelessness correlates with serotonine (5-HT2a) receptor functioning in the prefrontal cortex, which is involved in the generation and choice of response alternatives when confronted with particular problems, and with trait-dependent regulation of affect. It thus appears that, at the least, two inter-related clusters of psychobiological characteristics are involved in a persisting vulnerability for suicidal behaviour, i.e. a sensitivity for interpersonal events (or ‘resilience’) associated with the activation of the stress-system, and prefrontal serotonine (5-HT2a) functioning, hopelessness and the regulation of affect. These findings may have important implications for prevention and treatment. The recognition of the psychobiological characteristics, which differentiate between depressed suicidal and depressed non-suicidal patients, will substantially enhance our capacity to predict suicidal behaviour among depressed individuals, and to delineate specific targets for treatment. With regard to treatment the current state of knowledge suggests that all three cognitive characteristics have to be addressed in the psychological treatment of suicidal individuals. In addition, the relationship between psychological and biological characteristics suggests that pharmacological treatment may be useful, or even necessary, in preparing the substrate that is involved in the neuropsychological processes of memory and learning, which are the essential components of effective psychotherapy. S12.2 Functional neuro-imaging of suicidal behaviour Kurt Audenaert University Hospital Gent Abstract unavailable. S12.3 Suicidal behaviour, depression and eating disorders Myriam Vervaet University Hospital Gent Abstract unavailable.

Symposium Abstracts

S12.4 Depression and suicidal behaviour in adolescents Alan Apter University of Tel Aviv Among teenagers, both attempted and completed suicide is, in the great majority of cases, preceded by depressive symptoms. Depressed young people who attempt suicide often come from broken families and have had one or more relatives who have committed or attempted suicide. They have also, relatively often, run away from home and thus been brought up without favorable role models. Physical and mental abuse, as well as sexual assault, is also more common in this group. Young people who have attempted suicide often have lasting problems at school and also difficulties in achieving workable relationships with their peers, compared with young people who are depressed and have not attempted suicide. Abuse of alcohol and drugs, impulsive behavior and asocial behavior are additional risk factors for attempted and completed suicide among depressed young people. Owing to the high incidence of depression among young people who have attempted suicide, it is important to make a diagnosis and provide adequate treatment at an early stage. Studies show that depressive disturbances are more common among children and young people than has previously been believed. Unfortunately, many young people with depression are not identified, partly because their depressive symptoms are often atypical and partly because adults do not readily recognize depressive symptoms in the young, owing to their wish to see their children as happy and healthy. Since the number of young people with depression appears to have increased after the Second World War, and the age of onset of depressive disturbances has decreased, it is important to increase the effort to detect depressions in order to be able to prevent suicidal behavior. Major depression is most easily diagnosed when it appears acutely in a previously healthy child and in these cases the symptoms closely resemble those seen in adults. In many children, however, the onset is insidious and the child may show many other difficulties such as attention deficit disorder or separation anxiety disorder before becoming depressed. Mood disorders tend to be

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chronic when they start at an early age and the children come from families where there is a high incidence of mood disorders and alcohol abuse. In some cases the depressed adolescent may also be psychotic and have hallucinations and delusions that are usually mood congruent. When the psychotic themes are related to suicide such as in command hallucinations or delusions of guilt, the risk for suicide is very high. Bipolar disorder was once thought to occur only rarely in youth. However, approximately 20% of all bipolar patients have their first episode during adolescence, with a peak age of onset between 15 and 19 years of age. Adolescents with bipolar disorder are at increased risk for completed suicide. Twenty percent of adolescents with bipolar disorder made at least one medically significant suicide attempt. In the adult literature, a large review of studies examining depressive and manic depressive disorders found the mean rate of completed suicides to be 19%. Patients who are male, or who are in the depressed phase of their illness, are at the highest risk. S12.5 Can antidepressant medication prevent suicide? Goran Isacsson Division of Psychiatry, Karolinska Institute NEUROTEC, Huddinge University Hospital, M59, S-141 86 Stockholm E-mail: [email protected] Method: Review of evidence, and an analysis of Swedish toxicological data in 15,400 suicides, and their relation to population prescription data. Result: Several reports give evidence for that lithium prevents suicide in bipolar patients (Tondo et al., 2003). A long-term study of a cohort in Zurich found that the amount of received antidepressants was the best predictor for not having committed suicide at follow-up (Angst et al., 2002). It has been shown that only a minority of individuals committing suicide have received adequate antidepressant treatment (Isacsson et al., 1994). A recent report from Australia demonstrated that suicide rates declined in proportion to exposure for antidepressants among different demographic groups (Hall et al., 2003). A study from USA found that increased use of anti-

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Symposium Abstracts

depressants was one of the most plausible factors behind the decreased rate of youth suicide (Gould et al., 2003). However, meta-analyses of clinical trials have not found evidence for this, but these, as the naturalistic studies above, do not allow for definitive conclusions (Khan et al., 2000). A preliminary analysis of clinical trials of paroxetine in children has raised concerns regarding a possible suicidality inducing effect of the drug. Based on epidemiological studies until 1991, it was hypothesized by the author that a 5-fold increase in the use of antidepressants would lower suicide rates by 25% (Isacsson, 1994). Ten years later, the use of antidepressants in Sweden was five times higher than in 1991 and the suicide rate was 31% lower (Isacsson, 2000). The proportion of suicides found positive for antidepressants in forensic toxicology had increased from 16% to 23%. Since alternative causal factors could not be identified, this development supported the hypothesis that antidepressants do prevent suicide. When toxicological findings of specific antidepressant drugs in 15,400 suicides were related to their use in the population, it was found that paroxetine was the substance least commonly found in suicides. In all 365 suicides under age 20, antidepressants were found in 15 cases, seven of them SSRIs, none of these was paroxetine. Conclusion: Although definitive conclusions cannot be drawn, the increased use of antidepressants is the most probable cause of the decrease in suicide seen in Sweden and in several other countries. No evidence was found for a suicide provoking effect of paroxetine regardless of age. 1. Tondo, L., Isacsson, G., Baldessarini, R., 2003. Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs 17(7), 491 – 511. 2. Angst, F., Stassen, H.H., Clayton, P., Angst, J., 2002. Mortality of patients with mood disorders: follow-up over 34 –38 years. J. Affect. Disord. 68, 167– 181. 3. Isacsson, G., Holmgren, P., Wasserman, D., Bergman, U., 1994. Use of antidepressants among people committing suicide in Sweden. Br. Med. J. 308, 506 – 509. 4. Hall, W.D., Mant, A., Mitchell, P.B., Rendle, V.A., Hickie, I.B., McManus, P., 2003. Association between antidepressant prescribing and suicide in

Australia, 1991 – 2000: trend analysis. Br. Med. J. 326(7397), 1008. 5. Gould, M.S., Greenberg, T., Velting, D.M., Shaffer, D., 2003. Youth suicide and preventive interventions: a review of the past 10 years. J. Am. Acad. Child Adolesc. Psychiatry 42, 386 –405. 6. Khan, A., Warner, H.A., Brown, W.A., 2000. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch. Gen. Psychiatry 57(4), 311 – 317. 7. Isacsson, G., 1994. Depression, antidepressants and suicide. A study of the role of antidepressants in the prevention of suicide. [Thesis]. Karolinska Institute. 8. Isacsson, G., 2000. Suicide prevention—a medical breakthrough? Acta Psychiatr. Scand. 102(2), 113– 117.

Symposium 13 Genetics and pharmacogenetics of affective disorders S13.1 Genetics of BPD Elliot Gershon University of Chicago As evidence from linkage and association studies has accumulated, some broadly reproduced findings have emerged. Through meta-analysis of published whole-genome linkage studies, Gershon and Badner (2002) demonstrated significant support for linkage, independently, to Bipolar disorder and to Schizophrenia on two chromosomal regions, 13q and 22q. A third region, on 8p, had significant support for linkage to Schizophrenia. Positional cloning on 13q revealed association of Bipolar disorder with a newly discovered gene complex, G72/G30. This same complex had been earlier associated with Schizophrenia, and is thus a striking confirmation of the hypothesis that the overlapping linkage regions for each disorder would contain the same susceptibility gene for both. The neurobiological candidate gene approach has also yielded a recent positive association, of brain-derived neurotrophic factor, BDNF, with Bipolar disorder.

Symposium Abstracts

S13.2 Status of genetics of early onset recurrent depression Doug Levinson University of Pennsylvania Abstract unavailable. S13.3 Pivotal issues in designing and interpreting pharmacogenetic studies of antidepressant and mood-stabilizing drugs. Bernard Lerera, Ronnen H. Segmana, Fabio Macciardib a

Department of Psychiatry, Hadassah, Hebrew University Medical Center, Jerusalem, Israel b Department of Medical Genetics, Medical Genetics, University of Milan, School of Medicine, Italy Little solid evidence exists upon which clinicians can base a choice of the appropriate drug with which to initiate treatment of patients with affective and other psychiatric disorders. Consequently, there is considerable interest in the potential clinical application of pharmacogenetic strategies to predict response to psychotropic drugs and susceptibility to adverse effects (Lerer, 2002). Such strategies are based on the hypothesis that genetic variability in the enzymes which control bioavailability of drugs and in the target proteins upon which drugs act, result in variable clinical effects that can be anticipated if the patient’s genotypic characteristics are known when treatment is initiated. A rapidly increasing number of studies on the pharmacogenetics of antidepressant and mood stabilizing drugs are being published or are under way (Lerer and Macciardi, 2002). Some findings, such as the role of genetic variability in the serotonin transporter promoter in the response of depressed patients to specific serotonin reuptake blockers, have received fairly widespread support. However, efforts to move the field forward rapidly do not always take into account key design issues that can pivotally influence the results of such studies. Population stratification and admixture can lead to spurious results if ethnic background is not taken into consideration in planning studies and analyzing data and possible cryptic stratification is not examined in ostensibly matched sam-

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ples. Another key issue is the differentiation of specific from non-specific response. This is possible when the study includes a placebo group but is considerably more challenging when such a group is not part of the design. Other key considerations include the simultaneous typing of several polymorphisms in a single gene, which permits the analysis of haplotypes and affords the study considerably more power and consideration of epistatic (interactive) effects among genes. The latter issue is of great potential importance in that separate analysis of genes that act interactively may not demonstrate effects on the phenotype that are present when they are analysed jointly. The study of gene – gene interactions requires samples considerably larger than most being studied at present. A further issue, not generally appreciated, is that the effect of genes on a pharmacogenetic phenotype may be age related and, for example, be demonstrable in older but not in younger patients. Examples that illustrate these issues will be presented from the work of the authors and also from the published work of other investigators and their impact on the design and interpretation of pharmacogenetic studies of antidepressant and mood-stabilizing drugs will be discussed.

References Lerer, B. (Ed.), 2002. Pharmacogenetics of Psychotropic Drugs. Cambridge University Press, Cambridge. Lerer, B., Macciardi, F., 2002. Pharmacogenetics of antidepressant and mood stabilising drugs: a review of candidate gene studies and future research directions. Int. J. Neuropsychopharmacol. 5, 255 – 275. S13.4 Pharmacogenetics in geriatric major depression. Greer M. Murphy, Jr. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5485 E-mail: [email protected] Background: A major unanswered clinical question is why some patients respond to antidepressant medications whereas others do not. Pharmacogenetics seeks

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to individualize drug therapy based on DNA sequences. Patients carrying genetic variants resulting in poor metabolism of antidepressants may experience more side effects. Polymorphisms in genes for neurotransmitter receptors, reuptake transporters, and signal transduction molecules may enhance or interfere with antidepressant efficacy. Methods: We performed a multicenter pharmacogenetic study of 246 cognitively intact patients 65 years of age and older with major depression who were treated with either mirtazapine or paroxetine. Medications were administered in a double-blind design over an 8 week acute phase with a 16 week extension phase. Mood, cognition, and medication side effects were quantified throughout the study. Genotypes were determined for APOE ?4, serotonin 2A receptor polymorphisms, and the 5HTTLPR polymorphism at the SERT locus. Oligonucleotide microarrays (‘‘Gene Chips’’) were used to determine CYP2D6 genotypes. Results: The apolipoprotein E ?4 allele was found to be a predictor of antidepressant efficacy in the elderly, whereas polymorphisms in the serotonin 2A receptor gene were associated with antidepressant side effects. The 5HTTLPR polymorphism was also found to affect antidepressant efficacy and side effects. CYP2D6 is important in the metabolism of many antidepressants, but surprisingly CYP2D6 genetic variation had little effect on outcome. Conclusions: Genetic variation affecting antidepressant pharmacodynamics may be more important than genetic variation affecting pharmacokinetics. (Supported by Organon, NARSAD, VA Medical Research, and the Pritzker Network. Disclosure: Research support and consulting, Organon). S13.5 Genetics and pharmacogenetics of lithium response Martin Alda Dalhousie University The long-term treatment of bipolar disorder (BD) relies upon an ever-increasing number of medications. Several factors likely play a role in determining which patient responds to which treatment; these factors include the subtype of the illness, pharmacological effects of the medication, as well as patient’s genotype.

The biological mechanisms of psychotropic drugs have been proposed as keys to understanding the nature of disorders they treat, implying that there is a tight link between the disease and the cure. Yet, the interplay between these two appears complex. Several studies suggest that genetic factors independent of those involved in the aetiology of BD may be involved in the treatment response. In this presentation, we will review the present clinical and molecular data on response to lithium in BD. To this date, it is still not entirely clear to what extent are various treatment specific to individual patients. However, the preliminary data suggest that both acute and long-term treatments for BD might be specific. For example, patients who respond to lithium usually do respond poorly to the anticonvulsants carbamazepine or valproic acid. In a study comparing responders to lithium and lamotrigine we found robust differences with respect to clinical presentation, presence of comorbid conditions, course of the illness, and the family history. The lithium responsive probands had episodic clinical course prior to treatment while the lamotrigine responders had chronic course and rapid cycling. The rates of comorbidity were higher in lamotrigine responders, both for anxiety and substance abuse. In families of lithium responders we found a higher lifetime prevalence of BD, while relatives of lamotrigine responders had higher rates of schizoaffective disorder, major depression, and anxiety/panic attacks. Thus, patients responsive to two different mood stabilisers, may represent distinct subtypes of BD. Several research groups have investigated the role of genetic factors in treatment response to lithium. Conversely, the assumption that responders to certain treatments could represent genetically distinct forms of BD led us to investigate responders to lithium with the aim to map genes for the illness. In a series of studies we examined a number of candidate genes and performed a genome scan. The most promising findings are those of association with the phospholipase C and suggestive linkage in several chromosomal regions. The genome scan results suggest that several genes are involved, each playing a different role in different families. In a recent study, we investigated the effect of lithium on gene expression in lymphoblasts from responders to lithium. Using cDNA arrays we identified several genes for confirmatory studies using Northern blots, confirming all but one of the genes identified through

Symposium Abstracts

cDNA array. The expression of the alpha 1B receptor gene was 2.5-fold higher in patients and was significantly reduced by Li in patients, but not in controls. Lithium also decreased an expression of several other genes such as acetylcholine receptor alpha subunit and phosphodiesterase 4D. In conclusion, response to treatment in BD is a complex process involving multiple factors related to the patient and the treatment itself. Modern neurobiological techniques are now available to help in understanding the various facets of this process, a necessary step in better treatment of these conditions.

Symposium 14 Clinical research on ECT S14.1 Efficacy and cognitive effects of ECT in community settings

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rate was 64.3% during the follow-up. Relapse was more frequent in patients with psychotic depression or comorbid Axis I or Axis II disorders. Of the patients who did not remit following ECT, only 23.4% achieved remission without subsequent relapse during the 24-week follow-up. Fundamental aspects of cognitive function were differentially affected by right unilateral versus bilateral electrode placement and sine wave compared to brief pulse ECT. Conclusions: The remission rate with ECT in community settings is substantially below that observed in clinical trials. Providers frequently end the ECT course with the view that patients have shown full benefit, yet formal assessment shows significant residual symptoms. Patients who do not remit following ECT have a poor prognosis, underscoring the need to achieve maximal improvement with this modality. These data demonstrate that bilateral ECT is associated with persistent amnesia 6 months after the conclusion of an index course.

Joan Prudic, Mark Olfson, Steven C. Marcus, Rice B. Fuller, Harold A. Sackeim

S14.2 Personality disorder and ECT outcomes

Columbia University

Roger Haskett

Background: Electroconvulsive therapy (ECT) is the most effective short-term treatment for major depression. However, there is considerable variability among practitioners in treatment delivery, and efficacy and cognitive side effects of the treatment in community settings has not been examined. Methods: In a prospective, naturalistic study conducted at seven hospitals, 347 eligible patients participated in at least one clinical evaluation after starting ECT. Rates of response and remission and cognitive side effects immediately following ECT, clinical outcome over a 24-week follow-up, and longer term cognitive outcome at 6 months post-ECT were examined in relation to patient characteristics and treatment variables. Results: The sites differed markedly in patient features and ECT administration. There were no site differences in clinical outcome. In contrast to the 70– 90% remission rates often reported with ECT, remission rates, depending on criteria, were 30.3 – 46.7%. Longer duration of episode, comorbid personality disorder, and schizoaffective disorder were associated with poorer outcome. Among remitters, the relapse

University of Pittsburgh Abstract unavailable.

S14.3 The Efficacy of ECT in psychosis and suicidality Charles H. Kellnera, Georgios Petridesa, b, Mustafa Husainc, Teresa Rummansd, Max Finkb, Rebecca Knappe, Martina Muellere, Keith Rassmussend, Kevin O’Connord, Hilary Bernsteine, Glenn Smithd, Melanie Biggsc, John Rushc a

New Jersey Medical School, University of Medicine and Dentistry of New Jersey b Long Island Jewish Health System, The Zucker Hillside Hospital, Northshore c Southwestern Medical Center, University of Texas d Mayo Clinic and Foundation e The Medical University of South Carolina *C.O.R.E., Consortium for Research in ECT

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In this presentation data will be presented from Phase I an ongoing multisite, NIMH-supported trial comparing continuation ECT versus pharmacotherapy (lithium and nortriptyline) [the ‘C.O.R.E.’ study]. Phase I represents the acute course of ECT given prior to randomization to the two treatment arms in Phase II. In the C.O.R.E. study, patients with unipolar major depression, referred for ECT, receive a standardized course of bilateral ECT 3  per week at 1.5  seizure threshold. A HAMD24 score of z 21 is required for study entry and remission criteria include two consecutive HAMD24 ratings of V 10, with z 60% reduction from baseline. HAMD24 ratings are performed at baseline and 24 h after each ECT. We present data from the first 444 patients entered into the trial. Patient demographics are as follows: age (mean F S.D. = 55.6 F 16.8, Gender (%female) = 68.2 (303/444), psychosis status (% psychotic) = 29.7 (132/ 444), race (%white) = 91.7 (407/444). Overall remission rate was 68.5% (304/444). Remission rate in those patients with psychotic depression was

75% (99/132). Patients z 65 years of age had a remission rate of 71.3% (112/157). Patients responded very rapidly to ECT. After six treatments (2 weeks) 34.9% (155/444) of patients had reached remission criteria. ECT resolved suicidality very rapidly. Eighty-one percent of patients with high baseline suicide ratings were no longer suicidal after six treatments. These data, from one of the largest ECT datasets in the modern era, confirm the high and rapid efficacy of ECT in major depression, particularly in those with psychotic depression. Suicidality was also rapidly relieved in ECT. S14.4 Redesigning the ECT stimulus: Towards a more controlled and focal treatment Harold Sackeim New York State Psychiatric Institute Abstract unavailable.