keynotes, core symposia, symposia and parallels

Keynote 1: Childhood Bipolar Debate

Moderators: Eric Youngstrom, Michael Wong

1

A debate: what is pediatric bipolar disorder?B BirmaherUniversity of Pittsburgh School of Medicine, Western Psychiatric

Institute and Clinic, Pittsburgh, PA, USA

Introduction: Although the real prevalence of Pediatric Bipolar

Disorder (BD) in unknown, several retrospective studies by

different authors across the world have consistently shown that

up to 60% of the Bipolar cases start during adolescence and up to

15% during childhood. However, Pediatric BD is often unrecog-

nized or misdiagnosed.

Methods: The literature regarding the phenomenology, epidemiol-

ogy, family risk and longitudinal course of Pediatric BD will be

critically reviewed.

Results: Prospective and high risk studies in youth have confirmed

that Pediatric BD runs in families and is manifested by rapid

fluctuating mood states, particularly in children. Pediatric BD is

usually comorbid with other disorders and it is associated with

significant psychosocial consequences and increased risk for

suicidality, substance abuse, behavior, academic, legal and family

problems.

Discussion: Pediatric BD usually onsets during the adolescent

years, but due to the presence of comorbid disorders and the child’s

cognitive and emotional immaturity it is difficult to make this

diagnosis. However, it is important to be aware that this diagnosis

exists in children and adolescents because it is associated with

significantly psychosocial morbidity and increased suicidal risk

Keywords: bipolar disorder, children and adolescents, diagnosis,

longitudinal studies

2

What is pediatric bipolar disorder?E TaylorKing’s College London, Institute of Psychiatry, Denmark Hill,

London, UK

Proposition: Mood dysregulation is not always bipolar disorder.

Background: An overextended concept of PBD has led to a very

rapid increase of diagnosis and medication in the USA, and

considerable confusion elsewhere.

Method: This part of the debate will address the broad concept

from the point of view of validity of diagnosis, coherence of

aetiology and value of interventions.

Results: This contribution to the debate will argue that abnormal-

ities of regulating emotional expression are common, but hetero-

geneous. Clinicians are advised that most of the cases have not

been shown to be linked to classical bipolar disorder. The

treatment of non-episodic conditions involving irritability will be

discussed, and the concept of ‘‘disruptive mood dysregulation

disorder’’ described.

Conclusion: It remains important to identify the childhood pro-

dromes of, and risk states for, bipolar disorder; and to recognise

that classic bipolar disorder can occur and be disabling in children

and adolescents. Pediatric bipolar disorder (PBD) should be more

carefully defined.

Keywords: bipolar, child, adolescent, emotional self-regulation

Core Symposium 1: Optimizing FunctionalOutcomes in BD

Chair: Eduard Vieta

3

Lifestyle factors in optimising therapeuticoutcomesM Berk

Deakin University, Barwon Health, Orygen Youth Health Research

Centre, Mental Health Research Institute, and Melbourne

University, Australia

Many factors, including genetics, development, family, personal-

ity, stress and lifestyle contribute to the risk for and evolution of

mood disorders such as bipolar disorder. There is now a

comprehensive evidence base for lifestyle as a key aetiological

factor in mood disorders, including exercise, smoking, alcohol

and substance misuse, diet, exposure to green space (nature) and

social networks. Current clinical management however has had a

narrow focus on medication and psychotherapy, and has to date

12ª 2012 The Authors

Bipolar Disorders ª 2012 John Wiley & Sons A/S, Bipolar Disorders, 14 (Suppl. 1) 12–37

not incorporated the evidence regarding lifestyle factors into

management. The aim of this presentation is to provide a review

of key lifestyle factors that may contribute to mood disorders and

present a synopsis of current evidence of modifying these elements

to improve mood. There is evidence that level of physical activity

plays a role in the risk for depression, and there is a large and

validated evidence base for exercise as a therapeutic option.

Smoking, alcohol and substance misuse are risk factors for mood

disorders, there is new epidemiological evidence supports the

contention that diet is a risk factor for depression and bipolar

disorder. There is data that smoking worsens the course and

treatment outcome of people with bipolar disorder. Lifestyle

modification, with a focus on exercise, diet, smoking and alcohol,

may be of value in augmenting standard therapy. Lastly, novel

data on abnormal illness behaviour, illness investment, and its

contribution to outcome will be presented.

Keywords: diet, exercise, smoking, depression, prevention, lifestyle.

5

Psychoeducation in bipolar patientsF ColomInstitute of Neurosciences, Hospital Clinic, University of Barcelona,

Spain

The practice of psychotherapy is, and should be, constantly

evolving. Our understanding of psychiatric disorders has dramat-

ically grown in the last twenty years thanks to some key findings on

their biological basis but also some key developments on our

clinical knowledge. Moreover, a vast majority of severe psychiatric

conditions that used to be considered as untreatable are today

properly addressed thanks to the skyrocketing success of brand

new drugs which allow our patients to reach some wellbeing, better

quality of life and reduce suffering.

Psychological treatments for severe psychiatric disorders have also

evolved dramatically during the last decade. It has been a

troublesome and winding road but, finally, psychological treat-

ments have a central role –most of the times as an add-on to

pharmacological treatment- in the daily management of severe

psychiatric disorders.

Psychotherapy is, nowadays, an evidence-based treatment which

follows roughly the same rules and experiments which apply to

other treatment modalities (medication, biophysical treatments).

Models based on inspiration or subjectivity are left far beyond.

This lecture will review the evidence-based psychological treat-

ments which have shown prophylactic efficacy on bipolar disorders,

focusing mostly in psychoeducation and its long-term efficacy.

Novelties regarding the identification of predictors of response to

psychotherapy will be presented. The lecture also includes a view

on the limitations of psychological treatments for bipolar disorder

and how this may lead future developments.

Keywords: psychotherapy, psychoeducation

6

Functional remediation for bipolar disorderE VietaBipolar Disorders Program, Hospital Clinic, University of

Barcelona, IDIBAPS, CIBERSAM, ENBREC, Barcelona,

Catalonia, Spain

Functional remediation is an innovative intervention aimed at

targeting the main factors involved in the functional outcome of

bipolar illness. Hence, functional remediation tackles the neuro-

cognitive deficits and the practical nuances that are associated to

manic-depressive illness in a structured format that can be

delivered either as a group intervention or individually. This

intervention has been proven effective in a recent double-blind,

randomized trial comparing functional remediation to psychoed-

ucation and to treatment as usual. All patients received concom-

itant medication and had to be in remission at study entry. The

results show that functional remediation is more effective than

psychoeducation and treatment as usual in improving functioning

as measured with the Functional Assessment Short Test (FAST).

The characteristics of this innovative technique and the results of

the trial will be discussed.

Keywords: cognition, functional remediation, bipolar disorder,

clinical trial

Core Symposium 2: Interpreting clinical trialsin bipolar disorder/methodological issues inclinical trials in bipolar disorder

Chair: Paul Keck

7

Novel strategies to improve generalizability ofmaintenance trial results in Bipolar Disorder(BD)V Singh, J Mintz, M TohenUniversity of Texas Health Science Center at San Antonio, U.S.A

Background: All bipolar maintenance studies conducted for regu-

latory approval have employed Kaplan-Meier (KM) survival

analytic techniques which provide a single point in time efficacy

result, e.g., relapse, intervention, discontinuation. Neither tolera-

bility of regimens nor functionality is incorporated into the

primary outcome measures. If the longest recorded time is

censored, estimates of mean duration are biased by truncating

those cases to the time of the latest observed event, which may be

much shorter than the observed time of censoring. Additional

limitations of maintenance study designs in bipolar disorder are

that most enrich for tolerability and early benefit for the drug of

primary interest and that all have yielded high proportions of

missing data consequent to early study drop outs.

Methods: To address the limitations of KM techniques, we have

developed a multi-state statistical technique, and provide examples

14–17 March 2012, Istanbul, Turkey

ª 2012 The Authors

Bipolar Disorders ª 2012 John Wiley & Sons A/S, Bipolar Disorders, 14 (Suppl. 1) 12–37 13

of its performance. The method allows clinical episodes to be

entered multiple times and can incorporate weightings for adverse

effects and functional status. The procedure, Multistate Outcome

Analysis of Treatments in Bipolar Disorder (MOAT-BD), provides

statistical significance from bootstrapping estimates of the variance

for the estimated times spent in each clinical state. We applied a

midpoint conversion from one clinical state to another. To address

the problems consequent to missing data in maintenance studies,

we have refined an adaptive design first proposed by Lavori, and

are applying the procedure in an NIMH funded study, Sequential

Multiple Assignment Randomized Treatment (SMART) for BD.

Results: In re-analysis of lamotrigine maintenance registration

studies, lamotrigine monotherapy benefits depressive clinical states

during maintenance treatment of BD, but only partially, leaving

most patients with mild to moderate depressive symptoms, and was

also inferior to lithium in mixed states and overall symptomatology.

Lithiumwas superior to placebo on time spent in remission ofmania,

but, when analysis combining tolerability is applied, loses a major

part of its advantage.Lithiummonotherapydidnotprovide evidence

of benefit on any depressive clinical states in BD.Lithiumwas poorly

tolerated in recently manic patients, but not in recently depressed

patients. The SMART strategy employs predetermined criteria for

adding new treatments based on each patient’s current illness state

and prior response during the trial, mimicking the adaptive nature of

treatment selection which occurs in routine clinical settings, but in a

controlledwaywhichallows applicationof causal inference.Byusing

early indices of response to dynamically alter treatment decisions to

improve outcome, SMART eliminates unmeasured confounders

associated with treatment decisions that are not randomized, as

occurs in data mining exercises and in other non-randomized

decisions in studies which randomize one variable at baseline.

Discussion: Advantages of MOAT include the ability of quantify-

ing different clinical states over a period of time instead of just time

to a specified event. In addition, it enables incorporation of

tolerability weighting, and different functionality weighting if

patients are in full remission with absence of residual symptoms

or in remission with some residual symptoms. The sequential

adaptive design of SMART represents a methodological innova-

tion in bipolar trial history which may have particular implications

for effectiveness studies and personalized treatment.

Keywords: maintenance, clinical states, treatment outcome, effec-

tiveness

8

Design of clinical trials in bipolar disordersM Tohena, C Bowdena, M Berkb, C Berlangac, C Andraded, K Broiche,JR Calabresef, E Frankg, J Geddesh, G Goodwinh, K Hai, B Hirschfeldj,S Kanbak, P Keckl, B Laferm, R Lichtn, A Nierenbergo, WA Nolenp,T Suppesq, J Tamayor, E Vietas, LN Yathamt, B Carlsonu

aUniversity of Texas Health Science Center at San Antonio, San

Antonio, Texas, United States, bBarwon Health Swanson Centre,

Geelong, Australia, cInstituto Nacional de Psiquiatria, Mexico City,

Mexico, dNational Institute of Mental Health & Neuroscience,

Bangalore, India, eFederal Institute of Drugs and Medical Devices,

Bonn, Germany, fUniversity Hospitals Case Medical Center,

Cleveland, Ohio, United State, gUniversity of Pittsburgh School of

Medicine, Pittsburgh, Pennsylvania, United Statesh University of

Oxford, Oxford, United Kingdom, iSeoul National University

Bundang Hospital, Jongno-Gu, Seoul, Korea, jUniversity of Texas

Medical Branch, Galveston, Texas, United States, kKyushu

University, Fukuoka, Japan, lLindner Center of HOPE, Cincinnati,

Ohio, United States, m University of Sao Paulo, Sao Paulo, Brazil,nAarhus University Psychiatric Hospital, Risskov, Denmark,oMassachusettes General Hospital, Boston, Massachusetts, United

States, pUniversity Medical Center Groningen, Groningen,

Netherlands, qVeterans Affairs Palo Alto Health Care System, Palo

Alto, California,United States, rCESUniversity,Medellin, Colombia,sUniversity of Barcelona, Barcelona, Spain, tUniversity of British

Columbia Hospital, Vancouver, British Columbia, Canada,uBristol-Myers Squibb, New York, New York, United States

The clinical trials task has focused on the review of commonly

utilized designs in the treatment of bipolar disorder. In addition,

the group will also propose new and novel designs.

The most common clinical trial design for acute mania and bipolar

depression is a short, two arm study which in general can yield

differences between efficacious interventions and placebo. As

investigators, clinicians and regulatory authorities may recognize

symptomatic treatment of manic and depressive episodes is a

relatively small component of management of bipolar disorder

other designs need to be consider. The bipolar disorders task force

will review those areas where new paradigms are essential or

desirable.

In general, monotherapy, single point randomization and blinding

achieve major aims. One important advantage of these designs is

that they are relatively inexpensive and not subject to many

ambiguities of interpretation. Additionally, it is possible to include

an established efficacious treatment to provide ‘‘assay sensitivity’’

and allow for secondary analyses of comparative efficacy and

tolerability between a new and an established drug/regimen.

Limitations are that designs that utilize current DSM criteria and

total score on a manic rating scale have inherent weaknesses. DSM

criteria treat all symptoms as equal, when evidence does not

provide support. Similarly, total scores are subject to rater inflation

to qualify individuals, thereby reducing study power to detect

differences; as well as overweighting of non specific symptoms

which may advantage one drug over another. For example,

sedation alone can reduce many manic symptom scores, but the

aim of treatment is rarely principally sedation.

A major unmet need is that little recognition has been given to the

reality that most bipolar I patients have few full manic or

depressive episodes while in treatment. Rather, less severe, and

generally shorter periods of manic or depressive recrudescence

occur more often. Yet, almost no systematic experimental studies

have been conducted on this group.

In terms of maintenance or prophylactic studies adaptive designs

could include alternative randomized actions at the point of such

worsening in manic symptoms. Other investigative actions would

proceed without change. The analyses of results would include

additional hypotheses around the exacerbations in manic or

depressive symptomatology

Unmet needs:

Special populations: Special populations for bipolar studies fall

into two categories. First are characteristics which are unlikely to

have major impact on interventions and their effectiveness. These

include ethnic and racial group, sex and socioeconomic status.

However, this does not dismiss as without benefit some such

studies. For example, several studies have provided some evidence

for greater prevalence/severity of psychotic symptoms among

African American patients.

Quality of life: Quality of life is of limited relevance to bipolar

studies in the short run but of major importance in maintenance

studies. Studies have consistently reported that functional and

quality of life benefits lag behind recovery from syndromal clinical

states in BD. However, adequate and psychometrically sound

measures of QOL exist, and have yielded differences among

interventions. A general weakness in these and other ancillary

outcome measures is that lack of adequate rater training, and often

use of raters who are uninvolved in the clinical care of subjects can

result in loss of sensitivity of such measures.

Neurocognitio: Only recently have studies so persuasively shown

the plasticity of clinically significant cognitive function in BD

cognitive assessment tests generally required time and effort that

5th Biennial Conference of the International Society for Bipolar Disorders



was off-putting to patients and expensive as a component cost of

trials. Cognitive tests shown sensitive to changes with acute

treatments are now available; therefore, the practical barrier to

their more focused use is no longer paramount.

Challenges in countries with emerging economies: Perhaps the major

difference in such countries is that costs of certain regimens and

drugs are prohibitive for most patients. Therefore, studies which

compare drugs available generically, and their cost per year ranges,

warrant more attention. Emerging economies are also less likely to

have funding from federal revenues, therefore most potential

studies in such countries will be ones funded from the pharmaceu-

tical industry.

Keywords: clinical trial design, bipolar disorder

9

Lithium and anticonvulsant mood stabilizerslamotrigine and divalproex for bipolardepressionJR CalabreseDepartment of Psychiatry, Case Western Reserve University,

Cleveland, Ohio, USA

Few treatment options have consistently proven effectiveness for

bipolar I or II depression. Lithium, lamotrigine and divalproex are

extensively used to treat bipolar disorder; however, the benefits of

each are still debated. Lithium is more effective in treating mania or

hypomania than depression, both acutely and prophylactically.

Although lithium can be effective, it does pose a significant burden

of side effects (Young & Newham 2006). Lamotrigine is licensed

for the prophylaxis of bipolar depressive episodes and appears

superior to lithium in this setting (Bowden et al. 2003, Calabrese et

al 2003). Five different trials have investigated lamotrigine versus

placebo in acute bipolar I or II depression, but only one of these

has shown lamotrigine to be effective (Calabrese et al. 1999,

Calabrese et al. 2008); however, a meta-analysis of data from all

five acute trials found consistent evidence of a mild to moderate,

but clinically relevant, benefit of lamotrigine over placebo (Geddes

et al. 2009). However, the data now suggest the acute antidepres-

sant efficacy of lamotrigine is optimized when used adjunctively

with lithium (van der Loos et al. 2009). More recently, we

conducted an exploratory evaluation of the acute efficacy of

divalproex sodium compared to placebo in patients with bipolar I

or II depression. Divalproex demonstrated statistically significant

improvement in MADRS scores compared with placebo from week

3 onward. The proportions of patients meeting response criteria

was 38.5% in the divalproex group, versus 10.7% for placebo

(p = 0.017). The proportion of patients meeting remission criteria

was 23.1% for divalproex versus 10.7% for placebo (p = 0.208).

Subgroup analysis revealed no separation between divalproex and

placebo for those with bipolar II diagnoses (Muzina et al. 2011).

Keywords: lithium, lamotrigine, divalproex, bipolar depression

Keynote 2: Updates from the NIMH

Chair: Willem A Nolen

10

A translational perspective in the search forimproved treatments for bipolar disorderC Zarate, M FureyExperimental Therapeutics and Pathophysiology Branch and Section

on the Neurobiology and Treament of Mood Disorders, Division of

Intramural Research, National Institute of Mental Health, Bethesda,

MD, US

Introduction: There is little understanding on the precise molecular

and cellular processes involved in bipolar disorder despite the many

studies that have been conducted. This gap in knowledge has

resulted in treatments that are not efficacious for many of our

patients. Many patients with bipolar disorder continue to have

prolonged episodes, functional impairment, disability, comorbid-

ity, and mortality. A delay in onset of therapeutic action of

treatments for depression is another major limitation; few patients

improve by the end of the first week of treatment for depression.

This delay in therapeutic effects often results in considerable

disruption to an individual’s life. Therefore, pharmacological

strategies that work immediately would permit an individual to

maintain optimal functioning and continuity with their daily life.

Methods: Proof-of-concept trials, neurobiological and biomarkers

studies in mood disorders are being conducted at the Intramural

Research Program of the National Institute of Mental Health.

Novel treatments being studied include cholinergic antagonists,

non-selective NMDA receptor antagonists, subunit selective

NMDA antagonists (NR2AB, NR2B), delta opioid agonists, and

glycine modulators.

Results: Several converging lines of evidence suggest that dysfunc-

tion of the glutamatergic system—particularly the N-methyl-D-

aspartate (NMDA) receptor complex and AMPA receptors—and

the cholinergic muscarinic system may play an important role in

the pathophysiology of bipolar disorder. Modulatory agents of

these systems result in rapid antidepressant effects.

Discussion: Newer strategies targeting the glutamatergic and

cholinergic systems may have considerable utility in developing

rapid-acting antidepressants that work in hours instead of weeks.

Research being conducted at the Intramural Research Program of

the National Institute of Mental Health on the neurobiology of

bipolar disorder and in developing novel therapeutics and biomar-

kers of response will be presented.

Keywords: biomarkers, bipolar, cholinergic, glutamate, novel

treatments,


ª 2012 The Authors


Symposium 1: Efficacy versus pragmaticeffectiveness trials in the long-term treatment ofbipolar disorder: The Valproate/Lamotrigine/Lithium/Antipsychotic story?

Chair: Willem A Nolen

11

Efficacy versus pragmatic effectiveness trials inthe long-term treatment of bipolar disorder: Thelithium storyWA NolenDepartment of Psychiatry, University Medical Center Groningen,

University of Groningen, Groningen, The Netherlands

After its rediscovery by Cade in 1949 and the pioneering work of

Schou in the 1950-ies and 1960-ies, lithium was registered for the

treatment of bipolar disorder in the early 1970-ies. It has been

shown efficacious in acute mania and acute depression, both

bipolar depression and (especially as augmentation strategy)

unipolar depression. However, its main indication is the long-term

treatment of bipolar disorder.

The efficacy of lithium in maintenance treatment has been shown

in six placebo-controlled studies, two performed in the 1970-ies

and 1980-ies and four after 2000. In the latter studies lithium was

used as standard control while the main focus was to investigate

the efficacy of new treatments (valproate, lamotrigine and

quetiapine). Most studies had an enriched design, i.e. in a part

of the patients or in all patients lithium was already started to

treat an acute episode, after which patient who achieved

remission and tolerated the drug were randomized to continue

lithium or to switch to placebo.

A very recent study involved patients with an acute manic, mixed

or depressive episode who had responded to quetiapine. After

having achieved remission patients were randomized to continue

with quetiapine (enriched), or to switch to placebo or lithium (non-

enriched). In this study lithium was more effective than placebo in

the prevention of both manic and depressive events, proving for the

first time its efficacy against both poles of the illness. In a

subsequent post-hoc analysis of this study it was also found that

these effects were only achieved in patients with a lithium plasma

level of at least 0.6 mmol/l.

Several more pragmatic, comparative studies with other mood

stabilizers have shown that lithium is more effective than carba-

mazepine and valproate, while in comparison with lamotrigine (2/3

studies enriched) lithium (non-enriched) was more effective in the

prevention of mania, but less effective against depression.

Regarding effectiveness, a recent nation wide, naturalistic study in

Denmark showed that compared with valproate lithium was

associated with less hospitalizations for both mania and depression

and also with less medication changes, thus also showing its value

in actual clinical practice.

Conclusion: lithium is the only drug that has been shown effica-

cious (also in studies with a non-enriched design) as well as effective

in the long-term treatment of bipolar disorder, preventing manic as

well as depressive episodes/events.

Keywords: bipolar disorder, maintenance treatment, lithium

12

Efficacy versus pragmatic effectiveness trials –The antipsychotic storyJR CalabreseDepartment of Psychiatry, Case Western Reserve University,

Cleveland, Ohio, USA

Drug development in bipolar disorder (BD) is complicated by

high rates of lifetime comorbidity (Merikangas et al. 2007),

which places patients at high risk for suicidality (Nock et al.

2010). Pharma drug development begins with a lesser challenge

of conducting of efficacy studies, which prioritize internal

validity (assay sensitivity) at the expense of external validity

(generalizability) Calabrese and Kemp 2008). Once efficacy is

established, there exists a need to move forward on the

continuum of improved generalizability by studying more heter-

ogeneous subgroups (anxiety, substance abuse, metabolic bur-

den). Efficacy studies are allowed to artificially inflate effect size

by excluding hard-to-treat patients, whereas effectiveness studies

deflate effect size by including them. The field attempts to

manage this heterogeneity by increasing sample size, but sample

sizes continue to be modest due to pragmatic considerations.

Therefore, everything done by Pharma is just a beginning and

no one drug development effort is ever good enough because

numerous subgroups exist in BD. The challenge for the field is

how fast to we move forward on this continuum of improved

generalizability and how do we do so without compromising

assay sensitivity. This presentation will contrast the methodo-

logical features used in recent antipsychotic drug research to

manage these challenges, including the first generation of

antipsychotic BP depression studies (Baldessarini et al.. 2010),

the Systematic Treatment Enhancement Program for Bipolar

Disorder (STEP-BD), Lithium Use for Bipolar Disorder (LiT-

MUS) (Nierenberg et al. 2009), and Comparative Effectiveness

of a Second Generation Antipsychotic Mood Stabilizer

(CHOICE) studies.

Keywords: antipsychotics, bipolar disorder, effectiveness




13

Efficacy vs pragmatic effectiveness trials in thelong-term treatment of bipolar disorder: Thelamotrigine storyRW LichtMood Disorders Research Unit, Aarhus University Hospital,

Risskov, Denmark

Background: The antiepileptic drug lamotrigine was introduced in

psychiatry in the late 1990’s as a potential mood-stabilizer. Apart

from the risk of rash, the drug was relatively well tolerated and in

contrast to lithium it was easy to manage for the clinician since

there were no requirements for blood monitoring. The first

company-sponsored efficacy trials tested lamotrigine for the

indication of acute bipolar depression and for the indication of

acute mania. These trials were essentially negative. However the

first published depression trial was positive on a secondary

depression outcome measure. In contrast, two pivotal trials on

maintenance convincingly demonstrated that lamotrigine had long-

term mood-stabilizing properties, in particular preventing recur-

rences of bipolar depression.

Methods: This presentation focuses on a quantitative and a

qualitative comparison of the aforementioned company-sponsored

placebo-controlled efficacy trials for maintenance, using lithium as

an internal comparator for validating the study assay and an

investigator-sponsored effectiveness open randomized trial com-

paring lamotrigine with lithium under conditions mimicking

clinical practice.

Results: In the efficacy trials, the study samples were enriched prior

to randomization by selection of patients who tolerated lamotri-

gine and who were able to be maintained on lamotrigine

monotherapy for at least one week in the aftermath of an acute

episode without showing signs of major destabilisation. Due to

such sample enrichment lamotrigine might be favoured in a

comparison with lithium, since the lithium arm was incorporated

in a non-enriched way. In the effectiveness trial, the sample was not

enriched. Despite the major design differences, the lamotrigine-

lithium comparisons appeared similar across the trials.

Discussion: In contrast to what could be expected, lithium did not

perform better relative to lamotrigine under the non-enriched

conditions than under the enriched conditions. Potential explana-

tions for this will be presented.

Keywords: bipolar disorder, maintenance treatment, lithium, lamo-

trigine, randomized clinical trial

14

Efficacy vs pragmatic effectiveness trials in thelong-term treatment of bipolar disorder: thevalproate storyJR GeddesDepartment of Psychiatry, University of Oxford, Oxford, UK

Background: The antiepileptic drug valproate has been used in

bipolar disorder since the late 1960’s, based on the hypothesis that

its GABAergic effect might be antimanic. Its use increased –

particularly in the USA – as a possibly safe and effective treatment

for manic episodes and long-term relapse prevention. Industry-

sponsored trials demonstrated efficacy of valproate in the semiso-

dium form in acute mania. Evidence of long-term efficacy remained

unequivocal both compared to placebo and lithium. Despite the

absence of compelling evidence on safety and efficacy, prescribing

rates of valproate increased, overtaking lithium in the 1990s. The

independent and international BALANCE trial was conducted to

investigate the comparative efficacy of lithium and valproate alone

and in combination.

Methods: BALANCE was an open-label randomised trial with an

active run-in phase followed by randomisation to lithium, valpro-

ate semisodium or combination lithium plus valproate semisodium.

Participants were followed up for 24 months and the primary

outcome was initiation of new intervention for an emergent mood

episode. Systematic reviews and meta-analyses (including multiple

treatments meta-analyses) were also conducted to contextualise the

results.

Results: BALANCE randomised 330 patients with bipolar 1

disorder from 41 sites in 4 countries. Hazard ratios for the primary

outcome were 0Æ59 (95% CI 0Æ42–0Æ83, p = 0Æ002) for combination

therapy versus valproate, 0Æ82 (0Æ58–1Æ17, p = 0Æ27) for combina-

tion therapy versus lithium, and 0Æ71 (0Æ51–1Æ00, p = 0Æ05) for

lithium versus valproate. The systematic reviews provided evidence

on monotherapy valproate vs placebo, safety and comparative

efficacy. The updated systematic review of valproate vs lithium

found four RCTs (total sample size = 618 patients). Overall, there

is no strong evidence of a difference between valproate and lithium

(RR 1.02; 95% CI 0.87–1.20).

Discussion: The evidence for long-term efficacy of valproate

remains equivocal and the results of the largest comparative trial

are not entirely consistent with the pooled data.

Keywords: bipolar disorder, maintenance treatment, valproate,

lithium, randomized clinical trial, systematic review, multiple

treatments meta-analysis.


ª 2012 The Authors


Symposium 2: Molecular biology ofmitochondrial dysfunction: implication andnovel findings in bipolar disorder

Chairs: Trevor Young, Michael Berk

15

Neural basis of behavioral phenotypes of micewith neuron specific accumulation of mtDNAmutationsT KatoLaboratory for Molecular Dynamics of Mental Disorders, RIKEN

Brain Science Institute, Wako, Saitama, Japan

Previous studies implicated the role of intracellular calcium

signaling in bipolar disorder. Mood stabilizers reportedly have

neuroprotective effects. Multiple lines of evidence suggest a

possible role of mitochondrial dysfunction in bipolar disorder,

altered energy metabolism detected by magnetic resonance spec-

troscopy, comorbidity with mitochondrial diseases such as chronic

progressive external ophthalmoplegia, and accumulation of mutant

mitochondrial DNA (mtDNA) in the postmortem brains of

patients. We developed transgenic mice of mutant polymerase

gamma (POLG1) with neuron-specific accumulation of mtDNA

mutations. The mice show bipolar disorder-like phenotypes such as

periodic change of wheel running activity. This change was

improved by treatment with lithium, a mood stabilizer. These

findings suggest that this mouse model could be an animal model of

BD fulfilling the three validity criteria, construct, face, and

predictive validities. We also suggested that endoplasmic reticulum

stress pathway is involved in the pathophysiology of bipolar

disorder based on gene expression analysis in monozygotic twins

discordant for bipolar disorder. These findings suggest that

vulnerability of neurons is implicated in bipolar disorder. However,

both mitochondrial dysfunction and ER stress response dysfunc-

tion are not specific to bipolar disorder. The next step of our study

is to identify the neural systems responsible for bipolar disorder.

We have been trying to identify the region accumulating mtDNA

deletions in the brains of the transgenic mice, and found that

several brain areas accumulate mtDNA deletions. These brain

structures may be relevant to pathophysiology of bipolar disorder.

Keywords: bipolar disorder, mitochondrial DNA, animal models,

lithium

16

Synaptosomal associated protein-25 andoxidative damage in bipolar disorder.AC Andreazzaa,b, JF Wangc, F Salmazia, L Shaoc, LT Younga,b

aDepartment of Psychiatry, University of Toronto, Toronto, ON,

CanadabCenter for Addiction and Mental Health, Toronto, ON,

CanadacDepartment of Psychiatry, University of British Columbia,

Vancouver, BC, Canada

Introduction: Previous studies have demonstrated that protein

carbonylation (i.e. oxidation) is increased in synaptosomal fraction

from postmortem pre-frontal cortex of patients with bipolar

disorder (BD), while 3-nitrotyrosine levels (i.e. nitration) are

increased in mitochondrial fraction from both BD and schizo-

phrenia (SCZ). The study of synapse’s functionally deserved high

attention in BD. Synaptosomal associated protein 25 (SNAP25)

has been found increased in prefrontal cortex from patients with

BD. Therefore, the objective in this study was to evaluate the levels

of SNAP25 and verify whether this protein is a target for oxidative

or nitrositive damage in BD.

Methods: Postmortem pre-frontal cortex from subjects with BD or

SCZ, and from non-psychiatric comparison controls was gener-

ously provided by the Harvard Brain Tissue Resource Center.

Synaptosomal fractions were isolated using the percoll gradient

method. The quality of extraction was verified by electron

microscopy followed by immunoblotting analysis. Levels of

SNAP25 were evaluated using standardized immunobloting tech-

niques. To evaluate whether SNAP25 is a target for oxidative or

nitrosative damage we first immunoprecipitate SNAP25 from each

group of subjects (150 ug from pooled samples) and then samples

were electrophoresed, transferred to PVDF membrane and blotting

for oxidation or nitration using specific antibodies.

Results: Our results demonstrated increased levels of SNAP25 in

patients with BD, but not in SCZ when compared to CTL. To test

if SNAP25 were able to suffer oxidation or nitration we treated

immunoprecipated SNAP25 with H2O2 or SNI_1, respectively.

Our results demonstrated SNAP25 can be further oxidized by

H2O2 but not SIN-1. Pooled samples from patients with BD

showed higher levels of SNAP-25 oxidation when compared to

control.

Discussion: The results indicate that oxidative damage to SNAP25

might play a role to the pathophysiology of BD and deserved be

further studied.

Keywords: bipolar disorder, oxidative stress, mitochondrial dys-

function

17

Novel therapeutics opportunities for bipolardisorder: New research data.M BerkSchool of Medicine, Deakin University, Australia

There is an accumulation of evidence that there are abnormalities

in mitochondrial bioenergetics in bipolar disorder. This opens the

door to novel therapies targeting these pathways. There is a far

higher prevalence of both BD and depression in people with

mitochondrial disease than general population. Changes in brain

energy levels and markers of energy metabolism are altered in

depression and BD, also implicating the role of mitochondrial

changes in these illnesses. For example, resting energy expenditure

and VO2 max of individuals during the manic phase were increased




compared to controls and euthymic participants. There is an

established body of SPECT data showing blood flow is increased in

mania and decreased in depression. Increased phosphomonoester

and decreased adenosine triphosphate (ATP) and phosophocrea-

tine (PCr; a high energy phosphate) have been documented in

unmedicated patients with depression, and ATP and PCr appear to

normalize following treatment; this was correlated with symptom

change. Furthermore, Kato reported that frontal lobe PCr metab-

olite levels are decreased in patients with severe depression.

Subsequent studies suggested that such findings were also seen in

patients with bipolar depression in the left frontal region, especially

in those with bipolar II disorder, and correlated with HAM-D

ratings of depression Andreazza has shown alterations in complex

1 of the mitochondrial electron transport chain in bipolar disorder

and changes in mitochondrial gene expression are also seen in the

disorder. Critically, changes in mitochondrial ultrastructure using

electron microscopy have been recently demonstrated1. There is

thus rapidly mounting evidence of links between BD and

mitochondrial dysfunction. In this presentation, the evidence of

mitochondrial dysfunction in BD will be discussed in terms of the

development of a rational pathophysiologically based intervention

for this disorder. A novel project aims to target underlying

mitochondrial dysfunction in bipolar patients by the use of a

purpose-designed multi-component nutrient formula. This ratio-

nale is supported by the construct of systems biology, suggesting

that concurrently targeting interactive pathway elements may

result in synergistic benefit.

Keywords: mitochondria, depression, mania, bipolar disorder,

energy, treatment

18

A multi-disciplinary approach to studyingmitochondrial abnormalities in bipolar disorderD Ongur, BM CohenMcLean Hospital, Belmont, MA, USA and Harvard Medical

School, Boston, MA, USA

Bipolar disorder (BD) is a common and severe condition but its

pathophysiology is poorly understood. Several independent lines of

observation indicate that mitochondrial function is abnormal in

BD. However, we currently do not understand how these abnor-

malities fit into a broader picture of cellular dysfunction in BD,

ultimately leading to symptom expression. This understanding may

come from approaches which relate bioenergetic dysfunction to

alterations of neurotransmission and neuronal/glial cell function.

First, Dr. Dost Ongur will review neuroimaging studies examining

mitochondrial dysfunction in BD. Phosphorus magnetic resonance

spectroscopy (31P MRS) studies have suggested that oxidative

phosphorylation is disrupted particularly in the prefrontal cortex in

BD, leading to build-up of lactic acid and reductions in parenchy-

mal pH. In addition levels of total creatine, a high energy

phosphate store, are reduced in some patients with BD. New 31P

MRS approaches make it possible to measure creatine kinase and

ATP synthase reaction rates. These studies may provide new

insights into BD.

Next, Dr. Bruce Cohen will present a set of related genomic and

cellular studies on mitochondrial abnormalities in BD carried out

at McLean Hospital. First, results will be discussed suggesting

enrichment of single nucleotide polymorphisms in a set of genes

located on mitochondria-related pathways. Overall, the genomic

observations imply that there is no single gene strongly associated

with BD but that some or many mutations on a mitochondrial

pathway raises the risk of BD, in association with other genes.

Second, mitochondrial morphology is abnormal in fibroblasts and

lymphocytes from BD patients when compared with those from

healthy controls. These abnormalities to not appear to be

associated with prior drug treatment and are not replicated by

exposure to drugs in vitro. Third, there is growing clinical interest

and literature on using mitochondrial supplements (Coenzyme

Q10, ALA-AlCar, others) as adjunctive treatment in BD. Some but

not all small open-label studies have provided evidence of benefit.

Finally, both will discuss the implications of mitochondrial

dysfunction in BD for brain function including glutamatergic

neurotransmission and glial cell function – both of which are

implicated in the pathophysiology of BD, and will open a

discussion with the audience.

Keywords: bioenergetics, genetics, fibroblast, magnetic resonance

spectroscopy

Parallel 1: Multiple Co-morbidities in bipolardisorder: diagnostic and treatment challenges

Chairs: Ihsan Salloum, Warrier Mohandas

19

Optimizing treatment outcome for bipolardisorder with comorbid addictive disordersIM SalloumDepartment of Psychiatry and Behavioral Sciences, University of

Miami Miller School of Medicine, Miami, Florida, USA

Bipolar disorder has the highest association with alcohol or other

substance use disorders (SUD) when compared to any other major

psychiatric condition such as schizophrenia, major depression, or

any anxiety disorder. The multiple and intertwined problems of

these co-existing conditions represent major challenge to tradi-

tional model of care. Treatment needs for this high-risk population

have been largely unmet. There still exists paucity of data on

effective treatment approaches. Pharmacotherapeutic and psycho-

therapeutic approaches that specifically address comorbid popula-

tions is still a developing field. This presentation will review

available evidence of current pharmacotherapy and psychotherapy

in comorbid bipolar and substance use disorders, including the

emerging role of anticonvulsants, mood stabilizers, atypical anti-

psychotics, and combined pharmacological treatment strategies.

Keywords: bipolar, addictive disorder, pharmacotherapy, psycho-

therapy, optimized clinical Intervention, comorbidity


ª 2012 The Authors


20

Impulse control disorders comorbidity inbipolar disorderL TamamDepartment of Psychiatry Faculty of Medicine, Cukurova University

Adana, Turkey

Impulsivity is an important feature of many psychiatric disorders,

including impulse control disorders (ICDs), mood disorders,

substance abuse, and eating disorders. Among the various mood

disorders, impulsivity is found to be particularly closely associated

with bipolar disorder (BD). Impulsivity as a feature of BD is

related to impairment of mood stability, increased behavioral

problems, and action without planning. Impulsivity appears to be

prominent during manic episodes but may also be found during

euthymia and other mood states in patients with BD. It has been

reported that euthymic bipolar patients have significantly higher

impulsivity scores than do control subjects. Beside impulsiveness in

bipolar disorder has both trait and state components; i.e., a

baseline impulsive personality style that becomes exaggerated

(more impulsive) during mania, although not during depression.

Increased impulsivity levels suggest an increased rate of comorbid

ICDs in patients with BD. Bipolar disorder and ICDs have both

some common and some distinct features. Risky behavior, impul-

sivity, poor insight, and affective instability are common phenom-

enological symptoms in both disorders. Both disorders start in

adolescence or early adulthood and subsequently follow episodic

and/or chronic courses and. similar comorbidity patterns, abnor-

malities of central serotonin and noradrenalin neurotransmission,

and positive response to mood stabilizers and antidepressant are

the other common features. Another finding supporting a possible

ICD-BD relationship is the increased prevalence of mood disorders

in patients with ICDs and the increased prevalence of ICDs in

patients with BD. The lifetime prevalence rate of ICDs among

patients with mood disorders ranges between 23% and 35%, which

are much higher than those rates reported in the general population

(8.9%). The relationship between these two disorders may suggest

a shared pathophysiological abnormality which warranted detailed

research.

Keywords: bipolar disorder, mood stabilizer, long-term treatment

21

The journey of addiction in bipolar disorderMA FryeMayo Clinic, Rochester, MN, US

The prevalence rate and diversity of addiction, and its negative

impact on the course of bipolar disorder is strikingly impres-

sive.Since the Kraepelian observation nearly ninety years ago,

contemporary epidemiologic studies including the Epidemiologic

Catchment Area Study, the National Comorbidity Study, the

National Comorbidity Survey-Replication, and the National Ep-

idemiologic Survey on Alcohol and Related Conditions have

reported rates of alcohol abuse or dependence in bipolar disorder

that are consistently higher than the general population and most

other axis I disorders. While the prevalence rate of nicotine

dependence is not the highest of Axis I disorders, patients with

bipolar disorder have one of the lowest quit rates. Finally, other

addictive disorders such pathological gambling, food addiction /

obesity, polydrug use, and internet addictions either are relatively

over represented in bipolar disorder or phenomenologically have

similarities of illness presentation or treatment responses to mood

stabilizers. This presentation will review prevalence rates, clinical

correlates, gender differences, and treatment recommendations on

the diversity of addictions in bipolar disorder.

Keywords: substance use disorders, bipolar, alcohol, nicotine,

marijuana

Symposium 3: Modern Clinical Management ofBipolar Disorder

Chairs: Gin Malhi, Mark Frye

22

The treatment of complex bipolar disorderGS Malhia,b, M Berkc,d,e,f,g

aCADE Clinic, Department of Psychiatry, Royal North Shore

Hospital, Sydney, Australia, bDiscipline of Psychiatry, Sydney

Medical School, University of Sydney, Australia, cSchool of

Medicine, Deakin University, Geelong, Australia, dOrygen Youth

Health Research Centre, Centre for Youth Mental Health,

University of Melbourne, Parkville, Australia, eBarwon Health and

the Geelong Clinic, Swanston Centre, Geelong, Australia, fThe

Mental Health Research Institute of Victoria, AustraliagDepartment

of Psychiatry, University of Melbourne, Parkville, Australia

Introduction: The management of bipolar disorder is inherently

complex. To understand and manage the complexities of the illness

a new schema that provides a logical structure is needed.

Methods: A systematic literature search was conducted to identify

articles that describe the management of complex presentation of

BD.

Results: Five sets of factors contribute to complex manifestations

of BD. These can be best conceptualized as a stratified model.

Discussion: This brief presentation outlines a novel framework and

discusses the recommendations for managing complex bipolar

disorder. Specifically, factors contributing to treatment resistance

and the management of treatment non-response will be described

and the principles that underpin the recommendations for the

treatment of complex bipolar disorder presentations will be

discussed.

Keywords: bipolar disorder, complex bipolard disorder, treatment

resistance




23

Treatment options for acute depression inbipolar disorderM. BauerDepartment of Psychiatry and Psychotherapy, Carl Gustav Carus

University Hospital, Technische Universitat Dresden, Germany

The burden of depression represents the most debilitating dimen-

sion for the majority of patients with bipolar disorder and

dominates the long-term course of the illness. The purpose of this

presentation is to review the evidence base of the available

treatment options for bipolar depression assigned to two frequent

clinical scenarios. The evidence is largely based on a systematic

literature search. All relevant randomized controlled trials were

critically evaluated. Overall, the evidence from treatment trials in

bipolar depression is relatively sparse compared with the number of

controlled trials in unipolar depression and as such the choice of

treatment is governed by a multitude of factors. While clinical trials

provide evidence on the efficacy of a certain intervention in a

specific population, they cannot necessarily determine which

intervention will be optimal for a given patient in a given specific

situation. They can however inform the choice of intervention and

in particular prevent clinicians from choosing interventions that

have been shown to be ineffective. Monitoring of potential

unwanted effects and of the appropriateness of treatment can help

to effectively balance benefits and risks in individual situations.

However, the quality of the assessment and reporting of risks in

clinical trials need to be increased to better inform treatment

decisions.

Scenario A: if a patient with bipolar depression is currently not

being treated with a mood stabilizing agent (de novo depression),

then quetiapine or alternatively olanzapine are an option, carba-

mazepine and lamotrigine can be considered. Antidepressants are

an option for short-term use, but whether they are administered as

mono- or combination treatment with mood stabilizing agents is

still controversial. Most clinicians prefer to use antidepressants in

combination with an antimanic substance. Scenario B: If a patient

is already treated with a mood stabilizing agent (breakthrough

depression) once adherence has been confirmed and the dose has

been adjusted, lamotrigine is an option in patients on lithium.

There is no evidence for further effects of antidepressants in cases

where a patient is already receiving a mood stabilizer, however, an

additional antidepressant is preferred by most clinicians.

24

Maintenance treatments in bipolar disorderM GitlinGeffen School of Medicine at UCLA, Los Angeles, CA, USA

Bipolar disorder is an inherently recurrent disorder, requiring

maintenance preventive treatments in the vast majority of patients.

Over the last decade, a number of effective maintenance treatments

for bipolar disorder have been developed with an evidence base for

second generation antipsychotics and some anticonvulsants.

Increasing numbers of patients, therefore, are appropriately treated

with multiple medications as a maintenance regimen. For some

medications, maintenance treatment has been demonstrated in

randomized controlled trials for both monotherapy and in com-

bination with other mood stabilizers. Lithium continues as our

oldest well established maintenance treatment in bipolar disorder

with somewhat better efficacy in preventing mania than depression.

Lamotrigine, olanzapine and quetiapine have bimodal efficacy in

preventing both mania and depression, although lamotrigine’s

efficacy is more robust in preventing depression, and olanzapine’s

efficacy greater in preventing mania. Aripiprazole, ziprasidone and

risperidone long-acting injection all prevent mania, but not

depression. Less controlled investigations have suggested some

evidence of maintenance mood stabilization with carbamazepine,

oxcarbazepine, and adjunctive psychotherapy. Despite the number

of agents with demonstrated efficacy as maintenance treatments in

bipolar disorder, optimal treatment regimens are still a combina-

tion of evidence-based therapy in combination with individualized

creative treatment algorithms.

Keywords: bipolar disorder, maintenance treatment, psychophar-

macology, lithium, anticonvulsants, antipsychotics

25

Treatment of mania and mixed statesRS McIntyreAssociate Professor of Psychiatry and Pharmacology, University of

Toronto, Head, Mood Disorders Psychopharmacology Unit

During the past decade, substantial progress has been made in the

pharmacological treatment of bipolar mania and mixed states.

Over a dozen agents are now established as efficacious relative to

placebo in acute mania. Hitherto, no study has primarily evaluated

efficacy in an exclusively mixed subpopulation. Recent evidence,

based on network analysis, suggests that differences in efficacy

between acute anti-manic agents may exist. Moreover, emerging

evidence indicates that early partial symptomatic improvement (i.e.

at day 2) may identify individuals more likely to improve with

therapy. This presentation will update participants on efficacy data

in acute mania and mixed states, as well, results from network

analysis and other studies reporting on the positive and negative

predictive value of early symptomatic change in mania/mixed

states. Finally, a recent analysis of a registration dataset employing

the DSM V definition of mania with mixed state specifier will be

presented.

Keywords: acute mania, mixed states, antipsychotics, prediction


ª 2012 The Authors


Symposium 4: Development and determinantsof psychopathology in prospective bipolaroffspring cohorts

Chairs: Manon Hillegers, Ketil Odegaard

26

The pittsburgh bipolar offspring studyB Birmahera, D Axelsona, B Goldsteinb, K Monka, D Brenta, D Kupfera

aUniversity of Pittsburgh School of Medicine, Western Psychiatric

Institute and Clinic, Pittsburgh, PA, USAbUniversity of Toronto

Faculty of Medicine, Sunnybrook Health Sciences Centre, Toronto,

Ontario, Canada

Introduction: High-risk studies have shown that bipolar disorder

(BP) runs in families. However, few studies have included large

samples of offspring of parents with bipolar disorders and controls

and followed up with them for many years.

Methods: The ‘‘Pittsburgh Bipolar Offspring Study’’ (BIOS)

recruited a large sample (n = 388) of 6–18 years old, offspring of

parents with BP and followed them for about 10 years. To assess

whether BP is specifically transmitted from parents to their children

and it is not accounted by other non-BP psychopathology and

environmental factors, a comparison sample (n = 251) of off-

spring of parents with no-BP psychopathology or no psychopa-

thology at all was recruited.

Results: Analyses of the intake data showed that after adjusting

for several confounding factors, offspring of parents with BP had a

13-fold higher risk to develop BP than the controls. In addition,

they were at high risk to develop anxiety and behavior disorders.

Offspring with anxiety and disruptive disorders, with parents

whose BP onset early in life, or those where both parents had BP,

were at higher risk to develop BP. Preliminary analyses of the

follow-up data showed a 22-fold increase in the rate of BP

disorders when compared to the controls.

Discussion: Most of the BP disorders onset during the adolescent

years. Currently, we are in the process of analyzing the factors

associated with new BP onsets during the follow-up.

Keywords: bipolar disorder, offspring of parents with bipolar

disorder, high risk studies

27

Attachment, temperament, and cortisol profilesin the offspring of bipolar parentsS Doucettea, J Horrocksb, P Grofc, G Perssonb, C Keown-Stonemanb,U Lewitzkad, A Duffya

aDalhousie University, Department of Psychiatry, Nova Scotia,

Canada bUniversity of Guelph, Department of Mathematics and

Statistics, Ontario, Canada, cMood Disorders Centre of Ottawa,

University of Toronto, Department of Psychiatry, Ontario, Canada,dDepartment of Psychiatry, University Hospital Carl Gustav Carus,

Dresden, Germany

Objectives: To present new data on the association between

attachment, temperament, and cortisol profiles and the risk of

psychopathology in offspring of bipolar parents.

Methods: High-risk offspring (ages 7–25 years) had one parent

with a DSM-IV diagnosis of bipolar disorder determined by

SADS-L interviews and confirmed on a blind consensus review

using all available clinical information. A similarly recruited

control group of offspring of 2 well parents were included. All

offspring were assessed using KSADS-PL format clinical interviews

on average annually and completed measures of temperament and

perceived attachment, as well as collection of salivary cortisol upon

awakening and over the day according to research protocol.

Results: In high-risk offspring (n = 190), temperament, specifi-

cally high emotionality multiplied the risk of developing psycho-

pathology by a factor of 1.052, 95% CI (1.01, 1.096). Interestingly,

there was no difference in perceived attachment to parents between

high-risk and control samples (n = 63), however, in high-risk

offspring a negative perceived attachment increased the risk of

psychopathology by a factor of 1.011, 95% CI (1.001, 1.021). In a

separate analysis, there was a trend towards a higher cortisol

awakening response in remitted offspring of bipolar parents

compared to controls.

Conclusions: Bipolar disorder is a complex illness resulting from an

interplay of genetic and other risk factors to determine illness

onset. Genetically sensitive pathways impact the development of

psychopathology. In high-risk offspring, it is not clear if differences

in attachment and temperamental profiles reflect risk factors

(preceding illness) or a symptom (part of the early burden of

illness). Prospective, longitudinal investigations of offspring at

genetic risk can clarify risk from burden of illness and would have

implications for early intervention strategies in youth at-risk.

Keywords: bipolar disorder, cortisol, temperament, attachment,

early development

28

Predictors of the longitudinal course of mooddisorders in children and adolescentsM Preisiga, S Rothena,b, O Halfona, CL Vandeleura,b, S Vidala,b,JM Aubryb

aDepartment of Psychiatry, University Hospital Center and

University of Lausanne, Switzerland bDepartment of Mental Health

and Psychiatry, University Hospital of Geneva, Switzerland

Introduction: Follow-up studies on the offspring of parents with

psychiatric disorders offer the opportunity to study the influence of

parental disorders on both the incidence and course of psychopa-

thology in their children. Using this study design, we are examining

the impact of parental psychopathology and potential individual

risk factors including demographic characteristics, premorbid

personality features (Neuroticism) and early traumatic events on

the course of mood disorders in childhood and adolescence.

Methods: As part of a family study, we have collected extensive

clinical information on 72 probands with bipolar disorder, 56

probands with major depressive disorder, 29 probands with alcohol

or heroin dependence and 45 medical controls with 288 children in

the age range from 7 to 17 years, who had at least one baseline and

one three-year follow-up assessment. Probands and their spouses




were interviewed using the DIGS, offspring using the K-SADS.

Parents also provided diagnostic information on their children

using the FH-RDC.

Results: The main results regarding the impact of parental

psychopathology and potential individual risk factors on the

course of depression in children in terms of social impairment and

the occurrence of new episodes or switch to bipolar disorder at

later follow-up exams will be presented at the conference.

Discussion: Clinical and research implications of the results will be

discussed.

Keywords: major depressive disorder, bipolar disorder, high-risk

offspring, course, predictors

29

Prevalence and the course of psychopathologyin a prospective Dutch bipolar offspring cohort– A 12 year follow-upE Mesmana, MH Hillegersa, WA Nolenb

aDepartment of Psychiatry, University Medical Center Utrecht,

Utrecht, The NetherlandsbDepartment of Psychiatry, University

Medical Center Groningen, University of Groningen, Groningen, The

Netherlands

Objective: The aim of this study is to determine 1) the prevalence

of psychopathology from early adolescence into adulthood in

children of bipolar parents; 2) the development and course of mood

disorders in this high risk cohort.

Methods: The study presented is part of an ongoing prospective

study among children of bipolar parents in the Netherlands. At the

first measurement in 1997, 140 children (aged 12–20 years), were

evaluated with the K-SADS-PL. Fourteen months later, 132

children were reassessed. After 5 years, the third measurement

was conducted among 129 children. At the third measurement the

K-SADS-PL was replaced by a more age-appropriate instrument:

the SCID. Currently, 12 years after the first measurement, we are

completing the fourth measurement with an expected follow-up

rate of at least 70% of the original cohort.

Results: Between the first and third measurement lifetime preva-

lence of bipolar disorder increased from 3 to 10%, of overall mood

disorders from 27 to 40% and of overall psychopathology from 44

to 59%. In all subjects but one bipolar disorder debuted with a

depressive episode. The fourth measurement shows a further

increase of psychopathology, especially of mood disorders. We will

focus on the course of the development of psychopathology during

twelve year follow-up; 2) determinants of psychopathology.

Conclusion: To our knowledge this study is one of world’s largest

prospective bipolar offspring cohort followed for more than

10 years. Eight years after the third measurement there is again

an increase of the level of psychopathology, especially of mood

disorders. Once more, all new subjects with bipolar disorder

debuted with a depressive episode prior to their first (hypo) manic

episode.

Keywords: bipolar, offspring, psychopathology, determinants

Parallel 2: ISBD Women’s Health Task Force

Chairs: Aysegul Ozerdem, Danilo Quiroz

30

Women are more vulnerable for thyroid functionabnormality in bipolar disorderA Ozerdema,b,c,d, Z Tuncaa, D Cimrine, C Hidiroglub, G Ergorf,N Rasgong

aDepartment of Psychiatry, Faculty of Medicine, Dokuz Eylul

University, Izmir-TURKEY, bDepartment of Neuroscience, Health

Sciences Institute, Dokuz Eylul University, Izmir-TURKEY, cBrain

Dynamics and Research Center, Dokuz Eylul University, Izmir-

TURKEY, dBrain Dynamics, Cognition, and Complex Systems

Research Center, Istanbul Kultur University, Istanbul- TURKEY,eCentral Laboratories, Dokuz Eylul University Hospital, Izmir-

TURKEY, fDepartment of Public Health, Faculty of Medicine,

Dokuz Eylul University, Izmir-TURKEY, gStanford Center for

Neuroscience in Women’s Health, Department of Psychiatry and

Behavioral Sciences, Stanford University School of Medicine,

Stanford, CA, USA

Background: Evidence shows subtle thyroid hormone metabolism

abnormalities in patients with mood disorders.

Method: Serum TSH levels of 3204 patients with bipolar disorder

(n = 469), unipolar depression (n = 615), other psychiatric diag-

nosis (n = 999), patients from endocrinology (n = 645), and from

dermatology clinics (n = 476) were compared in a retrospective,

cross-sectional, naturalistic design. TSH levels of high (0.4–

5.0 mIU/L) and low 0.3–3.0 mIU/L normal range were assessed

specifically for gender difference.

Results: Patients with bipolar disorder showed significantly higher

serumTSHlevels comparedtoallothergroups.Rateofabovenormal

range females was the highest in patients with bipolar disorder both

for high (5.0 mIU/L) (12.1%), and low (3.0 mIU/L) (30.4%) upper

normal limits. In bipolar patients, serum TSH levels did not differ

significantly between different mood states. In the lithium treated

patients (n = 240) significantly lower rate of the females (55.9%)

compared to males (71.2%) fell within low (0.3–3.0 mIU/L) TSH

window (p = 0.016). For the upper normal range (0.4–5.0 mIU/L)

serum lithium levels above 0.8 mmol/L group was associated with

significantly lower proportion of female patients (59.2%) falling

within the normal range than the proportion of males (88.9%).

Conclusions: Our findings point at a higher vulnerability of bipolar

patients for thyroid dysfunction compared to other psychiatric and

medical conditions.Womenwith bipolar disorder are more prone to

develop TSHabnormality especially under lithium treatment, and at

therapeutic serum levels. Lowering upper-normal TSH values at

follow up can provide a useful screening tool to prevent development

of subclinical hypothyroidism and adverse course of illness.

Keywords: bipolar disorder, female, thyroid function, gender

difference, lithium


ª 2012 The Authors


31

How to be a mother: Pregnancy andbreastfeeding planning for women with bipolardisorderF AkdenizProfessor of psychiatry, Ege University School of Medicine

Department of Psychiatry, Izmir, Turkey

Anyplans for pregnancymust bediscussed indetailwithwomenwith

bipolar disorders. Theymust be informed about the risks related to it

and the need for some precautions. Because of the risk of relapse

during pregnancy, the risk/benefit ratio of maintaining or starting

prophylactic treatment should be assessed, taking into account

family history and frequency of recurrences. Lithium may be used

during pregnancy under close monitoring. Most anticonvulsants are

contraindicated because of their teratogenicity. During the post-

partum period, prophylaxis is required in most cases because of the

high risk of relapse. If no prophylaxis was given during pregnancy, it

must be started quickly after delivery to be effectivewhen the risk is at

its highest, i.e., during the first twoweeks after delivery.Womenwith

bipolar disorders should be advised against breast-feeding to avoid

exposure of the infant to psychotropic medication. Because breast-

feeding can be stressful and causes sleep deprivation, it may increase

the risk of relapse. Second-generation antipsychotic agents should

not be used during pregnancy or breast-feeding because inadequate

information is currently available about their safety.

Keywords: bipolar disorder, pregnancy, breastfeeding

32

Childbirth and bipolar disorder: challenges andopportunitiesV SharmaDepartment of Psychiatry and Obstetrics & Gynaecology, University

of Western Ontario, London, Canada, and Perinatal Clinic, London

Health Science Center, London, Canada

A wide variety of psychiatric disorders occur in the puerperium,

but childbirth is a particularly potent trigger for mood episodes in

bipolar disorder. Women with bipolar disorder are also at a high

risk for postpartum psychosis, with episodes closely following 25–

50% of deliveries. The rate increases to approximately 60% among

women who have both bipolar disorder and a personal or family

history of puerperal psychosis. The puerperium is also a vulnerable

period for a diagnostic switch from major depressive disorder to

bipolar disorder, and in some women an episode of postpartum

depression may herald bipolar disorder.

The proximity of mood and psychotic episodes to the time of

delivery, and the brief duration of the high-risk period (approx-

imately two weeks) pose treatment challenges. Misdiagnosis of

bipolar disorder as major depressive disorder is not uncommon and

can be associated with serious consequences. Unfortunately, there

is a paucity of pharmacological and psychotherapeutic studies on

the preventative and acute treatment of postpartum mood and

psychotic episodes. Currently there are no treatment strategies for

primary prevention of postpartum-onset bipolar disorder in

women who are at-risk for onset of bipolar disorder.

The close temporal association of childbirth and bipolar disorder

should provide a window of opportunity to improve maternal and

neonatal outcomes via interventions aimed at early detection and

diagnosis of bipolar disorder, prevention of mood and psychotic

episodes, and prompt recognition and treatment of emerging

psychopathology. Given the rapid onset of puerperal psychosis and

bipolar mood episodes, universal screening during pregnancy is

critical for early identification of women who are at high risk for

bipolar disorder and puerperal psychosis. Women with postpartum

depression should also be routinely assessed for bipolar disorder. It

is important to address modifiable risk factors (such as sleep

deprivation) that might increase the risk of postpartum mood

instability. An understanding of how biological and psychosocial

factors interact to increase the risk for onset or exacerbation of

bipolar mood episodes should stimulate a search for new strategies

in the prevention and treatment of bipolar disorder in the

postpartum period.

Keywords: bipolar disorder, childbirth, postpartum, depression

33

Brain derived neurotrophic factor in womenwith bipolar disorder compared to controlsNL Rasgona, MF Reynolds-Maya, HA Kennaa, W Marshb, PG Stemmlea,P Wanga, TA Kettera

aDepartment of Psychiatry and Behavioral Sciences, Stanford

University School of Medicine, Stanford, CA, bDepartment of

Psychiatry, University of Massachusetts Medical School, Worcester,

MA

Background: Brain-derived neurotrophic factor (BDNF) has been

implicated in the pathophysiology of mood disorders such as

depression and bipolar disorder (BD), as well as with metabolic

variables, particularly in women. The purpose of this study was to

evaluate BDNF plasma levels and the val66met genotype in women

with BD compared to controls.

Methods: Women diagnosed with BD I and II and healthy controls

with no psychiatric history ages 18 to 45 were recruited from a

University clinic and surrounding community. Participants com-

pleted a baseline reproductive health questionnaire and serum

hormone assessment for a larger study regarding the reproductive

health in BD. In addition, blood samples from these two groups

were randomly selected for further analysis of plasma BDNF

concentration, and assessment for the val66met genetic polymor-

phism.

Results: Women with BD (n = 60) did not differ from controls

(n = 30) in demographic variables. Of BD women, 26% were

found to be val/val genotype, 72% val/met, and 2% (one subject)

met/met. These rates were similar to the control group (24%, 71%,

and 5%, respectively). Mean BDNF plasma concentration as well

as other variables did not differ between the genotype groups.

Plasma BDNF levels were not correlated with age, duration of

illness, type of BD, or genotype. However, BDNF was positively

correlated with fasting plasma insulin and waist-to-hip ratio in BD

subjects (p = 0.046 and 0.034 respectively). When subjects were

analyzed by type of BD (I vs II), BDNF plasma levels in Type II

women were negatively correlated with depression rating scores

whereas no significance was found in Type I subjects. Plasma levels

were not associated with mania rating scores.

Discussion: Rates of val66met genotypes and plasma BDNF

concentrations are similar to those previously reported and did

not differ between women with BD and controls. Though this study

is small, the finding that BDNF plasma levels are correlated with

measures of insulin resistance suggests future areas of study, as

does the tentative observation that correlations between BDNF

and mood ratings differ between BD subgroups.

Keywords: bipolar disorder, women, brain-derived neurotrophic

factor, genotype, metabolic function




Core Symposium 3: Special Session on DSM-5(ICD) Updates: Focus on Bipolar

Chair: David J. Kupfer

34

Update on diagnostic criteria for bipolardisordersDJ KupferUniversity of Pittsburgh School of Medicine, Department of

Psychiatry, Pittsburgh, PA, USA

Background: The road to the DSM-5 revision began almost a

decade ago as clinicians and researchers developed an agenda to

incorporate scientific and methodological advances in the next

nomenclature.

Methods: The emphasis on utilizing a developmental approach

across the life span, adopting methodological strategies utilizing

both dimensional and categorical approaches, and re-thinking the

larger organizational framework of the DSM itself has led to a

number of interesting recommendations. Since many of the recent

advances in the neurosciences and behavioral sciences are not

ready for clinical application, it is likely that the DSM-5 will not

represent a revolutionary shift, but rather an evolutionary process

based on some new empirical data. However, we have made the

decision to make the DSM-5 a living document, with permanent

infrastructure to enable revisions of specific diagnostic areas

where new evidence is replicated and reviewed as ready for

adoption.

Results: The DSM-5 Task Force work Group on Mood Disorders

has made a number of recommendations consistent with the

strategies described above that directly affect bipolar disorders.

First, the new organizational structure of DSM-5 will place bipolar

disorders as a separate chapter between schizophrenia and other

psychoses and depressive disorders. This placement recognizes the

link between psychoses and depressive disorders inherent in bipolar

disorders. Second, the recommendation of a new disorder to parse

out early bipolar disorder from anxiety/depressive trajectories in

children and adolescents reflects the strong interest in develop-

mental trends. Third, the recommendation to increase the prom-

inence of energy and activity in the criteria set is consistent with

empirical data published in the last twenty years. Finally, the

importance of mixed states has been recognized in the recom-

mended change for mixed specifiers in both bipolar and unipolar

states.

Discussion: While these changes represent the current proposals

for DSM-5, additional changes may occur based on field trial

findings and continuing input from advisors.

Keywords: DSM-5; bipolar diagnoses; development; energy

35

The DSM-5 field trials and bipolar disordersE Franka, HC Kraemera, DJ Kupfera, WE Narrowb, DE Clarkeb,DA Regierb

aDepartment of Psychiatry, University of Pittsburgh, Pittsburgh,

PA, USA, bDivision of Research, American Psychiatric Association,

Arlington, VA, USA

Background: Like all field trials, those being conducted for DSM-5

represent an effort to evaluate a product in the context in which it

will be used. This presentation will focus on the rationale, design

and conduct of the formal DSM-5 field trials, with a specific

emphasis on the various bipolar disorder diagnoses.

Methods: The formal field trials for DSM-5 differ substantially

from those carried out for previous revisions of the manual

inasmuch as: 1) they are being carried out by specially trained

clinicians who were not involved in the development of the new

criteria, 2) in addition to the clinical utility and inter-rater

reliability focused on in previous field trials, test-retest reliability

(precision), and criterion validity (accuracy) are being assessed and

3) the field trial sites reflect the heterogeneity of the settings in

which the criteria will be used, including general medicine, general

psychiatric and specialty psychiatric clinics. Each site involved

focuses on two to five specific diagnoses and a carefully constructed

stratified design involving a successive-entry stratum and an

enriched stratum allows for weighting all findings with respect to

reliability and validity. The two interviewing clinicians are

informed of the site’s target diagnoses, but are blinded to the

patient’s stratum. Reliability of diagnoses are calculated using the

intraclass kappa, while validity is calculated using Cohen’s kappa.

Results: The sites focusing on bipolar disorder are currently

completing their work. Results for the reliability and validity of

the various bipolar diagnoses will be presented, with a particular

emphasis on changes that have been proposed for DSM-5,

including greater emphasis on increased activity in the A criterion

for mania and the proposed change from a mixed episode diagnosis

to a mixed specifier, applicable to episodes of both mania and

depression.

Discussion: The reliabilities and validities obtained for bipolar

disorders, in general, and for these proposed changes will be set in

the context of diagnostic reliability and validity in other areas of

medicine.

Keywords: DSM-5; bipolar diagnoses; field trials


ª 2012 The Authors


Keynote 3: Bipolar Spectrum

Chair: Gary Sachs

37

The Bipolar spectrum: from temperament togenesH AkiskalUniversity of California at San Diego, La Jolla, US

‘‘Bipolar spectrum’’ first appeared in the psychiatric literature in a

1977 paper on a prospective follow-up of cyclothymic individuals:

Most developed depression or bipolar II, fewer developed full

blown manic-depressive illness and, significantly, nearly half the

sample treated with antidepressants developed increased cycling.

Much of the evidence for this broadened bipolar concept has come

during the past few years. Subthreshold bipolar conditions have

been identified in the community and several epidemiological

studies in Europe the United States, Latin America, and the

Middle East, showing an average population prevalence of 2–4%.

Prospective follow-up has shown progression of subthreshold

bipolarity to full-blown bipolar disorders. There has been great

momentum in the clinical literature to study the various forms of

the bipolar spectrum, which in addition to the well-known types I

and II in the DMS-IV and ICD-10 language, include depressions

with shorter hypomanias, hypomanias elicited by antidepressant

treatment, depressions arising from various bipolar temperaments

such as the cyclothymic and the hyperthymic, as well as depressions

with inter-episodic hypomania (depressive mixed state). Despite

criticism from some quarters, bipolar validation has been achieved

for most of these in rigorously conducted studies coming from

various clinics in the world, particularly the United States, Italy,

France and Hungary, as well as two national studies from Poland

and France. Other proposed bipolar concepts refer to issues that

have to do with ‘‘unipolar’’ depressions with high recurrence,

atypicality, seasonality, early age at onset, depression with bipolar

family history, and affective states occurring in the setting of

multiple anxiety disorders, as well as those in the postpartum

period. In addition, there is the controversial proposal that

polysubstance abuse, particularly cocaine and stimulant, might

be related to the bipolar spectrum. This is a large terrain and

beyond the conventional literature but of major significance for

public health, clinical psychiatry, psychiatric theory and research

methodology, including genetics. Thus, the field has progressed to

the point of proposing some ‘‘soft’’ bipolar conditions as behav-

ioral endophenotypes for bipolar disorder; left amygdala activation

is the brain correlate of those with cyclothymia. Furthermore,

recent data from Italy and Scotland have identified, respectively,

white matter abnormalities based on dysthymia/hyperthymia ratio,

as well as, among unaffected relatives from bipolar families,

including those with cyclothymia. More recently, our group, with

Norwegian collaboration, has identified genes comorbid for

bipolar spectrum and migraine. Finally, provocative data on

distinct longitudinal temperamental patterns associated with 4

distinct genes on the pathway to mania, have been delineated by

our group in San Diego.

Keywords: bipolar spectrum

Core Symposium 4: Molecular Genetics

Chairs: Charlie Nemeroff, Luis Madrid Peroza

38

Individual differences and evidence basedpsychopharmacologyRH BelmakerBen Gurion University of the Negev, Beersheva, Israel

Considerable controversy surrounds the question as to whether all

or most decisions in psychopharmacologic treatment can be

evidence based. While large placebo controlled trials, mostly for

registration purposes, clearly provide important evidence for the

clinician, many patients do not fit the criteria for such trials and the

results of such trials are not always applicable to such patients.

Major findings in psychopharmacology and biological psychiatry

have not been replicated consistently and thus the clinician is faced

with a question of judgment as to when to change his clinical

practice based on a new finding. Moreover, research results in

psychopharmacology are almost always published as mean effects.

Examples of individual differences in biological and psychophar-

macological studies are presented. These individual differences do

not disappear even when inbred genetically identical mouse strains

are used and molecular studies have confirmed the existence of

consistent individual differences even in genetically identical cell

lines maintained under identical conditions.

These facts suggest that the history of the individual patient may be

at least as important in determining the best clinical treatment for

that patient as the existing evidence on large heterogeneous clinical

patient samples. The implications of this for developing guidelines

and algorithms are discussed. The possible use of a new Bayes�Theorem based algorithm is proposed.

Keywords: individual differences, genetics, treatment, psychophar-

macology




39

Genetic studies in bipolar disorderM RietschelCentral Institute of Mental Health, Ruprecht-Karls-University of

Heidelberg, Mannheim, Germany

Introduction: Bipolar disorder (BD) is a severe mental illness. It is

characterized by recurrent episodes of mania and depression which

are often accompanied by behavioral and cognitive disturbances.

The etiology is complex, with genetic factors contributing around

80% to the variance. Prior to the recent introduction of genome-

wide association studies (GWAS), linkage and candidate gene

association studies were the only available approaches to unrav-

eling the genetic underpinnings of the disorder.

Methods: Seven GWAS of BD have been published at the time of

writing, and a large meta-analysis is currently underway and to

four of these studies we have contributed. Genome-wide significant

associations (p = 5 · 10-8) have been reported for variants

rs10994336 and rs1064395 in the ANK3- and the NCAN gene,

respectively. Another strong association finding (p = 7 · 10-8) has

been reported for rs1006737 in the CACNA1C gene (p = 7 · 10-8).

Results: We have now followed up our genome-wide significant

association finding for NCAN using a reverse phenotyping

approach, i.e. examining how patients carrying the risk allele differ

from non-risk allele carriers in terms of symptom dimensions. This

showed that NCAN influences the mania dimension. A refined

analysis showed that the association was mainly based on the

overactivity dimension.

Discussion: Thispresentationwill includebeside thediscussionof the

GWAS findings a brief overview of our other work, including a

description of our reverse phenotyping approach to neuroimaging

data, and our latest genome-wide significant finding in BD patients,

whichwasobtainedfromanassociationanalysisoffactordimensions.

Keywords: Genome-wide association studies, genome-wide signif-

icant findings in bipolar disorder, CACNA1C gene, ANK3 gene,

NCAN gene

40

Prediction of disease vulnerability andtreatment response in mood disorders:Personalized medicine in psychiatryC NemeroffUniversity of Miami Leonard M. Miller School of Medicine,

Department of Psychiatry and Behavioral Sciences, Miami, FL,

USA

The heterogeneity of complex diseases such as diabetes, cancer and

major psychiatric disorders has led to the inexorable realization that

these diagnostic entities are pathophysiologically heterogeneous. In

addition, vulnerability to all of these disorders are now known to be

regulatedbygene x environment interactions.Amajor component of

personalized medicine in psychiatry is concerned with the identifi-

cation of discrete endophenotypes of mood disorders with their own

unique pathophysiology. In the past several years considerable

progress has been made on both the identification of risk factors for

vulnerability tomood disorders and equally important, predictors of

treatment response/non-response. The former allows the identifica-

tion of ‘‘at risk’’ populations and offers an opportunity for a

preventative approach to psychopathology. The latter would mark-

edly alter the current trial and error approach to treatment of

patientswithmooddisorders.Results froma variety of studieswith a

focus on candidate genes and functional brain imaging, as well as

environmental factors such as child abuse and neglect, will be

reviewed. Predictors of responses to pharmacotherapy and psycho-

therapy will be described. Combinations of biological markers hold

great promise in predicting disease vulnerability and treatment

response in patients with mood disorders.

Keywords: personalized medicine, endophenotypes, genetics, brain

imaging, biomarkers

Symposium 5: Psychosocial Treatments forBipolar Disorder: Cross-Cultural Approaches

Chair: Sibel Cakir

41

Cross-Cultural insights into the assessmentand treatment of bipolar disorder

EA YoungstromDepartment of Psychology and Psychiatry, University of North

Carolina at Chapel Hill, NC, USA

Psychosocial treatments for bipolar disorder are gaining traction in

a number of countries. This symposium discusses cross-cultural

adaptations of psychoeducational treatments in South Korea,

Mexico, and Turkey. Elements of treatment that are common

across cultures will be discussed, as will hurdles to implementing

psychoeducation in different cultural settings.

Keywords: bipolar, psychoeducation, psychotherapy, psychoso-

cial, cross-cultural

42

Psychosocial approach to bipolar disorders:Developing a culture-specific modelS CakirIstanbul University, Istanbul Medical School, Psychiatry

Department, Mood Disorders Clinic, Istanbul, Turkey

Structured psychotherapeutic models have been shown to improve

clinical course and outcome in bipolar disorders. However some

shared elements the variety of models, adaptation difficulties to

different cultures, subtypes and different stages of the illness and

diverse needs of patients are obstacles to set up of a worldwide

standard model.

Following the review of the literature, group psychoeducation was

seem to be a first step for setting up a psychosocial approach in

Turkish Bipolar Patients in our Mood Disorders clinic at four


ª 2012 The Authors


years ago. We had difficulties for recruiting patients even for 6

sessions. The patients with good prognosis; good response to

prophylactic treatment, full medication adherence, regular follow-

up visits and less total number of episodes were more willing to

attend to group psychoeducation. We concluded that specific

subgroups of patients with bipolar disorders, suitable psychother-

apeutic tools, and timing of inception are crucial for setting up a

psychosocial approach for bipolar disorder. Alternative to group

psychoeducation, an individual psychoeducation was administered

afterwards. In the symposia the 4 years follow up (effectiveness on

relapse rates and other outcome measurements) of group psycho-

education, comparison of attitudes of patients for attending

individual and group psychoeducation will be presented. Finally

an inclusive psychosocial model for unmet needs will be presented.



43

The effect of group psychoeducation on theKorean patients with bipolar disorderS Wona, S Jeonga, H Job, HD Rima

aDepartment of Psychiatry, Kyungpook National University

Hospital, Daegu, South Korea, bDepartment of Psychiatry, Daedong

Menal Hospital, Daegu, South Korea

Objectives: Several previous studies have established the effect of

psychoeducation on patients with bipolar disorder. To date, studies

assessing the usefulness of psychoeducation in Korean patients are

lacking. This study was conducted to evaluate the efficacy of the

structured group psychoeducation on patients with bipolar disor-

der in Korea.

Method: This was a clinical trial on the efficacy of psychoeducation

in remitted DSM-IV bipolar I&II patients (n = 23) who were

compared with a group with similar characteristics (n = 46) who

did not receive psychoeducation. Follow-up phase comprised more

than 1 year during which all patients received pharmacotherapies

and supportive psychotherapies. Two groups� treatment compli-

ances were assessed at endpoint. Standardized insight assessments

were made in the psychoeducation group using Scale to Assess

Unawareness of Mental Disorder-short form at the baseline and

after the 10 sessions of psychoeducation were completed.

Results: At the endpoint, whereas only 48% of the patients who did

not receive psychoeducation were compliant, 87% of the subjects in

psychoeducation group were compliant to outpatient clinic sched-

ules (p < 0.01). SUMD scores were diminished significantly after

the subjects underwent group psychoeducation (p > 0.01).

Conclusion: Psychoeducation showed its efficacy in improving

insight and treatment compliance in patients with bipolar disorder

in Korea.

Keywords: bipolar disorder, psychoeducation, psychosocial treat-

ment

44

Psychosocial community approach for bipolarpatients from mexicoM Sanchez de CarmonaISBD Board Councilor and ISBD Advocacy Committee Co-chair,

Mexico City, Mexico

Mexico is a diverse Latin American country. Traditional values,

moral beliefs, and a nuclear paternalistic familial structure, specif-

ically mold the way bipolar disorders are perceived. Most Mexican

citizens live in the city where they were born, and they begin

independent life late into adulthood. Social stigma towards bipolar

disorder is the main factor that delays punctual psychiatric

treatment. The ISBD Mexican Chapter has developed a commu-

nity psychoeducative psychosocial approach directed to bipolar

patients and its families with adaptations to Mexican family

dynamics. Life mood charting and specific learning material have

been designed and adapted to meet the needs of Mexican society.

Cognitive logo-therapeutic techniques are applied by psychiatrists

and trained clinical psychologists to the stable bipolar patient and

patient and family support groups are strongly reinforced.



Symposium 6: Functional Consequences of RiskGenes for Bipolar Disorder

Chairs: Carrie Bearden, Carlos Lopez

45

The effect of CACNA1C rs1006737polymorphism on brain structure, function andconnectivity in BDS FrangouInstitute of Psychiatry, King’s College London, UK

Background: Large genome-wide association studies in bipolar

disorder (BD) have implicated a single nucleotide polymorphism

(SNP) in the CACNA1C gene (rs1006737, G to A), which encodes

for the voltage-dependent calcium (Ca2+) channel L-type, alpha

1c subunit. We undertook a number of studies to determine

whether the risk associated with the CACNA1C rs1006737 is

mediated through changes in brain structure, function and

connectivity particularly within networks involved in emotional

processing.

Methods: Anatomical (sMRI) and functional magnetic resonance

imaging (fMRI) data were acquired from 77 healthy adults and 41

euthymic patients with BD were genotyped for the CACNA1C

rs1006737 polymorphism. Participants performed an affect labeling

task (fearful, angry and sad facial expressions versus neutral

expressions). sMRI and fMRI data were analysed using Statistical

Parametric Mapping v.8 software (www.fil.ion.ucl.ac.uk/spm/soft-

ware/spm8) and effective connectivity within the facial affect

processing network was examined using Dynamic Causal Model-

ling (DCM).




Results: Analysis of the sMRI data revealed a diagnosis indepen-

dent increase in the volume of the right hypothalamus and right

amygdala in carriers of the risk allele. A diagnosis by genotype

interaction was noted for the volume of the putamen which was

increased in healthy but reduced in BD carriers of the risk allele.

During facial affect processing, architecture of the facial affect

processing network was preserved in patients but there was

evidence of significant main effects of genotype and of diagnosis

by genotype interactions in the strength and modulation of

network connectivity. Specifically, we found a diagnosis indepen-

dent increase in connectivity between visual cortical areas with the

fusiform gyrus (FG) and inferior frontal gyrus (IFG) in the risk

allele carriers; affective modulation of these connections decreased

in BD carriers and increased in healthy carriers.

Conclusions: Our data demonstrate that the CACNA1C rs1006737

polymorphism mediates the risk for BD through changes in brain

morphology and connectivity within regions involved in affect

processing.

46

Delineating the genetic architecture of bipolardisorder with neurocognitive, neuroimagingand transcriptional endophenotypesDC GlahnOlin Neuropsychiatric Research Center, Institute of Living, Hartford

Hospital and Department of Psychiatry, Yale University

Introduction: Risk for bipolar disorder appears to be associated

with multiple genes of relatively small effects. While we have made

recent progress delineating some of these risk genes, our under-

standing of the genetic architecture of bipolar disorder is still

incomplete. Endophenotypes, heritable traits that are genetically

correlated with disease liability, provide a complementary strategy

for discovering and characterizing bipolar risk genes. We recently

identified a set of neurocognitive endophenotypes for bipolar

disorder in large Latino pedigrees selected for a sibling pair

concordant for the illness. Here, we present recent findings that

extend this work in two ways. First, we examined the genetic

underpinnings of these endophenotypes in Latino individuals from

randomly selected extended families from the ‘‘Genetics of Brain

Structure and Function’’ (GOBSF) study. Second, we search for

additional neuroimaging and transcriptional endophenotypes for

bipolar disorder in a novel discordant sibling pair sample.

Methods: The GOBSF sample included 1342 Mexican-American

individuals from ~50 extended pedigrees. The average age of the

sample was 49.13 + 11.29 and 62% were female. Neurocognitive

measures of interest included the Digit Symbol Coding Task,

Letter-Number Span, CVLT learning, Object Delayed Response

Task, and Immediate and Delayed Penn Facial Memory. Subjects

were genotyped with an Illumina 1M SNP chip. Association

analyses were performed with SOLAR and included age, sex and

interactions and a population stratification measure as covariates.

In addition, genetic correlations between cognitive measures and

11,337 lymphocyte based transcriptional measures were performed.

The discordant sib-pair sample included 55 individuals with

remitted bipolar disorder, 53 of their siblings and 40 demograph-

ically matched healthy controls. FreeSurfer derived neuroanatom-

ical measures, track-based DTI white-matter measures and resting

state blood-oxygen-level-dependent (BOLD) measures acquired at

3T were compared between probands, siblings and controls.

Finally, those transcripts identified in the GOBSF sample were

examined in the discordant sib-pair sample.

Results: Four genome wide significant quantitative trait loci were

identified. Neurocognitive endophenotypes were genetically corre-

lated with zinc finger transcriptional. Individuals with bipolar

disorder showed reduced prefrontal and occipital cortical thickness

and reduced putamen volume, reduced superior longitudinal

fasciculus and thalamo-cortical FA and recued orbital prefrontal

and anterior cingulate connectivity from resting state data. In

contrast, unaffected siblings showed only reduced superior longi-

tudinal fasciculus FA and anterior cingulate connectivity.

Discussion: These data extend our understanding of the genetic

underpinning of neurocognitive endophenotypes for bipolar dis-

order and functional and structural connectivity makers of genetic

liability for the illness.

Keywords: Bipolar disorder, endophenotype, genetic, connectivity,

genome-wide association

47

Bipolar endophenotypes in a geneticallyisolated populationCE BeardenDepartments of Psychiatry and Biobehavioral Sciences and

Psychology, Semel Institute for Neuroscience and Human Behavior,

University of California, Los Angeles

Objective: Investigation of the genetic architecture of intermediate

traits associated with bipolar disorder may be a powerful strategy

for understanding the genetic basis of this illness. Applying this

strategy in rapidly growing genetically isolated populations offers

an exceptional opportunity for mapping disease-related loci.

Methods: Our multi-dimensional phenotyping approach includes

measures of gene expression, neuroimaging, neurocognition and

temperament, and circadian rhythm. Analyses to date include over

400 members of multi-generational pedigrees consisting of multiple

Bipolar I (BP-I) affected individuals and their unaffected relatives,

ascertained from two closely related genetically isolated popula-

tions, the Central Valley of Costa Rica and Antioquia, Colombia.

Statistical analyses of heritability and genetic correlations between

phenotypes (qG) were conducted using SOLAR.

Results: Virtually all of the 36 neuroanatomic phenotypes exam-

ined were significantly heritable, and more than half had herita-

bility estimates greater than 0.50, indicating that the majority of the

phenotypic variance is attributable to genetic sources. Genetic

correlation (qG) estimates indicate that structures within the same

anatomic lobe had higher estimates of common genetic sources of

variation, relative to more distant structures. The most heritable

actigraphy phenotypes were midpoint of sleep (h2 = 0.96) and

acrophase (0.80). Temperament measures- in particular, anxious

temperament, perceptual creativity, and delusion proneness - were

also significantly heritable. In the neurocognitive domain, verbal

abilities showed the highest heritability (h2 = 0.43).

Conclusions: The incorporation of a diverse array of endopheno-

types across physiologic levels holds particular promise for

unraveling the complex biologic processes underlying psychiatric

disorders. Analyses applying multivariate phenotypes to combined

genome-wide linkage and association analysis are now underway.

Keywords: heritability, intermediate trait, magnetic resonance

imaging, population isolate, circadian, pedigree


ª 2012 The Authors


Parallel 3: Lithium

Chairs: Simavi Vahip, Oscar Heeren

48

Lithium, still a major option in the managementof bipolar disorderRW LichtMood Disorders Research Unit, Aarhus University Hospital,

Risskov, Denmark

Background: After more than 50 years, lithium is still a main

treatment of bipolar disorder, even though it has not been

promoted by the pharmaceutical industry over the last decades.

During the recent years the evidence base on lithium for treatment

of bipolar disorder has been substantially increased by results from

a number of trials. Therefore, a review of this evidence is timely.

Methods: The efficacy of lithium as an acute treatment and as a

maintenance treatment of bipolar disorder was evaluated through a

review of the evidence, focusing on modern, randomized, parallel-

group designed trials. Additionally, the evidence was sought

translated into the use of lithium in clinical practice.

Results: As to the antimanic efficacy of lithium, modern parallel-

group designed trials have confirmed earlier positive findings.

However, due to lithium’s narrow therapeutic index requiring

blood monitoring and due to a relatively late onset of action, which

is related to the safety issues, lithium monotherapy generally has a

limited place in the acute treatment of more severe manic states.

For acute bipolar depression, there are conflicting results, in

particular due to recent industry-generated studies showing no

advantage of lithium over placebo. Recent long-term trials have

added substantially to the documentation of the long-term stabi-

lizing properties of lithium in bipolar disorder. In particular, it has

now been shown, that lithium is efficacious as maintenance

treatment independently of any acute response to the drug. It has

also been convincingly demonstrated that lithium not only prevents

mania, but also depression in bipolar disorder. It is still debated

whether lithium has a specific anti-suicidal effect beyond its

recurrence preventive effects.

Discussion: Lithium is still to be considered a main if not the main

mood stabilizer, at least for maintaining long-term stability in

patients with bipolar disorder. The potential risks of lithium should

be weighed up against its benefits and the fact that serious adverse

effects are usually avoidable, when treatment is properly managed

and monitored.

Keywords: bipolar disorder, treatment, lithium, review

49

Reasons to use lithium in bipolar disorders andobstacles in real worldS VahipAffective Disorders Unit-Ege University, Izmir Turkey

Lithium is the drug which had opened the era of modern

psychopharmacology. More than 60 years had passed since its

first use in bipolar patients. There is fairly enough evidence

supporting its antimanic, prophylactic and also -at least modest-

antidepressant properties. On the other hand there are many

difficulties and problems associated with lithium use. Side effects,

toxicity risk, drug interactions, relatively narrow therapeutic index,

and adherence problems are several of these difficulties. It is

obvious that these are patients� and clinicians� concerns which need

to be handled with special efforts. As in almost all treatments in

medicine, evaluation of risk-benefit ratio and individual tailoring of

the treatment is the basic and essential principle. However, in last

couple of decades, use of long-term lithium is rapidly decreasing in

the daily practice of many clinicians. Many factors might be

associated with this attitude. Some of them are related with

tolerability and side effect issues as mentioned above. However, it is

not limited with these issues. Launch of new drugs for bipolar

disorders might influence this attitude in many ways. Recent

ongoing rapid changes in health systems, locally and globally, also

have significant impact on these attitudes.

All these possible factors will be evaluated with the data collected

from patients and clinicians and also with the guidance of

literature. Perspectives from patients and clinicians might shed

light to the question of reasons for using lithium and obstacles

against its use.

Keywords: lithium, bipolar disorder, prophylaxis, clinicians� atti-tudes

50

Combination of lithium with atypicalantipsychotics for the long-term management ofbipolar disorderAC Altamura, B Dell�OssoUniversity of Milan, Fondazione IRCCS Ca Granda, Ospedale

Maggiore Policlinico, Milano, Italy

Bipolar Disorder (BD) is a chronic and disabling condition with a

dramatic impact on quality of life of patients and relatives. The

prevalence of the disorder is approximately 1–2.5% of the general

population and in recent years, numerous treatment options have

become available to clinicians for the management of BD. These

target the acute treatment of the index episode and the long-term

management of BD, the goal of which is represented by the

prevention of recurrences.

In addition to pioneering the acute and long-term treatment of BD,

Lithium is still considered among the gold-standard therapies of

the disorder, given its well-established properties of preventing

relapses and reduced suicide attempts. In addition, over the last

decade, Lithium has been evaluated in association with other

mood-stabilzers including anticonvulsants (e.g., valoproate) and

atypical antipsychotics (e.g., quetiapine, risperidone, olanzapine

and aripiprazole) (1,2). The possible superiority of combined

treatments vs monotherapies over the maintenance treatment of

BD has given positive and mixed results and is till object of debate.

Nevertheless, combination treatments might be advantageous

because of therapeutic synergy which may result in a more rapid

and robust response. Nevertheless, combinations may present

higher rates of side-effects and drug interactions that could be

limited by using lower dosages of each compound. With respect to




combination treatment for the long-term phase of BD, currently

the Food and Drug Administration has only approved Quetiapine

plus Lithium (or Valproate), despite being the use of other

combinations in clinical practice very common. In a naturalistic

setting with a follow-up of 4 years it was shown by our group that

the combined treatments with quetiapine plus lithium or sodium

valproate were more effective than monotherapies overall in

maintaining euthymia in a large sample of bipolar patients (3).

The presentation will provide the state of the art on the use of

combination therapies with Lithium and atypical antipsychotics in

BD according to recommendations of international treatment

guidelines (4,5) and metanalyses over the last years.

Keywords: bipolar disorder, long-term management, lithium, atyp-

ical antipsychotics

Symposium 7: Genomic and ClinicalPhenotypic Considerations in EvaluatingAntidepressant-Induced Mania to Individualizethe Treatment for Bipolar Depression

Chairs: Mark A. Frye, Shigenobu Kanba

51

Clinical correlates of antidepressant – inducedmaniaSL McElroya, MA Fryeb

aLindner Center of HOPE, Mason, Ohio, Department of Psychiatry

and Behavioral Neuroscience, University of Cincinnati College of

Medicine, Cincinnati, Ohio, bDepartment of Psychiatry &

Psychology, Mayo Clinic, Rochester, MN, USA

Introduction: Identifying demographic and clinical risk factors

associated with antidepressant-induced mania (AIM) may promote

individualized treatment strategies for bipolar depression.

Methods: Medline up to March 2011 was searched for key words

related to antidepressant-induced mania, including, bipolar, anti-

depressant, induced, mania, and switch.

Results: A number of demographic and clinical risk factors were

reported to be associated with antidepressant-induced mania.

These included tricyclic antidepressant liability, substance abuse

comorbidity, younger age, decreased TSH, rapid cycling, bipolar

I vs. II subtype, hyperthymic temperament, mixed depressive

symptoms, past number of manic episodes, absence of mood

stabilizer, female gender, and psychosis. Most of these factors

were found by studies that were single site, retrospective in

design, or small in sample size and inconsistently reported, but

several factors (mixed depressive symptoms, tricyclic type anti-

depressant, bipolar I vs. II subtype) were also found in larger,

controlled trials.

Discussion: Although further studies are needed, preliminary

research suggests tricyclic antidepressant type, mixed depressive

symptoms, and bipolar I versus II subtype may be the

more consistent factors associated with antidepressant-induced

mania.

Keywords: antidepressant-Induced Mania

52

A meta-analysis examining risk of switchfollowing treatment with antidepressants inpatients with bipolar depression.G MacQueena, M Sidorb

aDepartment of Psychiatry, University of Calgary, Calgary, AB,

Canada, bUniversity of Pittsburgh; Pittsburgh, PA, USA

Introduction: The role of antidepressants in the acute treatment of

bipolar depression remains a contentious issue. This systematic

review and meta-analyses reexamined the efficacy and safety of

antidepressant use for the acute treatment of bipolar depression.

Methods: EMBASE, MEDLINE, CINAHL, PsycINFO, and the

Cochrane Central Register of Controlled Trials databases were

searched using the medical subject heading terms: bipolar disorder,

bipolar depression, bipolar I disorder, bipolar II disorder, bipolar

III disorder, bipolar mania, cyclothymia, manic depressive psy-

chosis, mixed mania and depression, and rapid cycling and bipolar

disorder. Databases of trial registries were also searched for

unpublished trials, supplemented by hand searches of relevant

articles and review articles. Trials that compared acute (<16 wk)

antidepressant treatment with either an active drug or a placebo

comparator in adult bipolar patients, depressive phase were eligible

for inclusion. Main outcome measures were clinical response,

remission, and affective switch.

Results: Fifteen studies containing 2,373 patients were examined.

Antidepressants were not statistically superior to placebo or other

current standard treatment for bipolar depression. Antidepressants

were not associated with an increased risk of switch. Studies that

employed more sensitive criteria to define switch did report

elevated switch rates for antidepressants.

Discussion: Antidepressants did not appear to pose a significant

risk of switch in most subjects treated for an acute period, but

degree of risk was in part a function of how switch rates were

monitored and defined. The overall risk: benefit ratio of antide-

pressants in the treatment of bipolar depression does not appear to

be robust.

Keywords: bipolar, depression, antidepressants, switch, meta-anal-

ysis


ª 2012 The Authors


53

The clinical phenotype of antidepressant-induced mania: Previous methodologiclimitations and recommendations for futurestudiesMA Fryea, JM Biernackab

aDepartment of Psychiatry & Psychology, Rochester MN, USA,bDepartment of Health Sciences Research, Mayo Clinic, Rochester

MN, USA

Introduction: Identifying genetic risk factors associated with anti-

depressant induced mania (AIM) may enable individualized

treatment strategies for bipolar depression. This review and

meta-analysis of the serotonin transporter gene promoter poly-

morphism (5HTTLPR) and antidepressant induced mania

(AIM+) illustrates the potential of genomic research and the

challenges of phenotype assessment.

Methods: Medline up to November 2009 was searched for key

words bipolar, antidepressant, serotonin transporter, SLC6A4,

switch, and mania.

Results: Five studies have evaluated the SLC6A4 promoter poly-

morphism and AIM in adults (total n = 340 AIM+ cases,

n = 543 AIM- controls). Although a random effects meta-analysis

showed weak evidence of association of the S allele with AIM+

status, a test of heterogeneity indicated significant differences in

estimated genetic effects between studies.

Conclusion: The AIM+ pharmacogenomic studies are underpow-

ered and often do not control for important phenotype potential

confounders such as concurrent use of mood stabilizers, rapid

cycling, and time course of AIM+. While pharmacogenomic

studies have high potential clinical impact, rigorous phenotyping

will be critical for future success in utilizing pharmacogenomics in

the individualized treatment of bipolar depression.

Symposium 8: ISAD Session Biomarkers inMood Disorders: Integrative Analysis AcrossMolecular, Imaging and Clinical Domains

Chair: Sidney H. Kennedy

54

Biomarkers in mood disorders: What role mightgenes play?A YoungChair of Psychiatry, Director of the Centre for Mental Health,

Imperial College London

Mood Disorders comprise a diverse group of disorders which

present across the life span and are commonly comorbid with

physical ill health. Diagnostic systems are currently being reviewed

and recent evidence suggests that, for example, a ‘‘broader’’

diagnostic concept of Bipolar Disorders may be no less valid than

the narrow DSM version; these data have considerable implica-

tions for biomarker studies. Recently, a number of genes have been

identified which may be linked to bipolar disorder. In particular a

role for ANK3 and CACNA1C has been suggested in bipolar

disorder. Some work has also suggested that certain genetic

polymorphisms may moderate the effects of environmental stress.

The potential interactions between genes, environmental factors

and responses to drug treatment will be reviewed.

Keywords: bipolar disorder; depression; genes; drug treatments.

55

Biomarkers in mood disorders: Integratingneuroimaging and clinical markersSH KennedyPsychiatrist in Chief, University Health Network, Professor of

Psychiatry, University of Toronto, Canada

Neuroimaging offers a window into brain structure and function,

bridging the gap between the genomic and proteomic foundations

of mood disorders and their outward clinical manifestations.

Structural and functional imaging abnormalities have been found

in major depressive disorder (MDD) and bipolar disorder (BD). In

the treatment of mood disorders, clinical dimensions and func-

tional neuroimaging variables are potential biomarkers of response

to antidepressant monotherapy, cognitive behavior therapy, as well

as combination pharmacotherapy and neurostimulation. Prelimin-

ary evidence suggests that personality factors can predict antide-

pressant response (Quilty et al.., 2010). Neuroimaging methods can

also be used to effectively identify potential mediators of treatment

response (Konarski et al.., 2009). High resting metabolic rates in

the subcallosal cingulate area predict response to various pharma-

cotherapies, psychotherapy and neurostimulation in major depres-

sive disorder (Mayberg et al.., 1997). However, biomarkers from a

single modality generally have low effect size. Multi-modal studies

combining information from across clinical, molecular and imag-

ing domains are increasingly recognized as requirements for

building a biomarker algorithm with predictive utility. This

presentation will examine preliminary data on the potential use

of combined clinical and functional neuroimaging biomarkers as

part of an integrative analysis.

Keywords: depression, bipolar disorder, neuroimaging, clinical,

biomarkers

56

Plasma proteomics and High DimensionalBioinformatics: New tools for understandingthe mechanisms of depressive illness.KR EvansOntario Cancer Biomarker Network

There is evidence from numerous sources that levels of circulating

proteins have relevance to the manifestation of various CNS




diseases, however there have been few systematic, targeted

attempts to understand this relationship, primarily due to technical

challenges associated with proteomic research in blood. Unlike

‘‘hypothesis-free’’ approaches, Selected Reaction Monitoring Mass

Spectrometry (SRM-MS), allows researchers to select hundreds of

proteins which can then be measured within a single MS run in a

robust and reliable manner. Our team has recently completed a

series of studies in depressed patients vs health volunteers, as well

as treated vs untreated patients using our established workflow for

systematic profiling using SRM-MS. Our preliminary results reveal

that a high percentage of CNS-relevant proteins are not only

present in blood, but are differentially expressed in relation to

disease. However, these experiments produce large volumes of high

dimensional data that are difficult to understand using conven-

tional statistical approaches. To address this a number of sophis-

ticated mathematical modeling approaches were utilized, including

novel applications of dynamical systems theory, topology and

other techniques. These techniques can produce powerful classifiers

of response, but can also be used to stratify patient populations on

the basis of their biochemical profile rather than clinically

observable symptoms alone. Data will be presented from proteo-

mic investigations in several disease states that demonstrate that

grouping patients in this manner is not only clinically meaningful,

but has significant potential for identifying novel drug targets and

disease pathways.

Keywords: proteomics, depression, treatment response, bioinfor-

matics

57

Imaging central GABA and glutamateabnormalities in MDDGregor HaslerPsychiatric University Hospital Bern

The dramatic progress in safe and affordable molecular imaging

methods including magnetic resonance spectroscopy (MRS) and

positron emission tomography (PET) has the potential to identify

subtle abnormalities of neural structures and neurotransmitter

function that are potentially useful as biomarkers in mood

disorders. There is increasing evidence that major depressive

disorder (MDD) is associated with perturbations of the metabolism

of the major inhibitory neurotransmitters, gamma-amino butyric

acid (GABA). Data will be presented from a series of GABA MRS

studies which suggest that reduced cortical GABA concentration is

the most promising imaging endophenotype in MDD. Glutamate is

the major excitatory neurotransmitter in the brain, playing an

important role in neuronal plasticity, learning and memory. There

is exciting new evidence that MRS glutamate measures can be used

as a biomarker to neurobiologically differentiate between unipolar

and bipolar affective disorders. Recently, the metabotropic gluta-

mate receptor 5 (mGluR5) has been proposed as an attractive

target for discovery of novel therapeutic approaches against

depression. Data will be presented from a study combining PET

and [11C]ABP688 that binds to an allosteric site of the mGluR5

with high specificity, with a postmortem study using Western blot

method. The potential of mGluR5 binding as a biomarker in MDD

will be discussed.

Keywords: GABA, glutamate, neuroimaging, endophenotype

Parallel 4: ENBREC

Chair: Lars Vedel Kessing

58

Research networks for bipolar disorder: Whyand What For?E VietaBipolar Disorders Program, Hospital Clinic, University of

Barcelona, IDIBAPS, CIBERSAM, ENBREC, Barcelona,

Catalonia, Spain

Bipolar disorder is a multidimensional condition which requires

specific expertise for its management, education, and research. In

order to disseminate systematic clinical assessment and high quality

treatment protocols and to foster research to improve the

management of bipolar illness and to develop a better understand-

ing of the mechanisms underlying this complex condition, we have

developed a network of bipolar expert centre at a European level:

ENBREC (European Network of Bipolar Research Expert Cen-

tres, www.enbrec.eu). This network is also supported by the

European College of Neuropsychopharmacology Network Initia-

tive (ENI). Research networks such as ENBREC may help to

develop large multicenter studies that cannot be answered in single

site studies. They also promote education and expertise which has a

direct impact on quality of care. Before ENBREC, initiatives like

the Stanley Network and the STEP-BD project proved to be useful

to promote further knowledge in bipolar disorder. ENBREC is

currently conducting specific studies and plans to expand to several

more European countries.

Keywords: bipolar disorder, research, network, europe

59

Factors associated with age at onset of bipolardisorderM BauerDepartment of Psychiatry and Psychotherapy, University Hospital

Carl Gustav Carus, Technische Universitat Dresden, Germany

Introduction: Bipolar disorder may emerge during several decades

of life. Studies from many countries have reported three peaks in

the distribution of the age of onset, occurring at about ages 17, 26

and over 40. Differences in the distribution of the age of onset were

also reported among countries, although only limited data are

available from some regions of the world. Although bipolar

disorder has high heritability, the onset occurs during several

decades of life, suggesting that social and environmental factors

may have considerable influence on disease onset. This study

examined the association between the age of onset and sunlight at

the location of onset.


ª 2012 The Authors


Methods: Datawere obtained from2414 patientswith a diagnosis of

bipolar I disorder, according to DSM-IV criteria. Data were

collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4

degrees from the equator, including data from both hemispheres.

The age of onset and location of onset were obtained retrospectively,

from patient records and/or direct interviews. Solar insolation data,

or the amount of electromagnetic energy striking the surface of the

earth,were obtained from theNASASurfaceMeteorology andSolar

Energy (SSE) database for each location of onset.

Results: The larger the springtime maximum monthly increase in

solar insolation at the location of onset, the younger the age of

onset (coefficient = -4.724, 95% CI, )8.124 to )1.323, p = 0.006),

controlling for each country’s median age. No relationships were

found between the age of onset and latitude, yearly total solar

insolation, and the maximum monthly decrease in solar insolation.

The largest maximum monthly increases in solar insolation

occurred in diverse environments, including Norway, arid areas

in California, and Chile.

Discussion: Sunlight has a broad impact on human life. The findings

of this study suggest that environmental variation in the size of the

maximum monthly increase in solar insolation in springtime may

have an important influence on the age of onset of bipolar disorder.

Keywords: age at onset, environmental factors, sunlight, bipolar

disorder

Keynote 4: WPA Address

Chair: Levent Kuey

60

Depression among women's adolescents: AWPA concernP RuizProfessor & Executive Vice Chair, Department of Psychiatry &

Behavioral Sciences, University of Miami Miller School of Medicine,

Miami, Florida, USA

Despite abundant access to birth control measures, the United

States has one of the highest rates of adolescent pregnancy in the

Western hemisphere, and 10% of women become pregnant during

their high school years. In this regard, adolescent pregnancy is

more prevalent among black adolescents (27.7%) and Native

American adolescents (20%). Also, it is more prevalent among

lower socioeconomic groups and in families with a highly chaotic

environment. It is not surprising, therefore, to find high rates of

depression among women that are exposed to these types of

stressors and environments.

From a clinical point of view, mood disorders among pregnant

women are quite common and can also manifest themselves in

many different ways; for instance, in the form of ‘‘baby blues’’, or

as a major depression or recurrent depression, or clear manic

episodes among others. In this regard, post-partum depression is

very common as well. Each of these clinical possibilities and/or

manifestations needs to be carefully evaluated, assessed, treated

and followed up. These depressive episodes can also take place

during different stages of the pregnancy and, thus, can have

potentially serious negative consequences due to the medications

that can be used to manage these depressive episodes.

In this context, we will examine all of the most relevant and critical

issues related to depression during pregnancy.

Educational Objectives: At the end of this presentation, the

participants should be able to:

Assess depression manifestations during pregnancy.

Appropriately treat depression from a psychopharmacological

point of view among depressed pregnant women.

Implement appropriate psychotherapeutic measures with pregnant

women who suffer from depression.




Core Symposium 5: Neuroimaging andNeurocognition

Chairs: Sophia Frangou, Stephen Strakowski

61

Examination of the predictive value of structuralMR scans in bipolar disorder: a patternclassification approachS Frangouc, V Rocha-Regob,c, AF Marquandb, J Mourao-Mirandab,e,J Jogiaa, A Simmonsb,c,d

aSection of Neurobiology of Psychosis, Department of Psychosis

Studies, Institute of Psychiatry, King’s College London, UK,bDepartment of Neuroimaging, King’s College London, Institute of

Psychiatry, UK, cNIHR Biomedical Research Centre for Mental

Health at South London and Maudsley NHS; Foundation Trust and

Institute of Psychiatry, King’s College London, UK, dMRC Centre

for Neurodegeneration Research, Institute of Psychiatry, King’s

College London, UK, eComputer Science Department, Centre for

Computational Statistics and Machine Learning, University College

London, UK

Background: Although Bipolar Disorder (BD) is amongst the

leading causes of disability worldwide delays in accurate diagnosis

are common and typically range between 5–10 years. Neuroimag-

ing studies have established that BD is reliably associated with

spatially distributed neuroanatomical abnormalities but the trans-

lational potential of this information has not been realized.

However, recent advances in pattern recognition techniques

represent a major opportunity for bridging the gap between

neuroscience and clinical practice in BD. In this study, we

evaluated the utility Gaussian Process Classifiers (GPCs), a pattern

recognition technique, as a diagnostic aid for BD using structural

magnetic resonance imaging (sMRI) data.

Methods: GPCs were applied to sMRI data from 26 individuals

with BD and 26 healthy age, sex and IQ matched controls using

Results: Classification accuracy for gray matter was 73% (sensi-

tivity 69%, specificity 77%) and 69% for white matter (sensitivity

69%, specificity 69%). Spatially distributed networks discriminat-

ing between bipolar and controls in the gray matter included the

right frontal gyrus, right lingual gyrus, right claustrum/insula, the

right cerebellum, left superior temporal gyrus, left inferior parietal

lobule, left claustrum/insula, and left cingulate gyrus. White matter

discriminative regions were identified within the left inferior frontal

gyrus, left postcentral gyrus, the left cingulate gyrus and, right

subgyral temporal gyrus.

Conclusions: BD disorder patients can be identified on an individ-

ual basis by assessing the pattern of sMRI changes. The observed

overlap between discriminative networks and the regions impli-

cated in the pathophysiology of BD supports the biological

plausibility of the classifier.

Keywords: neuroimaging, sMRI, pattern recognition

62

ISBD neuroimaging task force reportSM StrakowskiDepartment of Psychiatry & Behavioral Neuroscience, University of

Cincinnati College of Medicine, Cincinnati, OH

Background: he ISBD Neuroimaging Task Force met in December

2010 with two goals: 1) review research from leading bipolar

disorder neuroimaging groups represented at the meeting; and 2)

develop consensus around a functional neuroanatomy for bipolar I

disorder.

Methods: The task force started with the clinical assumption that

bipolar disorder is a primary mood disorder; i.e., that neural

systems most likely to underlie the condition involve those that

modulate mood. Two ventral prefrontal networks appear to

modulate emotional behavior. These networks serve as likely

substrates for the functional neuroanatomy of bipolar disorder.

Results: Neuroimaging studies suggest abnormalities in key com-

ponents of these networks occur in bipolar disorder. For example,

excessive amygdala activation in bipolar individuals during mania

compared with healthy subjects is commonly reported. Abnormal

amygdala activation has also been observed in bipolar disorder

during other mood states. Similarly, abnormal ventral prefrontal

activation is commonly observed and often occurs concurrently

with amygdala over-activation. Moreover, disrupted functional

connectivity between amygdala and ventral prefrontal cortex has

been reported during mania. These findings suggest that loss of

prefrontal modulation of amygdala may underlie development of

mood symptoms in bipolar disorder. Disruptions in white matter

connections between ventral prefrontal cortex and amygdala

provide a structural basis for these functional observations.

Bipolar disorder typically begins in adolescence. Recently, Bitter et

al. (2011) found that new-onset adolescent bipolar subjects did not

exhibit amygdala growth that was seen in healthy adolescents and

adolescents with ADHD. However, baseline volumes were the

same, suggesting that amygdala developmental abnormalities occur

with illness progression, rather than at onset. In contrast, white

matter abnormalities appear to precede onset of bipolar illness as

observed in studies of at-risk children.

Conclusions: These data suggest a model of bipolar disorder in

which abnormalities within ventral prefrontal networks lead to

expression of bipolar disorder. Disruptions in regional white

matter connectivity may precede illness onset, representing a

potential vulnerability marker for bipolar illness.

Keywords: neuroimaging, fMRI, task force


ª 2012 The Authors


63

Imaging genetic risk in bipolar disorderAM McIntoshDivision of Psychiatry, University of Edinburgh, Edinburgh, UK

Background: Bipolar disorder (BD) is associated with changes in

brain structure, connectivity, function and cognition that may be

related to its underlying aetiology. However, prospective studies of

unaffected at risk groups are needed in order to know if these

findings are related to its genetic aetiology and if they could be used

for risk-stratification.

Methods: In a prospective cohort study of individuals at high or

low risk of bipolar disorder (the Scottish Bipolar Family Study), we

selected unaffected, unmedicated individuals at high or low genetic

isk on the basis of the presence of an affected close relative. All

participants have undergone baseline and –year follow-up assess-

ments separated by an interval of 2 years. Subjects were between 15

and 25 years of age at study entry.

Results: Individuals at high genetic risk of bipolar disorder showed

widespread reductions in brain white matter connectivity and over-

activation of the amygdala.Widespread cognitive impairments were

conspicuously absent, although an impairment in processing speed

was found in high risk individuals. These findings were related to

depressive symptoms or cyclothymic temperament, behaviors com-

monly associated with increased risk of bipolar disorder.

Discussion: Individuals at high genetic risk of bipolar disorder

have reductions in brain connectivity, impairments in processing

speed and increases in amygdala activation that are likely to be

related to its largely genetic aetiology. Further rounds of assess-

ment from the same cohort will reveal if these findings predict the

emergence of clinical illness.

Conclusion: Impaired white matter connectivity and increased

activity of the amygdala may partly mediate the effects of a family

history of bipolar disorder on increased genetic risk.

Keywords: bipolar disorder, risk, cohort

64

Imaging oxidative stress cascade in bipolardisorderLN YathamProfessor of Psychiatry, UBC Department of Psychiatry, The

University of British Columbia

It is well known that increased dopamine levels are an important

source of oxidative stress in the brain, due to oxidative metabolism

of dopamine. This presentation will review brain imaging studies

that assessed oxidative stress cascade in bipolar disorder.

Neurobiological studies of bipolar disorder (BD) over the past

40 years have implicated excessive dopaminergic neurotransmis-

sion in mania and our brain imaging program using Positron

Emission Tomography (PET) has provided further insights into

precise alterations in dopaminergic system in BD. However,

dopamine hyperactivity hypothesis alone is insufficient to fully

explain the complex clinical manifestations as well as neurobio-

logical findings in BD such as cognitive impairments and reduc-

tions in brain volumes etc. More recently, several investigators

including our own group have begun investigating the role of

mitochondrial dysfunction and oxidative stress in the pathophys-

iology of BD.

Indeed, a growing body of evidence suggests that patients with BD

have oxidative damage. A meta-analysis conducted by our group of

studies of oxidative markers in BD patients indicated increased

levels of a free radical nitric oxide (NO) as well as increased lipid

peroxodation as indicated by elevated levels of Thiobarbituric acid

reactive substances (TBARS). We will present MRI data showing

some changes in brain grey matter concentration and SWI studies

that assessed brain iron levels. This presentation will suggest that

increased dopamine hyperactivity might be responsible for oxida-

tive stress and mitochondrial dysfunction reported in BD.

Keywords: bipolar disorder, brain imaging, oxidative stress

Core Symposium 6: Meeting the Needs of OurPatients through Advocacy: Cross-culturalSimilarities and Differences

Chairs: Kyooseob Ha, Lars Haggstrom

65

Challenging the stigma in bipolar disordersManuel Sanchez de CarmonaISBD MEXICO

Stigma is the main contributing factor to the burden of disease that

bipolar disorder accounts. The origins of social stigma towards

bipolar disorders reside in negative stereotypes and erroneous

perceptions of mental illness. Ignorance, inaccurate portrayals of

the disorder in media and job discrimination are some of the

factors that contribute to the development of stigma.

The individual who receives his diagnosis has to deal with the

acceptance of the disorder, learn all the clinical relevant issues for

its proper treatment and understand the social consequences that

may arise. Stigma begins the patient self perception of having

bipolar disorder. It is fundamental to work in different levels to

achieve a successful stigma reduction.

Besides formal psycho education, professionals should carefully

address and help the patient struggle with stigma in a personal,

family and social level. One of the main objectives of the ISBD

Advocacy Committee is to encourage programs that may increase

population awareness of bipolar disorders. This may be achieved




through establishing contact with different sectors of society:

patients, families, caregivers, advocacy and support groups,

professional health workers and government health officials.

Keywords: bipolar stigma, community awareness, advocacy

groups.

66

Where do bipolar support groups fail? Lessonsfrom turkeyT OrhanIndustrial Engineer, Member of the Board, Lithium Association,

Izmir, Turkey

Although there is awhole rangeof advocacygroups, a typicalBipolar

Support Group (BSG) includes patients and their families. Profes-

sionals like psychiatrists and psychologists almost always take active

roles in such groups either as members or counselors. Themission of

thesegroupsis toprovidemeansforthewell-beingofpatientsandhelp

their families to better understand and cope with the illness and with

the bipolar individual through the experience of others.

While families have always been proactive in founding such

associations, bipolar patients are not so keen on participating in

BSGs. This is because bipolar patients generally feel as if nothing

would help them during their lows, and that they would not be

bothered to spare time for advocacy groups when in their highs.

Therefore, BSGs should aim to support families, not patients.

What patients need is a doctor’s professional support, proper

medication, and ample amount of patience. It is the families who

are in constant pain, and in need of support through advocacy

efforts.

Keywords: bipolar support groups, families in pain, advocacy

groups

67

International issues in patient advocacyA Doederleina, C Beckmanna, L Jewella, T Orhanb,M Sanchez de Carmonac

aDepression and Bipolar Support Alliance, Chicago, IL, United

States, bBagımsız Yonetim Danısmanlıgı Profesyonel, Turkey,cInternational Society of Bipolar Disorders Mexico, Mexico

Background: The US patient advocacy movement crystallized in

the middle of the twentieth century as overall improvement in

treatments for people living with psychiatric diagnoses coincided

with concerted efforts to form patient-led and/or patient-focused

non-government organizations. Internationally, patient-driven

efforts have progressed to varying degrees, from emerging advo-

cacy leaders such as Brazil and Mexico to fledgling efforts in

countries like India and Russia. The US-based Depression and

Bipolar Support Alliance (DBSA) has been a leader in the area of

patient advocacy among people living with depressive conditions.

In DBSA’s experience, peer support can be a platform of

empowerment for patients� self-advocacy, which can in turn lead

to advocacy for mental health issues in general.

Discussion: A coalition of leading international patient advocates,

policymakers, and clinicians has an important opportunity to

continue to advance advocacy efforts within more entrenched

structures, while at the same time educating and helping to

mobilize patient groups within countries where the need is acute yet

the support and understanding of advocacy are nascent. We project

that there may be universal efficacy of a peer support group model

in increasing and maintaining mental health. With this session, we

aim to outline a plan for determining how best to implement peer

support for mood disorders in various cultures and countries. An

exploration of best practices among existing advocacy organiza-

tions will precede an open forum to delineate and examine the

barriers to and opportunities for patient advocacy within the

international community.

Conclusion: The ultimate goal of a dialogue regarding interna-

tional patient advocacy is to identify and develop action steps for

the key issues that must be addressed within various regions of the

globe. Peer support, which can be responsive to the needs and

concerns of diverse populations, can be a universal tool for both

advocacy and wellness.

Keywords: advocacy, patients, consumers, peer support

* Abstracts 4 and 36 have been withdrawn as the authors were not

able to attend the conference.


ª 2012 The Authors


keynotes, core symposia, symposia and parallels

Documents