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Keywords:

  • bipolar disorder;
  • early intervention;
  • early recognition;
  • prevention;
  • psychotherapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Aim

Accumulating data show that patients with bipolar disorder (BD) experience substantial symptomatology months or years before full manifestation. Based on the need for early preventive interventions in BD as well as data suggesting effectiveness of psychotherapeutic interventions for BD, we aimed to review the evidence for psychotherapeutic treatments in help-seeking individuals considered at risk for BD (At-Risk-BD).

Methods

Searching PubMed and PsycINFO, clinical trial registries and recently published systematic reviews, a systematic review was performed of psychoeducational and psychotherapeutic intervention studies in At-Risk-BD individuals.

Results

Only three completed studies were identified, two of which were randomized trials (n = 77) and one was an open pilot study (n = 13). Two ongoing studies (projected n = 150 and n = 100, respectively) were found in trial registries. The available evidence suggests potential effectiveness of multi-family psychoeducational psychotherapy and family-focussed therapy for symptom reduction and prevention of BD conversion.

Conclusions

Psychotherapeutic treatments are a reasonable starting point for At-Risk-BD subjects when symptom severity, distress and impairment are sufficiently significant to initiate treatment. Ongoing studies will further clarify the effectiveness and timing of psychotherapeutic interventions for At-Risk-BD individuals and whether or not they should be given alone or in conjunction with other treatments. Large multi-site studies with standardized procedures/manuals are needed to advance the field.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Accumulating data from retrospective[1-4] and prospective,[5-8] observational studies show that patients with bipolar disorder (BD) experience substantial symptomatology (e.g. mood swings, specific sleep disturbances, symptoms of anxiety/worries or subthreshold depressive or hypomanic symptoms) months or even years before full manifestation of the disorder.

Additionally, there is a known increased risk for the development of BD in individuals with a positive family history for the disorder[6, 8-10] and a confirmed family history is the most robust and reliable risk factor for development of the illness.[11] In offspring of parents with BD, there is independently replicated evidence that symptoms of anxiety/worries and anxiety disorders, respectively, are an antecedent to subsequent mood episodes.[7, 12-14] Furthermore, there are hints for a heightened risk in subgroups of individuals with a history of attention deficit hyperactivity disorder symptoms,[15, 16] substance misuse[17, 18] and stressful life events (with interaction by timing[19]). Recently, structured instruments have been developed to map potential risk factors and symptoms, quantify the risk, as much as currently possible and evaluate the predictive value for conversion to full threshold illness onset prospectively (e.g. Bipolar Prodrome Symptom Scale-Prospective (BPSS-P),[20] EPIbipolar[21] and Bipolar at Risk criteria from Bechdolf et al.[22]

Despite many uncertainties about risk constellations and symptomatology in these early stages of potentially developing BD, many adolescents and young adults seek help and advice in counselling services, early recognition centres or with outpatient psychiatrists or psychologists. Therefore, with the present article, we aimed at reviewing the evidence of treatment options most useful for adolescents and young adults that are considered to be at high risk for the development of BD. We explicitly cover adolescents and young adults because two thirds of patients with BD suffer their first symptoms before the age of 19 and 80% before the age of 25[1, 23] with a mean of 17.5 years for the manifestation of the disorder.[24]

At time of the first clinical contact, most help seekers already suffer substantially from symptoms, leading to educational, vocational and social impairments. The accumulation of dysfunction and disability prior to the first mental health contact is probably due to high perceived barriers to appropriate care, despite increasing attempts to provide low-threshold services, which may not uniformly be available either.[25, 26] As adolescence and young adulthood is a vulnerable phase for individual development, negative consequences of emerging BD can already negatively affect the chances for further adequate individual maturation. However, based on theoretical considerations and early clinical data, there is legitimate hope that with early identification and intervention, one might be able to not only decrease current symptomatology, but also be able to postpone the manifestation of the disorder, decrease the disease severity or, ideally, even fully prevent BD illness manifestation.[21, 27-39]

Choosing the appropriate interventions in each individual case always requires the careful weighing of benefits and risks. The use of psychoeducational and psychotherapeutic interventions has a lot of appeal as a first step in often ill-defined and lower severity presentations because the early symptoms (i.e. mood swings, impairment in social interactions and disruption of diurnal rhythm) could be especially responsive to psychotherapy. Psychotherapeutic interventions have an exceptionally favourable benefit/risk ratio and are therefore more acceptable to young patients and their families than pharmacologic treatments. Moreover, previously employed pharmacologic interventions in at risk for BD (At-Risk-BD) individuals have not been more successful compared to placebo (although often, sample sizes were small) and carry the risk of adverse effects (lithium,[40] divalproex[41]). However, some data suggest that high-risk offspring can be stabilized early in the course on monotherapy with mood-stabilizing agents and that response may be predicted by prior efficacy in family members and by the clinical course of the parent.[42] However, as conversion rates to bipolar disorder type I even after 12 years of follow-up have been as low as 3%,[8] it is hard to judge the true value of these early intervention in the absence of a randomized control group. In this context, it is very important to understand whether timely psychotherapeutic interventions (individual, group or family based) are effective in treating early antecedent symptoms and, perhaps, even in delaying or preventing full threshold illness onset and whether or not psychotherapies should be offered in conjunction with other interventions. The goal of this systematic review was to determine what effective options clinicians have when dealing with symptomatic high-risk individuals – in order to be able to help with the least potential for harm. Therefore, we aimed to critically review the emerging evidence for psychoeducational and psychotherapeutic interventions for individuals considered at risk for BD and to discuss it in the aforementioned mentioned context.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We conducted a systematic literature search, for manuscripts published in English or German, using PubMed and PsycINFO from database inception until March 2013 for psychoeducational and psychotherapeutic intervention studies in individuals considered at-risk for BD. We used the following search terms: (‘bipolar disorder’ or ‘mania’ or ‘manic’) and (‘risk’ or ‘prodrome’) and (‘psychoeducation*’ or ‘psychotherapy*’ or ‘family-focussed treatment’ or ‘interpersonal therapy’ or ‘social rhythm therapy’ or ‘family therapy’ or ‘group therapy’ or ‘cognitive’ or ‘behavioural’ or ‘behavioral’ or ‘stress management’ or ‘relaxation’ or ‘self help’ or ‘counselling’ or ‘self-monitoring’ or ‘self monitoring’). Titles and abstracts were scanned for relevance. Full texts were ordered in case of uncertainty to maximize sensitivity. Reference lists of retrieved systematic reviews were checked. All full texts were checked for eligibility. Only relevant clinical studies were included: abstracts, pooled analyses, editorials, reviews, case reports, observational studies and unpublished reports were excluded. In addition, we hand-searched reference lists of identified articles and pertinent reviews for additional studies.

All studies that described methods for the definition of at-risk states for BD and employed a non-pharmacological intervention, independent of randomization or blinding status were eligible for this review.

Published intervention studies with the terms ‘risk’ or ‘prodrome’ were evaluated, the respective definition of ‘at-risk for BD’ is reported from the included trials, no a priori definition was formulated. As mentioned in the introduction, we explicitly wanted to focus on adolescents and young adults; however, we also considered studies in (pre)pubertal children.

Furthermore, clinical trials registries (clinicaltrials.gov of the US National Institutes of Health and the WHO International Clinical Trials Registry Platform (ICTRP)) were searched for ongoing trials.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Psychotherapeutic interventions in individuals at-risk for BD: published studies

The systematic review yielded 1327 hits, with one being a duplicate. 1319 hits could be excluded based on the information in the title or abstract. The full texts of seven hits were critically reviewed,[37, 43-48] leading to exclusion of another four articles because these were only reviews or comments and no new original data were included. Only three studies were eligible for the review, an exploratory analysis from a controlled study of multi-family psychoeducational psychotherapy from the group of Fristad and colleagues,[44] an open, uncontrolled feasibility study of family-focussed therapy[43] and the subsequent randomized controlled study of the same group[47] (Table 1).

Table 1. Published studies of psychotherapeutic interventions in subjects at risk for bipolar disorder
AuthorDesign/durationnMean age (years) [range]At-risk definitionInterventionControlMajor results
  1. a

    SD, as range was not mentioned in publication.

  2. TAU, treatment as usual.

Nadkarni and Fristad 2010[44]

Controlled, (total sample randomized, post-hoc analysis of a subgroup)

Intervention 8 weeks

Follow-up 12 months for comparison intervention versus control

3710.2 [8–11]Depression spectrum disorder with (n = 37) or without (n = 13) additional transient manic symptoms (manic-like symptoms with insufficient duration or number to warrant a diagnosis of BD spectrum disorder, including standardized criteria for BD-NOS 50)

Multi-family psychoeducational psychotherapy (MFPE) (additionally to TAU)

n = 17

1-year wait list (additionally to TAU)

n = 20

Trend for lower conversion rate to BD spectrum disorder with MFPE compared to 1-year wait list at 12 months
Miklowitz et al. 2011[43] (NCT00943085)

Uncontrolled, open

Intervention 12 sessions plus monthly booster sessions up to 12th month

Follow-up 12 months

Recruitment period: 01/09/07–31/08/08

1313.4 [2.7a]
  • Parent with bipolar I or II disorder
  • Major depressive disorder, cyclothymic disorder or BD-NOS (DSM-IV)
  • Active mood symptoms in the past month

Family-focussed therapy adapted for youth at high risk for bipolar disorders (FFT-HR) (additionally to TAU)

n = 13

Significant improvement in depression, hypomania and psychosocial functioning at 12 months compared to baseline
Miklowitz et al. 2013[47] (NCT00943085)

Randomized, controlled, rater-blind

Intervention 12 sessions

Follow-up 12 months

Recruitment period: 06/2008–08/2010

4012.3 [9–17]
  • First-degree relative with bipolar I or II disorder
  • Major depressive disorder, cyclothymic disorder or BD-NOS (DSM-IV-TR)
  • Active mood symptoms in the past 2 weeks

Family-focussed therapy adapted for youth at high risk for bipolar disorders (FFT-HR) (additionally to TAU)

n = 21

1–2 educational sessions (EC) (additionally to TAU)

n = 19

Significantly shorter time to recovery over 12 months with FFT-HR compared to EC

In an exploratory analysis[44] from a controlled study of multi-family psychoeducational psychotherapy,[49] 50 of 165 children with mood disorders fulfilled the diagnosis of depression-spectrum disorder with or without additional transient manic symptoms (37 and 13, respectively, mean age 10.1 ± 1.3 years and 10.4 ± 1.4 years).[44] Transient manic symptoms were defined as manic-like symptoms with insufficient duration or number to warrant a diagnosis of BD-spectrum disorder, including standardized criteria for BD-not otherwise specified (NOS).[50] The intervention tested versus waiting list consisted of 8 weekly, 90-min-long group sessions for parents and children (separately, but with joint beginning and ending). Here, psychoeducation, social support and skills development were emphasized based on cognitive behavioural and family systems interventions. Both in the intervention and wait list condition, additional usual treatment, including medications, was permitted. Over the 18 months course of the study, 12 (32.4%) of the 37 children with depression-spectrum disorder with additional transient manic symptoms converted to BD-spectrum disorder (3 to BD-I, 5 to BD-II, 3 to BD-NOS and one to substance-induced mood disorder with manic features). Of the 11 patients who had converted until month 12, only 2 (11.8%) came out of the 17 patients who had been randomized to multi-family psychoeducational psychotherapy, compared to 9 (45.0%) out of the 20 subjects who had been randomized to the 1 year waiting list group (intention-to-treat: P = 0.07). Although this was only a trend-level finding, the resultant number-needed-to-treat of 3 suggests a large effect size for the prevention of BD-spectrum outcomes.[44]

In the open, uncontrolled, rater-blind feasibility study, family-focussed treatment (FFT) adapted for youth at high-risk for BDs (FFT-HR) was provided. The 13 included children (mean age: 13.4 ± 2.7 years) had a parent with BD-I or II and met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depressive disorder, cyclothymic disorder or BD-NOS, with active mood symptoms in the past month. FFT-HR sessions consisted of psychoeducation, communication enhancement training and problem-solving skills training (four sessions each). Eleven children participated in at least 9 of the 12 sessions over 4 months with their parents, and all but three received psychotropic medications, mostly initiated before study entry (including antidepressants, antipsychotics, mood stabilizers and stimulants). Three of the children additionally continued individual psychotherapy. Eight families used the offered monthly booster sessions after the 12-session intervention phase. Over the first year, participants showed significant improvements in depression, hypomania and psychosocial functioning (P = 0.013 to P = 0.0001).[43]

In the subsequent randomized, rater-blind controlled study,[47] 40 youth (mean age 12.3 ± 2.8 years) at high risk for BDs were randomized to FFT-HR (n = 21) or to education control (EC, n = 19). All had a first-degree relative with BD-I or II and met DSM-IV-TR criteria for major depressive disorder, cyclothymic disorder or BD-NOS, with activemood symptoms in the past 2 weeks. 17/21 families attended at least 10 of the 12 FFT-HR sessions over 4 months, some used up to six additional crisis sessions. 18/19 families attended at least one of the maximally two offered education sessions (EC). In addition, as needed crisis sessions were offered. All subjects were offered 12 months follow-up; the mean follow-up time was 45 weeks in both groups. Regarding the primary outcome, time to recovery was significantly shorter in subjects of the FFT-HR group compared to the EC group (13.0 ± SE 2.9 weeks vs. 21.3 ± SE 4.2 weeks, P = 0.022; HR = 2.69, P = 0.047; n = 32 in the analysis who were not remitted at baseline). In subjects with subthreshold (n = 20) or syndromal (n = 9) depressive syndromes at baseline, FFT-HR led to a faster recovery from depressed mood compared to EC (9.2 ± SE 3.0 weeks vs. 21.4 ± SE 4.1 weeks, P = 0.006; HR=2.63, P = 0.006). Over the 1 year follow-up, youth with FFT-HR spent significantly more weeks in remission compared to EC (26.8 vs. 19.5 weeks, P < 0.001). At study entry, 60% of subjects received at least one psychotropic drug (including antidepressants, antipsychotics, mood stabilizers and stimulants). Changes in medication regimen were rare over the time of the study and not related to treatment group.

Psychotherapeutic interventions in individuals at-risk for BD: ongoing studies

In addition to the three published studies, two controlled studies were found searching the clinical trials registries that are underway and that aim to further clarify whether psychotherapeutic interventions can decrease symptomatology, preserve psychosocial function and postpone and/or even prevent conversion to manifest BD (Table 2). Regarding FFT-HR, the group of Miklowitz and colleagues started another randomized, rater-blind controlled study in October 2011, now in a multi-centre approach to increase the sample size and allow for a longer follow-up time (http://www.clinicaltrials.gov; NCT01483391). The study targets to include 150 children aged 9–17 years old, again with a parent with BD-I or II meeting DSM-IV criteria for major depressive disorder or BD-NOS, with active mood symptoms in the past weeks. Participants are randomly assigned to receive one of two treatments for 4 months each: FFT-HR (intervention) or enhanced care (active control condition). Participants receiving FFT-HR complete 12 therapy sessions (content as described above). Participants receiving enhanced care have three sessions, which involve the youth and all family members. After the acute, 4-month intervention period, follow-up assessments will be conducted every 4 months in the first year and 6-monthly during the remainder of the 2–4-year follow-up period. The primary outcome is change in symptom severity, secondary end-points are onset of a mixed or (hypo)manic episode, psychosocial functioning and mental health service use. Estimated primary completion date of the study is September 2017.

Table 2. Ongoing studies of psychotherapeutic interventions in subjects at risk for bipolar disorder
AuthorDesign/durationnMean age [range]At-risk definitionInterventionControlMajor results
  1. a

    Targeted number of patients.

Miklowitz et al. (http://www.clinicaltrials.gov; NCT01483391)

Randomized, controlled, rater-blind

Intervention 16 weeks

Follow-up 24–48 months

Start: 10/2011

150a[9–17]
  • Parent with bipolar I or II disorder
  • Major depressive disorder or bipolar disorder NOS (DSM IV)
  • Active mood symptoms in the past weeks

Family-focussed therapy (FFT)

target n = 75

Enhanced care

target n = 75

Not available
Pfennig et al. (http://apps.who.int/trialsearch/default.aspx, identifier: DRKS00000444)

Randomized, controlled, patient-, rater- and statistician-blind

Intervention 14 weeks,

Follow-up 18 months

Start: 10/2010

100a[15–30]
  • Positive family history of affective or schizoaffective disorder (first- or second-degree relative)
  • Reduction in psychosocial functioning (last 12 months compared to before)
  • Affective symptomatology (subthreshold mania and/or at least subthreshold depression and/or cyclothymic features)

Early cognitive behavioural group therapy

target n = 50

Unstructured group sessions

target n = 50

Not available

The second ongoing study investigates the utility of cognitive behavioural therapy (CBT) for individuals considered at-risk for BD. This is a multi-centre, randomized controlled, patient-, rater- and statistician-blinded study funded by the German Research Foundation. It started in October 2010 and involves seven university departments (http://apps.who.int/trialsearch/default.aspx, WHO ICTRP identifier: DRKS00000444). This study targets to include 100 youth and young adults 15–30 years old with a positive family history of affective or schizoaffective disorder who are characterized by a reduction in psychosocial functioning (based on the Social Interview Schedule,[51, 52] and affective symptomatology (subthreshold mania and/or at least subthreshold depression and/or cyclothymic features; based on the BPSS-P,[20]). Participants will be randomized to CBT in a group setting (best (be)for(e) bipolar) (K. Marx, K. Leopold, A. Pfennig unpublished) versus unstructured group meetings. Each intervention consists of 14 weekly sessions lasting 90 min. In the developmental process of the treatment approach, two manuals[53, 54] out of a range of manuals focusing on psychoeducation and CBT for BDs,[53-56] for unipolar depression[57] and high-risk states for psychosis[58] were identified, which contained components highly compatible with what was considered needed for individuals at high risk for BDs. Additionally, techniques of mindfulness-based cognitive therapy for depression from Segal et al.[59] were included. Components of Best (Be)for(e) bipolar tackle symptomatology associated with factors that influence components of the vulnerability-stress system (e.g. sleep regulation, stress management and handling of personality features) and therefore should be best suited to alleviate, postpone or even prevent the conversion to BD. Primary outcomes are change in psychosocial functioning and affective symptomatology. Secondary end-points include effectiveness of stress management and conversion rates to BD. Estimated primary completion date of the study is September 2015.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

For youth with a confirmed family history, there are consistent prospective data to confirm the early natural history of BD.[5-8, 12, 13] There is still uncertainty whether the disease development in patients without specific familial risk (which represent the majority of bipolar patients) follows comparable pathways. In such individuals without a clear family history of BD, the exact nature and specificity of risk constellations and symptomatology in the early stages of potentially developing BD has to be evaluated.[21, 30, 32-39] However, many of the help-seeking adolescents and young adults suffer from substantial, though often subsyndromal symptoms that frequently result in psychosocial and educational/vocational impairment. Given the sensitive developmental period of adolescence and early adulthood, choosing an appropriate intervention requires an individualized careful weighing of the potential benefits and risks. Non-pharmacological approaches are mostly considered to be preferred when dealing with individuals who might be at risk, but who do not demonstrate syndromal levels of symptoms.[27] This way, potential negative short-term or long-term side effects associated with some medications and issues around compliance (e.g. because of concerns about psychotropic drugs) can be avoided. A discussion of whether non-pharmacological approaches should be used alone or in combination with pharmacological treatment options and the timing of these interventions is needed that has to be based on evidence.

Results from our systematic review indicate that there is only very limited empirical evidence yet for early psychotherapeutic interventions in high-risk states for the development of BD. Only three studies with a total of 90 subjects were identified (one exploratory analysis from a controlled study, one feasibility study and one active controlled, randomized study). Treatment with a multi-family psychoeducational intervention[44] or a family-focussed therapy approach (in addition to treatment as usual, including psychopharmacology) showed a potential for symptom reduction and prevention of conversion to BD[43, 44] and a significantly faster recovery from initial mood symptoms and more time in remission during follow-up.[47] The results have to be interpreted with caution, however, because of the small sample size and permission of medication treatments in the intervention and control groups in all studies, as well as lack of a control group or data on conversion in one of them.[43] Moreover, in one study,[44] only pre-pubertal children were included and the analyses were performed post-hoc in a subsample of the overall randomized group, calling successful randomization into question. Furthermore, in the randomized study,[47] the control condition was not matched for treatment intensity, follow-up was only 12 months and the sample size was too small to identify potential moderators of treatment effects.

To our knowledge, only two controlled studies are currently under way to further clarify whether psychotherapeutic interventions at the pre-syndromal BD illness stage can decrease symptomatology, preserve or restore psychosocial function, and postpone or, even, prevent conversion to manifest BD.

Based on the reviewed evidence and based on the efficacy of psychotherapeutic interventions in patients with fully manifested BD (see for instance,[60, 61]) there is reason to suggest that psychotherapeutic intervention can be adjusted and implemented to help preserve the chance for an adequate individual development in people who are at increased risk for BD, but who have not yet developed symptoms reaching the threshold for a full diagnoses. Current symptomatology (i.e. depression, anxiety, mood swings) can possibly be decreased and progression to the full blown disorder may be delayed or reduced.[21] Moreover, knowledge and strategies are learned during the course of psychotherapy (e.g. regarding sleep regulation, stress management and replacing dysfunctional behaviours or thoughts with more functional ones), which are considered fundamentally useful, regardless of whether the primary goal is preventing future episodes or preventing or postponing conversion to full BD. However, the known challenges of treatment recommendations involving psychotherapy, for example, provision of timely access to (specific) psychotherapy and monetary costs, have to be considered.

The results from this systematic review have to be interpreted within its limitations. Foremost, there was still an insufficient database of only three small studies of psychotherapeutic interventions for At-Risk-BD individuals. This lack of controlled studies is likely due to the fact that risk constellations and symptomatology in early stages of potentially developing BD have been studied only recently, that the criteria to define At-Risk-BD are still unclear and that studies investigating the effectiveness of psychotherapeutic interventions in At-Risk-BD are just emerging. However, with the much-needed validation of criteria defining at-risk status for BD, concerted high-quality studies will become possible. Learning from early psychosis research,[62, 63] clinical and research networks have to be strengthened and supported early on in this developing field (see also[25]). Such further development will help with standardizing diagnostic procedures and tools, and pooling of subjects in multi-centre intervention studies in order to investigate benefits and risks of specific interventions, such as adapted and integrated psychotherapeutic approaches in at-risk individuals. Moreover, only with larger numbers of study participants and adequate follow-up can moderators and mediators of successful treatment and true at-risk status be investigated.

Being aware of the particular responsibility when diagnosing and treating not yet manifest disorders, detailed counselling has to be the foundation of care, and follow-up has to be assured on a long-term basis. It is hoped that ongoing and future trials in At-Risk-BD subjects will inform research and clinical care alike. Until more data become available, using low-risk psychotherapeutic interventions in at-risk subjects for BD could be the first step in a ‘staged’ treatment approach that titrates the risk of the interventions to the severity and risk of the disorders.[27] Future studies are needed to clarify at what symptomatic stage, in the presence of which risk factors (family history, early trauma, comorbidities, etc.) and in which individual psychotherapies should be provided alone, when medications should be given first, and if and when combination treatments are most effective in addressing impairing symptoms and delaying or preventing progression to syndromal BD.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Funding sources and disclosures

A. Pfennig received a stipend/research support from GlaxoSmithKline and research support from AstraZeneca. A. Pfennig has received speaker honoraria from AstraZeneca and Eli Lilly and Company.

C.U. Correll has been a consultant and/or advisor to or has received honoraria from Actelion, Alexza; Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Janssen/J&J, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva and Vanda. He has received grant support from BMS, Janssen/J&J, and Otsuka.

T.D. Meyer did take part as a referent in a scientific meeting financed by Bristol-Myers Squibb.

M. Bauer has received grant/research support from The Stanley Medical Research Institute and NARSAD. He is a consultant for AstraZeneca, Lilly, Servier, Janssen-Cilag, Lundbeck and BMS & Otsuka. Dr Bauer has received speaker honoraria from AstraZeneca, Lilly, GlaxoSmithKline, Lundbeck, BMS, Otsuka and Pfizer.

K. Leopold has received speaker honoraria from AstraZeneca, BMS, Pfizer, Janssen-Cilag, Lundbeck and Lilly.

C. Marx and M. Rottmann-Wolf report no potential conflicts of interest.

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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