Cohort Profile: The St. Göran Bipolar Project

doi:10.21203/rs.3.rs-4436841/v1

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Study protocol

Cohort Profile: The St. Göran Bipolar Project

https://doi.org/10.21203/rs.3.rs-4436841/v1

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Background

The St. Göran Bipolar Project (SBP) was launched as a longitudinal outpatient study investigation. The overarching objective was to identify predictive factors associated with long-term outcomes of individuals with bipolar disorder, encompassing cognitive function, relapse rate, treatment responses, and functional outcome. Furthermore, the aim was to incorporate brain imaging, biochemical analyses of cerebrospinal fluid and blood, and genetics in a multifaceted approach that target several levels of observation.

Methods

The SBP is a collaboration between academia and healthcare, enrolling individuals treated at the respective bipolar outpatient clinics in Stockholm (SBP-S) and Gothenburg (SBP-G), Sweden. Healthy controls were identified through Statistics Sweden and enrolled at both sites. Data and sample collection included structured interview instruments, self-rated questionnaires, blood and cerebrospinal fluid samples, magnetic resonance imaging, and neuropsychological tests. A subset of study participants has completed 7- and 14-year follow-up visits.

Discussion

The SBP has generated many original findings and recent studies have used the advantages of longitudinal follow-ups and the presence of a replication cohort. While data collection is approaching completion, collected data continue to be used to address new research questions. The two key strengths of the St. Göran study are the detailed and multimodal information collected at each study visit and the extended follow-up period. The naturalistic setting of the study means findings are often applicable to individuals with bipolar disorder in real-world scenarios. However, the variability in completeness of collected information is substantial for some modalities and drop-out rates between baseline and follow-up study visits can introduce selection bias. Further, though the control population in the study was randomly selected from the general population, it may not be fully representative as recruitment was limited to individuals who actively responded to contact.

Trial registration

SBP is an observational clinical study, and it was registered on Researchweb (https://www.researchweb.org/is/vgr/project/39411) January 1st 2009 (project ID: 39411).

bipolar disorder

clinical study protocol

magnetic resonance imaging

genetics

cognitive function

biomarkers

cerebrospinal fluid

Longitudinal observational studies have played a pivotal role in advancing our understanding of bipolar disorder, addressing a wide range of scientific questions. Studies with comprehensive multimodal information, bolstered by long-term follow-up, have advanced our knowledge on brain morphology and neurochemistry, cognitive and neuropsychiatric deficits, as well as the genetic architecture of bipolar disorder. Additionally, from a clinical perspective, there is a need to increase our understanding of the importance of co-morbid conditions, the trajectory of illness progression, treatment response, and functional outcomes. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) stands as a noteworthy example of the potential of longitudinal clinical outpatient investigations. It was designed to ascertain the most effective treatments, or treatment combinations to manage bipolar disorder [1].

In 2005, drawing inspiration from the STEP-BD study, the St. Göran Bipolar Project (SBP) was launched as a longitudinal outpatient study investigation. By adding brain imaging, collection of blood and cerebrospinal fluid, and neurocognitive testing to the clinical assessments, the aim was to provide a broad scope of data for investigations. The overarching objective was to identify predictive factors associated with long-term outcomes of individuals with bipolar disorder, encompassing cognitive function, relapse rate, treatment responses, and functional outcome. The study also aimed to investigate sex differences regarding these outcomes. Furthermore, the aim was to incorporate brain imaging, biochemical analyses of cerebrospinal fluid and blood, and genetics in a multifaceted approach that target several levels of observation. The published findings from the study reflects both the breadth and depth of the scope of its research goals, shedding light on various facets of bipolar disorder. As ongoing research continues to unfold, we anticipate that the data collected in this study will yield further original scientific insights in the years to come.

This paper provides an overview of the research methods utilized in the SBP, along with a summary of research findings that have emerged since its commencement.

Collaborative arrangements

The SBP was established through a collaboration between the Karolinska Institutet and the St. Göran bipolar outpatient clinic at the Northern Stockholm Psychiatry in 2005. Subsequently, in 2009, a second study center was started through a partnership between the Sahlgrenska University hospital in Gothenburg and the Institute of Neuroscience and Physiology at the University of Gothenburg.

Recruitment approach

Participants in the SBP study were consecutively enrolled from new or ongoing individuals treated at the respective bipolar outpatient clinics in Stockholm (SBP-S) and Gothenburg (SBP-G), Sweden. Both these outpatient units provide long-term (usually lifelong) follow-up care for individuals diagnosed with bipolar disorder. Individuals were diagnosed after an initial evaluation using the Affective disorder evaluation (ADE). Individuals meeting the inclusion criteria (see below) were eligible for inclusion. Prior to inclusion, the study’s objectives, procedures, and the risks and benefits were presented to potential participants. The voluntary nature of research participation was explained, along with a presentation of the alternatives for non-research treatment. Patients retained the right to withdraw their consent or exit the study at any time during their participation.

For each included patient, seven age and sex-matched controls were randomly selected by Statistics Sweden and contacted by mail. Out of the controls that received the invitation mail, 14% reached out to the research team, a response rate that is on par with similar studies according to Statistics Sweden. A telephone screening was conducted by trained research nurses to exclude persons with severe mental health issues, neurological problems, and severe substance abuse. Persons who passed the telephone screening were scheduled for a 1-day comprehensive assessment as part of the study.

Baseline study procedures

The study procedures were performed when patients were judged to be in a mood stable state. At the visit for blood sampling and lumbar puncture, study participants were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) [2] and Young Ziegler Mania Rating Scale (YMRS) [3]. From 2012 and onwards, MADRS and YMRS were also administered in conjunction with the neuropsychological test sessions.

The structured interview instrument ADE (the Affective Disorder Evaluation) was used in the STEP-BD project [1]. The ADE includes a social anamnesis, medical history, and the affective module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The number and characteristics of lifetime affective episodes are documented. With the permission of the originator Gary S. Sachs (Bipolar Clinic and Research Program, Harvard Medical School, Boston, MA, USA), we modified the ADE to suit Swedish conditions. Specifically, we added a more detailed assessment of participants’ occupational level including details about sick- leave. We also included questions pertaining to the Swedish weapon law, as well as details about non-pharmacological treatment including electroconvulsive therapy, psychotherapy, and patient education. The structured interview instrument, referred to a as the Patient History Form, underwent minor refinements during the study and a more thorough revision was undertaken in 2014.

Further, the structured the Mini International Neuropsychiatry Interview (M.I.N.I.) [4] was administered to screen for other psychiatric diagnoses than bipolar disorder. The information for the Patient history form and the M.I.N.I. interviews were collected by board-certified psychiatrists, residents in psychiatry or a specialist nurse. Assessments were supplemented with information from medical records and interviews with next of kin when needed. A final best-estimate diagnostic decision was made at a diagnostic case-conference by a consensus panel (n = 2–5) of experienced board-certified psychiatrists specialized in bipolar disorder.

Participants also filled out self-report versions of the Alcohol Use Disorders Identification Test (AUDIT) [5] and the Drug Use Disorders Identification Test (DUDIT) [6]. Furthermore, both the symptom and function domains of the Global Assessment of Functioning (GAF) scales were scored to assess the overall psychosocial functioning.

Controls completed a structured interview to collect information on dwelling, educational and occupational level including details about sick-leave, questions pertaining to the Swedish weapon law, family history of psychiatric disorders, as well as reproductive and medical history. In addition, symptom and function domains of the Global Assessment of Functioning (GAF) scales were scored to assess the overall psychosocial functioning. The M.I.N.I. interview was administered to exclude psychiatric morbidity and SCID-II was administered to screen for personality disorders. Substance abuse was screened for at the telephone interview by the nurse, in the psychiatric interview, by AUDIT and DUDIT, as well as by determining serum levels of carbohydrate-deficient transferrin.

Inclusion and exclusion criteria

The inclusion criteria for patient participation in the SBP were as follows: 1) age of 16 years or older; 2) a diagnosis meeting the DSM-IV Criteria for bipolar I, bipolar II, bipolar not otherwise specified (NOS), cyclothymia, or schizoaffective disorder of the manic / bipolar subtype, and 3) completed the basic diagnostic Affective disorder evaluation. Exclusion criteria were: 1) Unwilling or unable to comply with study requirements or 2) Not competent to give informed consent in the opinion of the investigator. Notably, participants were not obliged to participate in all the study’s investigations. They had the option to choose which components of the study they wished to participate in.

Overconsumption of alcohol as revealed by carbohydrate-deficient transferrin (> 2.0%) or responses indicating large consumption (> 8 standard drinks per time more than 2 times per week) and/or amnesia and/or loss of control more than once per month were exclusion criteria for controls. Other exclusion criteria were neurological conditions (other than mild migraine), untreated endocrinological disorders, pregnancy, dementia, recurrent depressive disorder, and suspected severe personality disorders (based on interview and SCID-II personality assessment), and a family history of schizophrenia or bipolar disorder in first-degree relatives. We did not exclude controls with past minor depressive episodes, isolated episodes of panic disorder, eating disorders, or obsessive-compulsive disorder that had remitted spontaneously or with brief psychotherapy counselling.

Follow-up visit study procedures

The aim of the study was to conduct follow-up assessments with study participants at 7 and 14 years after their baseline visits. The time interval was chosen to balance study site workload, provide sufficient follow up length, and have an acceptable rate of study dropouts. The Patient History Form was modified for these follow-up visits. Changes included the addition of data collection regarding medication, episode relapse, inpatient care, suicide attempts that occurred during the follow-up period. Controls completed a shortened version of the modified Patient History Form at the follow-up visits.

Self-reported rating scales

The St. Göran study incorporates several self-reported rating scales. While some of these scales have been consistently used from study start throughout follow-up visits, other rating scales have been introduced or existing ones removed during the study. Table 1 provides an overview of rating scales across visits for both study centres.

Table 1

– Self-assessment rating scales in the St Göran project
	SBP-S						SBP-G
	Patients			Controls			Patients		Controls
Instrument	Baseline	7 y	14 y	Baseline	7 y	14 y	Baseline	7 y	Baseline	7 y
Alda scale	no	yes¹	yes	-	-	-	no	yes¹	-	-
BWAS	yes¹	yes¹	yes¹	yes	no	no	yes¹	yes	no	no
BIS-4	no	no	yes	no	yes²	yes	no	no	no	no
BRIEF-A	no	yes¹	yes	no	no	yes	no	no	no	no
BSRI	no	no	no	no	yes	no	no	no	no	no
DES	yes¹	yes	no	yes	no	no	yes	no	yes	no
EHI	yes¹	yes¹	no	yes	no	no	yes	no	yes	no
EQ-5D	no	yes	yes	no	yes	yes	yes	yes	no	yes
ISEL	yes	no	no	yes	no	no	no	no	no	no
Kinsey scale	no	yes	yes¹	no	yes	no	no	no	no	no
KSQ	no	yes	no	no	yes	no	yes	yes	no	yes
PDI	yes¹	yes	no	yes	yes	no	yes	yes	no	yes
PGWB	no	yes	yes	no	yes	yes	no	no	no	no
SCID-II	yes	yes	no	yes	no	no	yes	yes	yes	yes
SDS	yes	yes	yes	no	yes	yes	no	no	no	no
CAQ	yes¹	no	yes	yes	no	no	yes	no	no	no
SOC	yes	yes¹	yes	yes	no	yes	no	no	no	no
SPAQ	yes	no	no	-	-	-	no	no	-	-
SSP	yes	yes	no	yes	no	no	yes	yes	yes	yes
STAI-S	no	yes¹	yes	no	no	yes	no	no	no	no
TEMPS-A	yes¹	yes	no	yes	no	no	yes	yes	yes	yes
Table legend: Alda scale - The Retrospective Assessment of the Lithium Response Phenotype Scale, BWAS - Barron Welsh Art Scale, BIS-4 - Berlin Intelligence Structure Model test, BRIEF-A - Behavior Rating Inventory of Executive Function - Adult Version, BSRI - Bem sex role inventory, DES - Dissociative Experiences Scale, EHI - Edinburgh Handedness Inventory, ISEL - Interpersonal Support Evaluation List, KSQ - Karolinska Sleep Questionnaire, PDI - Delusions Inventory, PGWB - Psychological Well-Being Index, SCID-II - Structured Clinical Interview for DSM-IV - Axis II disorders, SDS - Sheehan Disability Scale, CAQ - Creative Achievement Questionnaire, SOC - Sense of Coherence Scale, SPAQ - Seasonal Pattern Assessment Questionnaire, SSP - Swedish Universities Scales of Personality, STAI-S – Spielberger State-Trait Anxiety Inventory, and TEMPS-A - Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire. ¹Administered to a subset of patients and ²administered to a subset of controls.

Delusional ideation and dissociative experiences were measured using the Peters et al. Delusions Inventory (PDI) [7] and the Dissociative Experiences Scale (DES) [8]. Anxiety was measured using the short version of the Spielberger State-Trait Anxiety Inventory (STAI-S) [9]. Patients in the SBP-S cohort were assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ) [10] at baseline. The Edinburgh Handedness Inventory (EHI) [11] was used to ascertain handedness. Gender traits were assessed in the SBP-S control group at the 7-year follow-up using the Bem sex role inventory (BSRI) [12]. Sexual orientation was assessed using the Kinsey Scale [13]. Data on personality were collected using the Structured Clinical Interview for DSM-IV - Axis II disorders (SCID-II) [14], the Swedish Universities Scales of Personality (SSP) [15], and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) [16]. Subjective well-being was rated using the Psychological Well-Being Index (PGWB) [17]. Study persons view of life was rated using the Sense of Coherence Scale (SOC) [18]. Functional level and quality of life were assessed using the Sheehan Disability Scale (SDS) [19], Interpersonal Support Evaluation List (ISEL) [20], and EQ-5D questionnaires [21]. The Karolinska Sleep Questionnaire (KSQ) [22] was used to collect information on sleep difficulties. Creativity was measured using the Barron Welsh Art Scale (BWAS) [23], the Creative Achievement Questionnaire (CAQ) [24], and the Berlin Intelligence Structure Model test (BIS-4) [25]. Everyday behavior associated with executive function was assessed by the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) questionnaire [26]. Finally, lithium response was measured using the The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) [27].

2.2.6 Neuropsychiatric assessment

As shown in Table 2, the presence of autism spectrum traits was assessed using the Autism-Spectrum Quotient Test (AQ test) [28] and the Ritvo Autism and Asperger Diagnostic Scale – 14 Screen (RAADS-14) [29]. ADHD symptoms were rated using the Adult ADHD Self-Report Scale (ASRS) [30], the Brown Attention-Deficit Disorder Scales (BADDS) [31], and the Wender Utah Rating Scale (WURS) [32]. Further, controls in the SBP-S cohort completed the Barkley self-assessment test for ADHD symptoms [33] at the 7-year follow-up visit.

Table 2

– Neuropsychiatric rating scales used in the St. Göran project
	SBP-S						SBP-G
	Patients			Controls			Patients		Controls
Instrument	Baseline	7 y	14 y	Baseline	7 y	14 y	Baseline	7 y	Baseline	7 y
AQ test	yes	yes¹	no	yes	no	no	no	no	no	no
ASRS	yes	yes	no	yes	yes	yes²	yes	yes	yes	yes
Barkley self-assessment	no	no	no	no	yes	no	no	no	no	no
BADDS	yes	yes	no	yes	no	yes²	yes	yes	yes	yes
RAADS-14	no	yes	no	no	yes	no	yes	yes	no	yes
WURS	yes	yes	no	yes	no	no	yes	yes	no	yes
Table legend: AQ test – Autism-Spectrum Quotient Test, ASRS – Adult ADHD Self-Report Scale, BAADS – Brown Attention-Deficit Disorder Scales, RAADS – Ritvo Autism and Asperger Diagnostic Scale, and WURS – Wender Utah Rating Scale. ¹Administered to a subset of patients and ²administered to a subset of controls.

Neuropsychological tests

Study participants were assessed with a comprehensive neuropsychological test battery covering several cognitive domains [34]. In the SBP-S cohort, the tests included the Claeson-Dahl Verbal Learning and Retention test (CDT), the Color-Word Interference Test, the Design Fluency Test, the Tower Test, the Trail Making Test, and the Verbal Fluency Test from Delis-Kaplan Executive Function System (D-KEFS), the Wechsler Adult Intelligence Scale (WAIS version III or IV; all subtests except All the Object Assembly were administered), the Continuous Performance Test II, and the Rey Complex Figure Test (REY). To reduce the workload for study participants, certain tests were omitted in the SBP-G cohort (at baseline and follow-up) and for follow-up examinations in SBP-S. Table 3 details the administered neuropsychological tests to the patient and control groups across visits.

Table 3

– Neuropsychological tests used in the St. Göran Project
SBP-S				SBP-G
	Baseline	7-year follow-up	14-year follow-up	Baseline	7-year follow-up
CDT	yes	yes¹	yes	no	no
D-KEFS	yes	yes²	yes³	yes³	yes³
WAIS	yes	yes	yes	yes	yes
REY	yes	yes	yes	yes	yes
CPT-II	yes	yes	yes¹	no	no
Table legend: CDT – Claeson-Dahl Test, D-KEFS – Delis-Kaplan Executive Function System, WAIS – Wechsler Adult Intelligence Scale, REY – Rey Complex Figure Test, and CPT-II – Connors Continuous Performance Test 2nd edition. ¹Administered to controls and a subset of patients, ²the Design Fluency Test and the Tower Test from D-KEFS were only administered to a subset of patients, ³the Design Fluency Test and the Tower Test from D-KEFS were excluded.

Blood sampling and lumbar puncture

Blood and CSF sampling was performed on the same day. Participants were in a stable euthymic mood and fasted overnight before the blood and CSF collection. Blood samples were drawn between 8–9 AM and CSF samples between 9–11 AM. An identical procedure was performed for the controls.

Blood samples were allowed to clot in room temperature for 30–60 min pending centrifugation (10 min at 1700 × g). In Stockholm, the supernatant was kept in low temperature (< 5°C) pending direct transport to the biobank within 4 h for long-term storage at − 70°C. In Gothenburg, the supernatant was immediately stored in a local − 70°C freezer awaiting bulk transport to the biobank.

For CSF sampling via lumbar puncture, the spinal needle was inserted into either the L3/L4 or L4/L5 interspace. A total volume of 12 ml of the CSF was collected, gently inverted to prevent gradient effects, and divided into 1.0–1.6 ml aliquots that were stored at − 80°C pending analysis. In SBP-S, baseline samples were not centrifugated up to May 2011, but in SBP-G all samples were centrifugated. The procedure for CSF and blood sampling remained identical at the 7-year follow-up visit. At the 14-year follow-up visit, blood but not CSF was collected.

Blood and CSF samples are stored at the Karolinska Institutet Biobank.

Magnetic resonance imaging

At the time of MRI scanning, patients were in a mood stable state. MRI scans for the SBP-S cohort were conducted at the MR Research Centre, Karolinska University Hospital, Stockholm. All subjects were examined in the same scanner for the baseline assessment and the first follow-up on a 1.5-Tesla MRI scanner (General Electric Signa Excite 1.5T) equipped with an eight-channel head coil. At second follow-up, the MRI scanner has been changed to a 3-Tesla General Electric Discovery MR750. Coronal 3D T1-weighted images were obtained using a spoiled gradient echo recall sequence (3D-SPGR), with the following parameters: repetition time (TR) of 21.0 milliseconds, echo time (TE) of 6 milliseconds, field of view (FOV) of 18 cm, flip angle of 30°, acquisition matrix of 256×256, 128 slices, and voxel size of 0.7×0.7×1.8 mm³. Axial fluid attenuation inversion recovery T2-weighted scans were acquired for examination by a senior radiologist. This assessment aimed to exclude clinically significant anatomical abnormalities or neuropathology. During the study, the calibration filter for the scanner was changed. This led to variations in the intensity distribution among subjects scanned with different filters. At the first follow-up, the scanning protocol was repeated, and two additional sequences were added: a resting-state functional magnetic resonance imaging (fMRI) sequence and a diffusion tensor imaging (DTI) scan. The resting-state fMRI sequence lasted 7.5 minutes and included the acquisition of 180 volumes. Each volume consisted of 39 BOLD-sensitive T2-weighted axial echo-planar images each. The imaging parameters were as follows: resolution of 3.79 mm x 3.79 mm, slice thickness 4 mm covering the whole brain, TR = 2.5 seconds, TE = 40 milliseconds, FOV = 243 mm, and flip angle of 85°. The DTI protocol included TR = 7.39 seconds, TE = 85 milliseconds, FOV = 220 mm, flip angle 90°, acquisition matrix 96x96, voxel size 0.94 x 0.94 mm, slice thickness 2.3 mm.

For the SBP-G cohort, MRI scanning was initially conducted on a Philips Achieva dStream 3T scanner using a 32-channel head coil. The scanner was replaced with a Philips M7700 3T scanner in January 2022. We conducted a structural T1-weighted 3D turbo field echo (TFE) HR sequence (TR = 6 milliseconds, TE = 2.8 milliseconds, FOV 240 mm x 240 mm, flip angle 8°, acquisition matrix 242x232, 180 slices, voxel size 1x1x1 mm³), a resting-state fMRI sequence (resolution of 3.06 mm x 3.06 mm, slice thickness 3 mm, TR = 2.47 seconds, TE = 30 milliseconds, FOV = 220 mm x 220 mm, flip angle = 75°), and a DTI sequence (TR = 7.62 seconds, TE = 92.46 milliseconds, FOV 224 mm x 224 mm, flip angle 90°, acquisition matrix 96x98, voxel size 2.33 mm x2.29 mm, slice thickness 2.3 mm).

General descriptive information

Table 4 shows the number of individuals with bipolar disorder and controls who have undergone clinical interview, collection of biological samples, MRI scan, and neuropsychological assessment stratified by center and time-point.

Table 4

– Number of individuals in the St. Göran project with data for specific study modules
	SBP-S
		Patients	Controls
Patient history form	Baseline	299	115
	First follow-up	153	74
	Second follow-up	70	49
Blood samples	Baseline	281	115
	First follow-up	156	74
	Second follow-up	69	57
Cerebrospinal fluid samples	Baseline	156	115
	First follow-up	106	60
	Second follow-up	0	0
MRI scan	Baseline	253	114
	First follow-up	123	83
	Second follow-up	47	50
Neuropsychological assessment	Baseline	177	115
	First follow-up	137	73
	Second follow-up	68	34
	SBP-G
		Patients	Controls
Patient history form	Baseline	454	56
	First follow-up	64	42
Blood samples	Baseline	287	56
	First follow-up	94	40
Cerebrospinal fluid samples	Baseline	158	55
	First follow-up	49	30
MRI scan	Baseline	173	40
	First follow-up	8	0
Neuropsychological assessment	Baseline	298	56
	First follow-up	44	30
Table legend: The second follow-up visits for the SBP-G cohort are ongoing and are not included in the table.

Neuropsychology and personality

We have shown lower performance on neuropsychological tests across multiple cognitive domains in patients with bipolar disorder compared to controls [35, 36]. Importantly, however, we found that clinically significant impairment was restricted to a subgroup of patients, suggesting that cognitive impairments are not a general trait in bipolar disorder [37]. In a subsequent investigation, bipolar disorder individuals with or without comorbid ADHD were compared. Interestingly, no disparities in neuropsychological profiles were observed, except for poorer working memory performance among those with comorbid ADHD [38]. The importance of cognitive functioning was demonstrated in a study investigating the association between cognitive performance and occupational functioning among the individuals with bipolar disorder. Executive functioning emerged as a key predictor of occupational status in the population [39]. To shed light on whether cognitive functions worsen over time in bipolar disorder, we compared cognitive test results obtained at the 7-year follow-up visit with baseline performance. Interestingly, results revealed that the trajectory of cognitive performance remained similar between patients with bipolar disorder and controls [40].

Building upon the MRI brain scans conducted with study participants, we were able to show a significant association between lower executive functioning and deep white matter hypointensities in bipolar disorder [41]. Similarly, we found CSF biomarkers of neurodegeneration and neuroinflammation to be associated with cognitive impairment in individuals with bipolar disorder [42, 43].

With respect to personality traits, we found that individuals with bipolar disorder scored higher on measures of Neuroticism, Aggressiveness, and Disinhibition compared with controls, but these personality traits were neither associated with worse outcome in bipolar disorder [44], nor with the presence of trigger factors for affective episodes [45].

Cerebrospinal fluid markers

To shed light on the pathophysiology of bipolar disorder, we have undertaken a series of studies comparing potential CSF biomarkers between individuals with bipolar disorder and controls. We found that individuals with bipolar disorder had altered concentrations of amyloid precursor protein metabolites [46], micrometer-sized particles in CSF [47], tryptophan metabolites [48], monoamine metabolites [49], secretogranin II [50], neurofilament light chain [51], amino acids related to glutamate signalling [52], interleukin 1β [53], monocyte and microglia markers [54], interleukin-8 [55], and blood-cerebrospinal fluid barrier dysfunction [56].

Cerebrospinal fluid metabolomics [57] and proteomics studies [58, 59] have also found differences between individuals with bipolar disorder and controls in the St. Göran project.

Fewer studies have revealed associations between CSF biomarkers and disease severity or outcome. We did, however, found low CSF concentration of neuropeptide Y to be associated with higher risk of suicide attempts [60], and low secretogranin concentrations to be associated with more severe bipolar disorder [50]. Further, we found higher concentrations of CSF kynurenic acid to be associated with manic and psychotic features [61], and lower concentration of CSF HVA and 5-HIAA to be associated with a history of childhood ADHD in bipolar disorder type 1 [62].

Blood markers

By comparing blood samples from individuals with bipolar disorder and controls, we have revealed altered concentrations of brain derived neurotrophic factor [63], zinc [64], and lipids [65, 66]. Further, blood metabolomics [67] and proteomics studies [68] have also found differences between individuals with bipolar disorder and controls.

Magnetic resonance imaging

We have found structural brain differences between individuals with bipolar disorder and controls [69]. Further, data from the St. Göran bipolar project has been included in the Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) consortium, thereby contributing to large-scale collaborative brain imaging studies [70–77]}. In addition, associations between brain structure, executive function [78], and psychomotor function have been demonstrated [79, 80]. Other studies have explored the association between psychotic symptoms and grey matter volume [81], and how manic episodes impacts brain structure [82, 83]. Furthermore, we found that the polygenic risk for bipolar disorder and schizophrenia was related to a thinner ventromedial prefrontal cortex [84]. Finally, cortical brain structure in relation to sexual orientation has been studied in females with bipolar disorder and ADHD [85].

Using functional MRI data, differences in functional connectivity measures between individuals with bipolar disorder and controls were shown in the default mode network and in the functional connectivity between the default mode network, the frontoparietal network, and the somatomotor network [84, 86]. Additionally, recent work has shown differences also in the somatomotor network in individuals with bipolar disorder as compared to controls [87].

Genetics

In the St Göran bipolar project, both candidate gene studies and genome wide analyses have identified genetic variants associated with blood or cerebrospinal fluid concentrations of biomarkers [88–92], brain structure and function [82, 84, 93, 94], and cognitive function [78, 95, 96]. Further, genome wide studies of cerebrospinal fluid biomarkers have identified biological pathways associated with bipolar disorder [58, 97].

Strengths and limitations

The two key strengths of the SBP are the detailed and multimodal information collected at each study visit and the extended follow-up period. The wealth of detailed information gathered allows for the exploration of a range of questions, drawing from diverse combinations of data sources. The longitudinal nature of the study enables the investigation of prognostic factors and the trajectory of the illness over time, offering valuable insights into the course of bipolar disorder. Moreover, the availability of two separate cohorts using the same study protocol enhances the reproducibility of findings. Lack of replication poses a significant challenge problem in research and causes of non-replication can be difficult to identify. By using a consistent study protocol across both cohorts in the SBP, several sources of error can be effectively controlled for, bolstering the reliability and validity of study results.

The naturalistic setting of the study is both a strength and a weakness. On the one hand, findings are often applicable to individuals with bipolar disorder in real-world scenarios. However, the variability in completeness of collected information is substantial for some modalities and drop-out rates between baseline and follow-up study visits can introduce selection bias. Various strategies, such as censoring of data and multiple imputation, have been employed in published work to deal with missing data. Nonetheless, the lack of data completeness and study drop-out remain potential sources of bias to be considered in the interpretation of results.

Even though the control population in the study was randomly selected from the general population, it may not be fully representative as recruitment was limited to individuals who actively responded to contact. This could introduce bias for comparisons between the patient and control groups.

Finally, since the study was primarily designed to provide a resource for research rather than to address a specific research question, the amount of information may not always be adequate for particular research questions. Ancillary information or biological samples that could be relevant are not always available. For example, published work on cardiometabolic risk factors [65, 66] would have benefited from more detailed information on diet and physical activity that were not available. And while MRI brain scans, blood, and CSF are available, the study lack for instance samples collected for mRNA expression analyses.

In summary, the SBP has generated many original findings since its inception, leveraging the advantages of longitudinal follow-ups and the presence of a replication cohort within the study framework. While data collection is approaching completion, there remain ample opportunities to address new research questions using the wealth of collected data. Further, SBP has served as a valuable platform for training junior researchers, involving numerous doctoral and post-doctoral researchers. The project provides an active research environment, robust research infrastructure, and access to a rich dataset, contributing to the advancement of knowledge in the field of bipolar disorder.

SPGR–Spoiled Gradient Echo Recall Sequence

ADE

Affective disorder evaluation

Alda scale

The Retrospective Assessment of the Lithium Response Phenotype Scale

AQ test

Autism–Spectrum Quotient Test

ASRS

Adult ADHD Self–Report Scale

AUDIT

Alcohol Use Disorders Identification Test

BAADS

Brown Attention–Deficit Disorder Scales

BIS

4–Berlin Intelligence Structure Model test

BRIEF

A–Behavior Rating Inventory of Executive Function–Adult Version

BSRI

Bem sex role inventory

BWAS

Barron Welsh Art Scale

CAQ

Creative Achievement Questionnaire

CDT

Claeson–Dahl Test

CPT

II–Connors Continuous Performance Test 2nd edition

CSF

Cerebrospinal Fluid

KEFS–Delis–Kaplan Executive Function System

DES

Dissociative Experiences Scale

DSM

IV–Diagnostic and Statistical Manual of Mental Disorders, fourth edition

DTI

Diffusion Tensor Imaging

DUDIT

Drug Use Disorders Identification Test

EHI

Edinburgh Handedness Inventory

ENIGMA

Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA)

fMRI

Functional Magnetic Resonance Imaging

FOV

Field of View

GAF

Global Assessment of Functioning

ISEL

Interpersonal Support Evaluation List

KSQ

Karolinska Sleep Questionnaire

M.I.N.I

Mini International Neuropsychiatry Interview

MADRS

Montgomery–Åsberg Depression Rating Scale

MRI

Magnetic Resonance Imaging

PDI

Delusions Inventory

PGWB

Psychological Well–Being Index

RAADS

Ritvo Autism and Asperger Diagnostic Scale

REY

Rey Complex Figure Test

SBP

The St. Göran Bipolar Project

SBP

G–The St. Göran Bipolar Project Gothenburg

SBP

S–The St. Göran Bipolar Project Stockholm

SCID

II–Structured Clinical Interview for DSM–IV–Axis II disorders

SDS

Sheehan Disability Scale

SOC

Sense of Coherence Scale

SPAQ

Seasonal Pattern Assessment Questionnaire

SSP

Swedish Universities Scales of Personality

STAI

S–Spielberger State–Trait Anxiety Inventory

STEP

BD–The Systematic Treatment Enhancement Program for Bipolar Disorder

Echo Time

TEMPS

A–Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire

TFE

Turbo Field Echo

Repetition Time

WAIS

Wechsler Adult Intelligence Scale

WURS

Wender Utah Rating Scale

YMRS

Young Ziegler Mania Rating Scale

Ethics approval and consent to participate

All study subjects consented orally and in writing to participate in the study. The ethical review board in Stockholm approved the study in 2005 (dnr 2005/3:7) and several amendments have been added to the original ethical approval: dnr 2008/1931-32, 2009/1221-32, 2011/1700-32, 2012/559 − 32, 2012/762 − 39, 2012/1488-32, 2013/43 − 32, 2013/1418-32, 2014/678 − 32, 2014/1789-32, 2015/618 − 32, and 2021 − 00326.

Consent for publication

Not applicable

Competing Interests

Mikael Landén declares that he has received lecture honoraria from Lundbeck pharmaceuticals and has served as consultant for AstraZeneca. Christoph Abé is an employee of Quantify Research. No other author has any conflict of interest to declare.

Funding

Open access funding provided by University of Gothenburg. The SBP was supported by grants from the Swedish Research Council (2008-14647-06-3, 2010–21569, 2010–21568, 2018–02653, 2022 − 01643), Hjärnfonden/the Swedish Brain foundation (FO2020-0261, FO2022-0217), the Swedish foundation for Strategic Research (KF10-0039), and the Swedish Government under the LUA/ALF agreement (ALF 20100305, ALF 20200036, ALFGBG-716801, ALFGBG-965444).

Author Contribution

EP wrote the main manuscript text and prepared figures. EP and MK prepared tables. All authors edited and reviewed the manuscript and approved the final version.

Acknowledgement

We are deeply grateful for the participation of all individuals contributing to this research, and to the staff at the St. Göran bipolar affective disorder unit and Gothenburg Bipolar Clinic (Bipolärmottagning), including study nurses Agneta Carlswärd-Kjellin, Annika Blom, Benita Gezelius, Lena Lundberg, Stefanie Unger, Stina Stadler, and Therese Turesson, coordinator Martina Wennberg, and data manager Haydeh Olofsson. Yngve Hallström is acknowledged for performing lumbar punctures in the SBP-S.

Availability of data and materials

Not applicable

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Competing interest reported. Mikael Landén declares that he has received lecture honoraria from Lundbeck pharmaceuticals and has served as consultant for AstraZeneca. Christoph Abé is an employee of Quantify Research. No other author has any conflict of interest to declare.

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Cohort Profile: The St. Göran Bipolar Project

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Abstract

Background

Methods

Discussion

Trial registration

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Background

Methods

Collaborative arrangements

Recruitment approach

Baseline study procedures

Inclusion and exclusion criteria

Follow-up visit study procedures

Self-reported rating scales

2.2.6 Neuropsychiatric assessment

Neuropsychological tests

Blood sampling and lumbar puncture

Magnetic resonance imaging

Discussion

General descriptive information

Neuropsychology and personality

Cerebrospinal fluid markers

Blood markers

Magnetic resonance imaging

Genetics

Strengths and limitations

Conclusions

Abbreviations

Declarations

Competing Interests

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Author Contribution

Acknowledgement

Availability of data and materials

References

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