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. Author manuscript; available in PMC: 2018 Jul 25.
Published in final edited form as: JAMA Psychiatry. 2017 Dec 1;74(12):1206–1213. doi: 10.1001/jamapsychiatry.2017.2943

A test of the trans-diagnostic dopamine hypothesis of psychosis, using PET imaging in bipolar affective disorder and schizophrenia

Sameer Jauhar 1,2, Matthew Nour 1,4, Mattia Veronese 3, M Rogdaki 4, Ilaria Bonoldi 1,2, Matilda Azis 1, Federico Turkheimer 3, Allan H Young 5, Oliver D Howes 5
PMCID: PMC6059355  EMSID: EMS76202  PMID: 29049482

Abstract

Importance

The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis irrespective of diagnosis, suggesting dopamine dysregulation in bipolar affective disorder as well as schizophrenia, in line with the research domain criteria (RDOC) approach. However, this has not been directly examined in people presenting with bipolar disorder with psychosis.

Objectives

To determine whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis, and how this compares to schizophrenia, and matched controls. Furthermore, to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class.

Setting

First episode psychosis services in an inner-city area.

Design

Cross sectional, case-control study.

Participants

60 people participated in the study (22 with bipolar psychosis, (18 antipsychotic naïve/free), 16 with schizophrenia (14 antipsychotic naïve/free) and 22 matched controls) and received 18F-DOPA PET examining dopamine synthesis capacity. Standardized clinical measures including the Positive and Negative Syndrome Scale (PANSS), Young’s Mania Rating Scale (YMRS), and Global Assessment of Functioning (GAF) were administered.

Main outcomes and measures

Dopamine synthesis capacity ([18F]-DOPA Kicer) and clinical measures (PANSS, YMRS, and GAF).

Results

Mean age (SD) of the people with bipolar psychosis (n=22, 13 male) was 23.6 (3.6) years, people with schizophrenia (n=16, 14 male) 26.3 (4.4) years and controls (n=22, 14 male) was 24.5 (4.5) years. There was a significant effect of diagnostic group on striatal dopamine synthesis capacity {Bibliography}(Kicer) (F (2, 57) =6.8, p=0.002). Kicer was significantly elevated in both bipolar (mean=13.18 x10-3 min-1 (SD 1.08 x10-3 min-1), p=0.002) and schizophrenia (mean=12.94 x10-3 min-1 (SD 0.79 x10-3 min-1), p=0.04) groups, compared to controls (mean=12.16 x10-3min-1 (SD 0.92 x10-3 min-1). There was no significant difference in dopamine synthesis capacity between bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode (n=32, r=0.52, p=0.003). There was a significant association between Kicer and positive psychotic symptom severity in people with bipolar disorder experiencing a current psychotic episode (n=16, r=0.6, p=0.01), which remained significant after adjusting for manic symptom severity.

Conclusions

These findings are consistent with a trans-diagnostic role for dopamine dysfunction in the pathoetiology of psychosis, and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder, as well as schizophrenia.

Introduction

Psychotic illnesses, such as schizophrenia and bipolar affective disorder, have a combined lifetime prevalence of around 3% 1. The research domain criteria initiative from the National Institute of Mental Health proposes common neurobiological mechanisms underlie symptom domains across disorders 2. The neuromodulator dopamine has been implicated in the pathophysiology of psychosis in schizophrenia 3–8,9 and psychosis in other disorders10. Studies employing positron emission tomography (PET) have demonstrated increased striatal dopamine synthesis capacity in schizophrenia11. Dopamine synthesis capacity is also elevated in people at high clinical risk of psychosis 12,13 14,15 16, some of whom may develop bipolar affective disorder with psychosis 17, and in people with psychosis in the context of temporal lobe epilepsy 10. These findings suggest elevated dopamine synthesis capacity may be trans-diagnostic, underlying psychosis across disorders, rather than specific to schizophrenia. Evidence also suggests dopamine dysfunction increases with development of psychosis 15, and is greater in acute psychosis relative to remission 9, suggesting a state component.

Bipolar affective disorder has an approximate lifetime prevalence of 1%18, and approximately half of patients develop psychosis, predominantly in the manic phase 19. Psychotic symptoms in bipolar affective disorder respond to antipsychotic drugs (dopamine D2/D3 blockers), suggesting a dopaminergic abnormality could underlie these symptoms 20,21–32,33. Dopamine synthesis capacity is unaltered in bipolar disorder without psychosis 34, though it remains unclear if dopamine synthesis capacity is altered in people with bipolar disorder with a history of psychosis, whether this is related to psychotic symptoms, or how this compares to schizophrenia.

We therefore sought to investigate dopamine synthesis capacity indexed using [18F]-DOPA PET imaging in people with bipolar psychosis. We hypothesized that:

  1. People with bipolar psychosis would have elevated striatal dopamine synthesis capacity compared to matched healthy controls, and that this elevation would be comparable to schizophrenia.

  2. Striatal dopamine synthesis capacity would positively correlate with psychotic symptom severity in people currently experiencing psychosis, irrespective of diagnosis, in line with evidence linking dopamine dysregulation to psychotic state 9,15.

Methods

Ethical permission was obtained from the local ethics committee. All participants provided informed written consent to participate. An a priori power calculation in G*power was used to determine the minimum sample size (see Supplementary Information, SI).

Participants

Patients with bipolar disorder were recruited from first episode psychosis services. Inclusion criteria were: 1) met diagnostic (DSM-IV) criteria for bipolar affective disorder type I as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders35; 2) at least one current or previous psychotic episode (defined below); 3) no evidence symptoms were drug-induced.

People with schizophrenia were recruited from the same first episode psychosis services, matched with the bipolar group for age (within 5 years). Inclusion criteria were: 1) met the Structured Clinical Interview for DSM-IV Axis I Disorders 35 criteria for schizophrenia, 2) at least one current/previous psychotic episode as defined below 3) no evidence the symptoms were drug- induced.

A psychotic episode was defined as at least moderate severity on one or more of delusion (P1), hallucination (P3), and persecution (P6) items on the positive and negative syndrome scale (PANSS) lasting for at least one week, consistent with research definitions 17. We excluded the conceptual disorganization item as this could be confounded by mania.

Age matched (within 5 years) healthy controls were recruited contemporaneously from the same geographical area through advertisements in local media. Healthy volunteers had no previous or current history of psychiatric illness (assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders) 35, no concurrent psychotropic medication and no family history of psychosis. See SI for full exclusion criteria.

Clinical assessments

Participants were assessed on day of PET scan with PANSS36, General Assessment of Functioning (GAF), and, in the bipolar group, Young Mania Rating Scale (YMRS)37.

All patients received clinical follow-up for a minimum of 18 months to determine diagnostic stability using DSM-IV criteria.

Medication history was recorded, and people sub-classified as antipsychotic naïve (no current/previous treatment), antipsychotic-free (not currently taking antipsychotic medication with at least 6 weeks or 6 months wash-out for oral and depot medication, respectively), or currently treated with antipsychotics38.

[18F]-DOPA PET imaging

Imaging data were obtained on a Siemens Biograph 6 HiRez PET scanner (Siemens, Erlangen, Germany) in three-dimensional mode. Participants were not permitted to smoke for four hours preceding the scan39. One hour before the scan, participants received 400mg entacapone, a peripheral catechol-o-methyl-transferase inhibitor, and 150mg carbidopa, a peripheral aromatic acid decarboxylase inhibitor, to prevent formation of radiolabeled metabolites that may cross the blood–brain barrier40. After acquiring a CT scan for attenuation correction, approximately 160 MBq of [18F]-DOPA was administered by bolus intravenous injection 30s after the start of PET imaging. (See SI.)

PET Image Analysis

The region-of-interest (ROI) analysis was conducted blind to group status. Our primary endpoint was whole striatal influx constant (Kicer, written as Ki in previous publications 41). In view of evidence that dopaminergic alterations may be more marked in schizophrenia in associative sub-division of striatum relative to other regions 13,42,43, and elevated in the substantia nigra43 we also conducted secondary analyses of these regions. SPM8 44 was used to automatically normalize a tracer-specific template 13,45 together with functional striatal and substantia nigra ROIs defined in MNI space46 47 to each individual PET summation realigned image. Further details of striatal sub-divisions are given in SI. The cerebellum was used as reference region, defined as per 47. Kicer was calculated using the Patlak-Gjedde graphical approach adapted for reference tissue input function, shown to have good reliability45. Though the reference region approach is robust to global differences in radiotracer delivery to brain48, we examined the reference region (cerebellum) to see whether there was any change in standardized uptake value (SUV) in cerebellum at 95 minutes.

An exploratory voxel-wise analysis was conducted to determine sub-regional differences in Kicer between groups (see SI).

Statistical Analysis

Statistical analyses were performed using Excel49 and SPSS Version 23 50. Normality of distribution was confirmed using Shapiro-Wilk’s test. Independent sample t tests for normally distributed data and Mann Whitney U tests for non-parametric data used to test if there were differences in demographic and clinical variables between groups.

To test for differences in striatal dopamine synthesis capacity between the three diagnostic groups we used analysis of variance (ANOVA), with Tukey’s tests for post-hoc pairwise comparisons. To test the association between dopamine synthesis capacity and positive psychotic symptom scores in people experiencing a current psychotic episode (irrespective of diagnosis) we used Pearson’s product moment correlation. We additionally restricted this analysis to people with bipolar affective disorder and schizophrenia separately. Manic symptoms may be linked to dopamine dysfunction 25,51,52, and may co-vary with psychotic symptoms. Therefore, we also conducted partial correlation with YMRS as covariate (excluding the ‘content’ item on the YMRS, as this indexes psychotic symptoms).

Plots were inspected for outliers, and Cook’s distance of 4/n was used to identify outliers. A two-tailed significance (alpha) threshold of 0.05 was used throughout.

Results

Demographic and clinical characteristics

22 people were included in the bipolar, 22 in healthy control and 16 in the schizophrenia groups. All bipolar patients received follow-up, which confirmed diagnoses remained stable.

Demographic details for all participants are given in Table 1. There were no significant differences between illness groups and healthy volunteers in age, gender, or radiation dose received.

Table 1.

Study participant demographic and clinical details.

Bipolar Schizophrenia Healthy volunteers P value
N 22 16 22
Age (mean, SD) 23.55 (3.62) 26.31 (4.4) 24.45 (4.54) p=0.14
Male (%) 13 (59.1%) 14 (87.5%) 14 (61%)
Medication status Antipsychotic naïve/free, N=18 (81.8%; naïve, n=10, free=8)
Taking antipsychotic, N=4 (18.2%)		 Antipsychotic naïve/free, N=14 (87.5%; naïve, n=11, free=3)
Taking antipsychotic, N=2 (12.5%)		 n/a
Ethnicity 9 Caucasian
8 Black
1 Asian
4 Mixed		 5 Caucasian
7 Black
1 Asian
3 Mixed		 13 Caucasian
3 Black
4 Asian
2 Mixed
Duration of illness, in months
(Median, IQR) 		12 (18.5) 24 (24) n/a p=0.04
Prior antipsychotic medication (CPZ dose years)
(Median, IQR) 		0.14 (1.33) 0.05 (0.03) n/a p=0.42
Radioactivity injected (MBq) 151.37 (13.7) 144.4 (12.29) 154.65 (14.51) p=0.71
PANSS Positive Subscale Score 16.05 (8.22) 18.81 (4.12) n/a p=0.18
PANSS Negative Subscale Score 12.27 (5.4) 17.75 (6.32) n/a p=0.01
PANSS Total Symptoms Score 56.48 (20.73) 72.94 (16.46 n/a p=0.01
Global assessment of function 61.73 (15.94) 46.5 (13.06) n/a p=0.01
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There were significant differences between bipolar and schizophrenia samples in PANSS negative and total symptom ratings, and duration of illness (See Table 1).

All 16 people with schizophrenia and 16 of the 22 in the bipolar group fulfilled criteria for a current psychotic episode, the remainder having a history of a psychotic episode within the last two years.

Of the 22 people with bipolar psychosis, 18 were not taking antipsychotics at time of PET scan (10 antipsychotic-naive, 8 antipsychotic-free; see SI).

Of the 16 people with schizophrenia, 14 were not taking antipsychotics at time of PET scan (see Table 2). Two people were taking aripiprazole at time of scan, one for less than 2 weeks.

Table 2.

Striatal dopamine synthesis capacity (Kicer) by group for the bilateral whole striatum, and bilateral functional striatal subdivisions.

Striatal region Mean (sd) Kicer Bipolar (n=22) Mean (sd) Kicer Schizophrenia (n=16) Mean (sd) Kicer Controls (n=22)
Whole striatum 13.18 x 10-3 (1.08 x 10-3) 12.94 x 10-3 (0.79 x 10-3) 12.16 x 10-3 (0.92 x 10-3)
Associative Striatum 13.22 x 10-3 (1.19 x 10-3) 12.95 x 10 -3 (0.86 x 10-3) 12.15 x 10-3 (0.89 x 10-3)
Limbic Striatum 13.05 x 10-3 (0.9 x 10-3) 12.56 x 10-3 (0.81 x 10-3) 11.95 x 10-3 (1.03 x 10-3)
Sensorimotor Striatum 13.16 x 10-3 (1.13 x 10-3) 13.09 x 10-3 (0.91 x 10-3) 12.31 x 10-3 (1.25 x 10-3)
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Dopamine synthesis capacity across illness and control groups

There was no significant effect of group on standardized uptake values in the reference region (see SI). There was no significant effect of group on head motion for the three conditions (mean (sd)/mm: bipolar=13.06 (9.07); schizophrenia=14.52 (6.46) and controls=9.61 (9.49); F (2,57)=1.68 (p=0.2).

Whole striatum

There was a significant effect of group on Kicer (F (2,57)=6.8 (p=0.002, see Table 1. Post-hoc comparisons showed that Kicer in both bipolar group and schizophrenia groups was significantly elevated relative to controls, with large effect sizes (Bipolar: Cohen’s d=1.02, p=0.002; Schizophrenia: Cohen’s d=0.91, p=0.04). There was no significant difference in Kicer between bipolar and schizophrenia groups (p=0.73). The effect of group on Kicer remained significantly after excluding people taking antipsychotic medication (leaving n=18 in the bipolar group, and n=14 in the schizophrenia group; F (2, 51)=6.4, p=0.003; mean Kicer (sd) x 10-3min-1: bipolar=13.17 (1.13), schizophrenia=12.94 (0.72) and controls=12.16 (0.92)). As the schizophrenia group had longer illness duration than the bipolar group we ran a secondary analysis of the relationship between Kicer and illness duration across patient groups. This showed no significant relationship (r=-0.05, p=0.78).

Voxelwise analysis identified a significantly greater Kicer in the bipolar group relative to controls (peak in the right striatum, Figure 1), and in the schizophrenia group relative to controls (peak in the left putamen.) Relative to controls, the sub-regional analyses showed significant elevations in all three functional striatal sub-divisions in the bipolar group, but only trend in the associative striatum in the schizophrenia group, and no differences in the nigra for either group (see SI).

Figure 1. Voxel-wise comparison of striatal dopamine synthesis capacity in the bipolar psychosis relative to control group.

Figure 1

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Increased striatal dopamine synthesis capacity is evident in bipolar psychosis (N=22) relative to controls (N=22). The color bar shows the t-statistic. The most significant increase was in right caudate (Peak at MNI coordinates x=8, y=10, z=-8; Tstat=3.96, pFWE corr=0.03). Image thresholded at P<0.001 (uncorrected) using inclusive striatal mask (for illustration purposes only).

Relationship between Kicer and PANSS positive symptoms across diagnostic groups

We found a significant association between Kicer and PANSS positive symptoms in the combined sample of patients experiencing a current psychotic episode (n=32, r=0.52, p=0.003). Cook’s distance test identified one potential outlier, but removal of this subject did not affect significance (r=0.49, p=0.01). There was no relationship between Kicer and PANSS negative or total symptom scores (p=0.48, p=0.1).

Symptom correlation in bipolar disorder

In the whole sample of people with bipolar disorder (with and without a current psychotic episode) there was a trend for a significant relationship between whole striatal Kicer and PANSS positive symptoms (n=22, r=0.42, p=0.05). This relationship was significant when the sample was restricted to bipolar patients with a current psychotic episode (n=16, r=0.6, p=0.01), and remained significant after co-varying for YMRS (excluding ‘content’ item, r=0.56, p=0.046).

Symptom correlation in schizophrenia

In the whole sample of schizophrenia patients (all experiencing a current psychotic episode) there was no correlation between whole striatal Kicer and PANSS positive symptoms (n=16, r=0.31, p=0.24).

Discussion

Dopamine synthesis capacity was elevated with a large effect size (Cohen’s d=1.02) in people with bipolar affective disorder and a current or previous psychotic episode, compared to healthy controls. Dopamine synthesis capacity was significantly elevated in the schizophrenia group relative to controls. Moreover, dopamine synthesis capacity was associated with the severity of psychotic symptoms in the bipolar group, explaining 36% of the variance in psychotic symptoms. This relationship remained significant after adjusting for severity of manic symptoms.

The finding of no difference in Kicer in substantia nigra between schizophrenia and controls differs from Howes et al 43, although it should be noted our current study is under-powered to detect this effect.

Our finding of a relationship between positive psychotic symptoms and dopamine synthesis capacity in the combined sample but not in the schizophrenia group could be due to lack of power, and/or inclusion of more treated patients in the schizophrenia group. Notwithstanding this, whilst some studies in schizophrenia have found relationships with symptoms 43,53, a number have not 53,54,55,56,57, suggesting further work is needed to disentangle these relationships.

Strengths and limitations

A strength is the relatively large number of antipsychotic naïve/free subjects. Furthermore, most subjects were symptomatic and experiencing an acute psychotic episode when scanned. Bipolar and schizophrenia groups were matched for age and medication status, but by chance the schizophrenia group had significantly longer illness duration. However, there was no relationship between illness duration and Kicer in either group. A concern in first episode samples is that diagnoses may change. However, in bipolar disorder over 90% of diagnoses made on initial presentation are stable two years later59, though, diagnoses may be more dynamic in the early intervention services that we recruited from, as they aim to see patients as soon as possible. On follow-up (minimum 18 months) none of the people classified with either schizophrenia or bipolar disorder had their diagnoses changed, and the validity of diagnosis is strengthened by the difference in negative, but not positive symptoms, between groups. We did not detect a difference in head motion between groups, though it was greater in absolute terms in patient groups. Given that motion, especially in basal ganglia, causes loss of resolution 60, any residual motion after motion correction would reduce Kicer. However, as this would lead to an under-estimate of Kicer, it would not account for our findings.

A possible limitation is the lack of a non-psychotic control group, given possible non-specific effects of illness, though a prior [18F]-DOPA study in non-psychotic mania failed to find a difference in comparison to control subjects 61. Our study was not constructed nor powered to detect a difference between bipolar psychosis and schizophrenia.

A small number of people were taking antipsychotic medication. Preclinical studies suggest antipsychotic blockade of autoreceptors should cause increased DOPA uptake62,63. However, these studies generally used relatively short exposures to antipsychotics, which may not be equivalent to months of patient exposure. Indeed, there is evidence from animal studies that 3 weeks of antipsychotic treatment leads to depolarization, decreasing spontaneous firing of dopamine neurons 64, which would reduce dopamine synthesis. Consistent with this, the one human study found that sub-chronic antipsychotic treatment reduced [18F]-DOPA uptake in people with schizophrenia65, which would not explain our results as it would mask any difference compared to controls. However, subjects in this study only took haloperidol and it remains to be determined in patients what effect other antipsychotics have on Kicer. Nonetheless, Kicer remained significantly elevated in the patient groups when our analysis was restricted to drug naïve/ drug free patients, indicating our findings are not explained by direct treatment effects.

Our outcome measure, Kicer, indexes the uptake of [18F]-DOPA into dopamine neurons, its conversion by aromatic acid decarboxylase into [18F]-dopamine and storage in terminals 48. Thus, the increased Kicer we report is likely to reflect an increase in one or more of these processes, and a net increase in dopamine synthesis capacity 66. However, as tyrosine hydroxylase, not aromatic acid decarboxylase, is the rate-limiting step in dopamine synthesis, this interpretation could be affected if there are alterations in tyrosine hydroxylase levels or activity. Indeed, reduced tyrosine hydroxylase levels could conceivably lead to reduced net dopamine synthesis despite a compensatory increase in aromatic acid decarboxylase activity detectable with [18F]-DOPA imaging.

We did not measure plasma input function. There could conceivably be alterations in the delivery of [18F]-DOPA, though the reference region approach is robust to global differences 48. To exclude this potential confounding factor, we examined the reference region to see whether there was any change across groups, finding no difference.

Kicer reflects a composite of kinetic parameters, including not only blood-tissue transportation (i.e. K1 and k2), but also relative activity of aromatic acid (DOPA) decarboxylase with respect to [18F]-DOPA (k3) and the elimination of decarboxylated [18F]-DOPA metabolites from the brain (kloss) 48,67. Therefore, whilst our findings indicate elevation in these aspects of dopaminergic activity, differences measured for Kicer could reflect change in one or more of these parameters. However, Kicer has been shown to correlate well with the [18F]-DOPA decarboxylation rate (k3D) derived from the 2 tissue compartmental model with a metabolite corrected arterial plasma input function in both normal and pathological conditions 68,69. Moreover, if any bias was introduced by the quantification approach in Kicer estimates it is likely to be consistent across all three groups in the case-control study. Notwithstanding this, future studies could address this by measuring the arterial input function.

Implications for the neurobiology underlying bipolar disorder

Our findings contrast with prior molecular imaging studies in bipolar disorder, which have found dopamine synthesis and release capacity was unaltered 34,70. However, in contrast to our study, neither study included people with bipolar illness with current psychosis, although the first did include manic patients, and did not find a relationship between manic symptoms and dopamine synthesis capacity. Moreover, the association between Kicer and psychotic symptoms in our sample remained after controlling for manic symptoms, suggesting it is not driven by mania. Thus, our findings, taken with the previous findings, suggests elevated dopamine synthesis capacity is linked to psychosis in bipolar disorder. However, a direct comparison between people with bipolar disorder with and without psychosis is needed to definitively test the specificity of our findings to psychosis in bipolar disorder. Whilst we have found an association between dopamine synthesis capacity and bipolar psychosis, this does not imply causality. Further studies are required to determine the relationship between dopamine synthesis capacity and development of psychosis in bipolar disorder.

Implications for a trans-diagnostic role for dopamine in psychotic disorders

Our findings, that dopamine synthesis capacity is elevated in psychotic bipolar affective disorder to a similar degree to schizophrenia, and is related to severity of psychotic (positive) symptoms, extend previous findings that dopamine synthesis capacity is elevated in schizophrenia 11 and psychosis associated with temporal lobe epilepsy 10, and increases with the onset of psychosis 15, to suggest that presynaptic dopamine dysfunction is associated with psychosis across diagnostic categories. This provides a potential neurobiological explanation for why antipsychotic drugs, which are all dopamine 2/3 receptor blockers, are effective in bipolar psychosis as well as schizophrenia 71,72, and identifies the regulation of dopamine synthesis as a potential target for novel treatments for bipolar psychosis as well as schizophrenia.

Supplementary Material

Supplementary

Key Points.

Question

Is dopamine synthesis capacity elevated in bipolar psychosis compared to control subjects, how does this compare to schizophrenia, and is there a relationship between dopamine synthesis capacity and positive psychotic symptoms, irrespective of diagnosis?

Findings

In this case-control PET study of 22 people with first episode bipolar psychosis, 16 people with first episode schizophrenia and 22 control subjects, there was a statistically significant elevation in dopamine synthesis capacity in bipolar psychosis, compared to controls. This difference was similar to that seen in schizophrenia. There was a statistically significant association between positive psychotic symptoms and dopamine synthesis capacity in the whole sample, explaining 27% of the variance.

Meaning

Dopamine synthesis capacity is elevated in bipolar psychosis, and is directly related to positive psychotic symptoms irrespective of diagnosis.

Figure 2. Relationship between dopamine synthesis capacity and positive psychotic symptom rating in bipolar and schizophrenia groups.

Figure 2

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There was a significant positive correlation between psychotic (positive) symptom severity and dopamine synthesis capacity (r=0.52, p=0.003).

Acknowledgements

Conflict of Interest Disclosure

Professor Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither Dr Howes or his family have been employed by or have holdings/ a financial stake in any biomedical company.

Professor Young has received payment for lectures and advisory boards for the following companies with drugs used in affective and related disorders

AstraZeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, Livanova

No share holdings in pharmaceutical companies

Lead Investigator for Embolden Study (AZ), BCI Neuroplasticity study and Aripiprazole Mania Study

Investigator initiated studies from AZ, Eli Lilly, Lundbeck, Wyeth

Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR

Funding support

This study was funded by Medical Research Council-UK (no. MC-A656-5QD30), Maudsley Charity (no. 666), Brain and Behavior Research Foundation, and Wellcome Trust (no. 094849/Z/10/Z) grants to Dr Howes and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Role of Funder/Sponsor Statement: The funding body had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Access to Data and Data Analysis: Dr Jauhar and Professor Howes had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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