Abstract: Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD). Aims To reach consensus regarding threshold definitions criteria for TRBD and MTRBD. Method Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method. Results TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. Conclusions The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research. Declaration of interest In the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J & J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.

Abstract: Individuals with treatment-resistant depression (TRD) experience a high burden of illness. Current guidelines recommend a stepped care approach for treating depression, but the extent to which best-practice care pathways are adhered to is unclear. Aims To explore the extent and nature of ‘treatment gaps’ (non-adherence to stepped care pathways) experienced by a sample of patients with established TRD (non-response to two or more adequate treatments in the current depressive episode) across three cities in the UK. Method Five treatment gaps were considered and compared with guidelines, in a cross-sectional retrospective analysis: delay to receiving treatment, lack of access to psychological therapies, delays to medication changes, delays to adjunctive (pharmacological augmentation) treatment and lack of access to secondary care. We additionally explored participant characteristics associated with the extent of treatment gaps experienced. Results Of 178 patients with TRD, 47% had been in the current depressive episode for 〉 1 year before initiating antidepressants; 53% had received adequate psychological therapy. A total of 47 and 51% had remained on an unsuccessful first and second antidepressant trial respectively for 〉 16 weeks, and 24 and 27% for 〉 1 year before medication switch, respectively. Further, 54% had tried three or more antidepressant medications within their episode, and only 11% had received adjunctive treatment. Conclusions There appears to be a considerable difference between treatment guidelines for depression and the reality of care received by people with TRD. Future research examining representative samples of patients could determine recommendations for optimising care pathways, and ultimately outcomes, for individuals with this illness.

Abstract: Childhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience. Aims To determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis. Method We investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum. Results Childhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD. Conclusions Childhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI. Declaration of interest D.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck.

Abstract: Surgically implanted vagus nerve stimulation (VNS) is a recognised treatment for depression. The vagus nerve can also be stimulated non-invasively via its auricular branch, using transauricular vagus nerve stimulation (taVNS). Heart rate variability (HRV) is a putative biomarker of autonomic nervous system (ANS) engagement. We aimed to test the impact of taVNS on the ANS of healthy volunteers by measuring HRV using a double-blind, sham-controlled, longitudinal design to acquire data over 7 days using wearable cardiac sensors. Methods taVNS was delivered to the left ear of healthy volunteers using a transcutaneous electrical nerve stimulation (TENS) device via a custom clip electrode (developed at Newcastle University). All participants were stimulated at 10 Hz, with pulse widths of 300 ms and variable current outputs, depending on perceptual thresholds. We delivered double-blinded active and sham taVNS for hour-long periods, in the morning and evening. We also recorded an electrocardiogram (ECG) lead I using a VitalPatch for 7 consecutive days. Python scripts were developed to produce HRV timeseries and plot data. ECG frequency domain parameters – low- (LF) (0.05–0.15 Hz) and high-frequency (HF) power (0.15–0.4 Hz) – were calculated for each stimulation period. The LF/HF ratio was used as a marker of autonomic modulation. The Wilcoxon signed-rank test was used to compare LF/HF ratio distributions. Results Initial data from the wearable sensors were used to develop interpolation scripts to improve the processing of noise, missed R waves and ectopic beats, to reduce errors when estimating HRV from the heart rate signal. Initial results from 97 individual 1-hour long stimulation periods, from 18 participants, show that active stimulation in the morning, when compared with sham stimulation in the same period, significantly reduces the LF/HF ratio. The median and interquartile range (IQR) of the LF/HF ratio for the active and sham periods was, respectively, 1.72 (1.99) and 2.75 (2.82), a statistically significant difference (p = 0.043). Conclusion taVNS modulates HRV frequency domains, suggestive of vagal cardiac effects, and replicates findings from previous taVNS studies. Reductions in the LF/HF ratio are suggestive of increased parasympathetic tone. As the auricular branch of the vagus does not have any direct cardiac efferents, this suggests central ANS modulation using taVNS. Secondly, it suggests that cardiac ANS modulation could be used as a proxy measure of afferent vagal stimulation, which could be of clinical utility. These effects warrant exploration in a larger cohort study, including wider demographics (including age range) and improved processing pipelines.

Abstract: The effects of in utero exposure to atypical antipsychotics on infant birth weight are unknown. Aims To determine whether atypical and typical antipsychotics differ in their effects on birth weight after maternal exposure during pregnancy. Method Prospective data on gestational age and birth weight collected by the National Teratology Information Service for infants exposed to typical ( n =45) and atypical ( n =25) antipsychotics was compared with data for a reference group of infants ( n =38). Results Infants exposed to atypical antipsychotics had a significantly higher incidence of large for gestational age (LGA) than both comparison groups and a mean birth weight significantly heavier than those exposed to typical antipsychotics. In contrast those exposed to typical antipsychotics had a significantly lower mean birth weight and a higher incidence of small for gestational age infants than the reference group. Conclusions In utero exposure to atypical antipsychotic drugs may increase infant birth weight and risk of LGA.

Abstract: Autonomic nervous system (ANS) dysregulation might be relevant to the pathophysiology of fatigue and cognitive impairment in depression and perhaps should be considered when making prescribing decisions. Aims To determine the relationship of self-reported ANS symptoms with fatigue, cognition and prescribed medication in people with a diagnosis of depression, in comparators without depression but with other mental health, neurodevelopmental or neurodegenerative disorders (active controls) and in healthy controls. Method Cross-sectional analysis of an opportunistic sample from England. Self-reported data were collected on demographics, diagnosis, medication, ANS symptoms (Composite Autonomic Symptom Scale-31, COMPASS-31) and fatigue (Visual Analogue Scale for Fatigue, VAS-F). A subsample completed cognitive tests (THINC-it), including the subjective Perceived Deficits Questionnaire five-item version (PDQ-5). Spearman's correlation and mediation models were used to explore the relationship between COMPASS-31, VAS-F and PDQ-5 scores. Results Data were obtained for 3345 participants, 22% with depression. The depression group had significantly ( P 〈 0.01) more severe autonomic dysregulation as measured by COMPASS-31 scores (median 30) than active (median 23) and healthy controls (median 10). The depression group had significantly higher symptom severity ( P 〈 0.01) than both control groups on the VAS-F and PDQ-5. Overall, there was a significantly positive correlation ( P 〈 0.01) between COMPASS-31, VAS-F scores (Spearman's rho r s = 0.44) and PDQ-5 scores ( r s = 0.56). COMPASS-31 scores mediated greater symptom severity on the VAS-F and PDQ-5 for those with depression. COMPASS-31 scores remained significantly different between the depression group and both control groups independently of medication. Conclusions People with a diagnosis of depression report worse fatigue and cognition than active and healthy comparators; this appears to be mediated by ANS dysregulation.

Abstract: When parenteral treatments are indicated for acutely disturbed behaviour, previous guidelines have recommended droperidol or haloperidol in combination with benzodiazepines. However, there has been recent concern over cardiotoxicity and sudden death associated with some antipsychotic medication and droperidol has now been withdrawn. Aims To ascertain what alternatives can be recommended to replace intramuscular droperidol. Method Selective review of current guidelines and the literature pertaining to rapid parenteral tranquillisation. Results Current guidelines recommend haloperidol as an alternative to droperidol. There is evidence of cardiotoxicity with haloperidol and it has a propensity to cause extrapyramidal side effects that may exacerbate disturbed behaviour and reduce longer-term compliance. The rapid-acting intramuscular formulations of atypical antipsychotic agents show promise. Conclusions It is recommended that the mainstay of pharmacological rapid tranquillisation should be parenteral benzodiazepines used with due care.

Abstract: Across the UK there are a number of tertiary level affective disorder services, usually based in academic centres, that provide support for the management of patients with complex and treatment-resistant conditions. Such services play a potentially important role in instilling hope into patients, carers and healthcare teams in situations where therapeutic nihilism has often developed. They also provide a valuable reservoir of expertise on the use of medications outside of licensed usage, and new and emerging treatments. To date there is relatively little data regarding patient outcomes after referral to such services; however, what there is does suggest important benefits for both patients and healthcare economies. As ever, more research is needed.