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1.  TSPAN5, ERICH3 and Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder: Pharmacometabolomics-informed Pharmacogenomics 
Molecular psychiatry  2016;21(12):1717-1725.
Millions of patients suffer from Major Depressive Disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, four and eight weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (p<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (p<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (p=7.84E-09) SNP clusters on chromosome four 5’ of TSPAN5 and a cluster across ERICH3 on chromosome one (p=9.28E-08) that were also observed during GWAS for change in serotonin at four (p=5.6E-08 and p=7.54E-07, respectively) and eight weeks (p=1.25E-06 and p=3.99E-07, respectively). The SNPs on chromosome four were eQTLs for TSPAN5. Knockdown (KD) and over expression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may play a role in SSRI treatment outcomes.
PMCID: PMC5003027  PMID: 26903268
Pharmacometabolomics; pharmacogenomics; selective serotonin reuptake inhibitors; ERICH3; TSPAN5; major depressive disorder
2.  Depressive Symptom Severity and Mortality in Older Adults Undergoing Percutaneous Coronary Intervention 
PMCID: PMC5106288  PMID: 27414733
cardiac; depression; elderly; outcome; revascularization
3.  Gender‐specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states 
Addiction (Abingdon, England)  2016;111(8):1366-1375.
Background and Aims
Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life‐time diagnoses of major depressive disorder (MDD), substance‐induced depression (SID), anxiety disorder (AnxD) and substance‐induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex.
Secondary analyses of baseline data collected in a single‐arm study of pharmacogenetic predictors of acamprosate response.
Academic medical center and affiliated community‐based treatment programs in the American upper mid‐west.
A total of 287 males and 156 females aged 18–80 years, meeting DSM‐IV criteria for alcohol dependence.
The primary outcome measure was ‘propensity to drink in negative emotional situations’ (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders).
The prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P < 0.01, each), while SIA was rare (3.3%) and did not differ by sex. Increased propensity to drink in negative emotional situations was associated with comorbid MDD (β = 6.6, P = 0.013) and AnxD (β = 4.8, P = 0.042) as well as a SID × sex interaction effect (P = 0.003), indicating that the association of SID with propensity to drink in negative emotional situations differs by sex and is stronger in males (β = 7.9, P = 0.009) compared with females (β = −6.6, P = 0.091).
There appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics. Substance‐induced depression appears to have a sex‐specific effect on the increased risk for drinking in negative emotional situations in males.
PMCID: PMC4940218  PMID: 27009547
Alcohol use disorder; anxiety; craving; depression; gender; substance‐induced
4.  Mixed mania associated with cessation of breastfeeding 
This case chronicles the unique presentation of psychotic mixed mania in a female 5 months after parturition and 1 week following breastfeeding discontinuation, highlighting a rarely recognized mania risk factor that is temporally delayed from parturition: breastfeeding discontinuation.
Case presentation
A 25-year-old G1P1 female with a past psychiatric history of a depressive episode in adolescence presented to the Emergency Department with her 5-month-old daughter, fiancée, and family 1 week after breastfeeding cessation. She endorsed sleep-deprived energy enhancement, unfulfilled goal-oriented productivity, hyper-talkativeness, hyper-sexuality and increased nicotine use. Concurrent depressive symptoms included hopelessness, worthlessness, poor concentration, lack of appetite, and ego-dystonic intrusive thoughts that she may kill herself or her child. She exhibited pressured speech, affective lability, expansiveness, distractibility, and tangential, grandiose, delusional self-referential content. Transient thoughts of self-harm and harm to her child were not associated with intent. Her family history was significant for a deceased mother who had bipolar I disorder. The patient was hospitalized for 5 days and diagnosed with bipolar disorder, type I, current episode manic with psychotic features with a mixed-feature specifier. Olanzapine and lithium were initiated and the patient’s acute episode of mania resolved prior to discharge.
This case extends the limited literature on mania following weaning and highlights the role of rapid serum dopamine rise following breastfeeding cessation in mania.
PMCID: PMC5011067  PMID: 27593209
Bipolar disorder; Breastfeeding; Weaning; Mania
5.  National Survey and Community Advisory Board Development for a Bipolar Disorder Biobank 
Bipolar disorders  2015;17(6):598-605.
To engage a national advocacy group and local stakeholders for guidance in developing a bipolar disorder biobank through a web-based survey and a community advisory board.
The Depression and Bipolar Support Alliance and the Mayo Clinic Bipolar Biobank conducted a national web-based survey inquiring about interest in participating in a biobank (i.e., giving DNA and clinical information). A community advisory board was convened to guide establishment of the biobank and identify key deliverables from the research project and for the community.
Among 385 survey respondents, funding source (87%), professional opinion (76%), mental health consumer opinion (79%), and return of research results (91%) were believed to be important for considering study participation. Significantly more patients were willing to participate in a biobank managed by a university or clinic (78.2%) than one managed by government (63.4%) or industry (58.2%; both p < 0.001). The nine-member community advisory board expressed interest in research to help predict the likelihood of bipolar disorder developing in a child of an affected parent and which medications to avoid. The advisory board endorsed the use of a comprehension questionnaire to evaluate participants' understanding of the study (e.g., longevity of DNA specimens, right to remove samples, accessing medical records) as a means to strengthen the informed-consent process.
These national survey and community advisory data support the merit of establishing a biobank to enable studies of disease risk, provided that health records and research results are adequately protected. The goals of earlier diagnosis and individualized treatment of bipolar disorder were endorsed.
PMCID: PMC4643402  PMID: 26291791
biobank; bipolar disorder; phenotype
6.  Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder 
Bipolar disorders  2015;17(6):645-652.
Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association.
DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset with the definition of first manic or depressive episode at age ≤ 19 years (versus adult-onset cases at age > 19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects.
Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04).
These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder.
PMCID: PMC4672380  PMID: 26528762
association; BDNF; bipolar disorder; brain-derived neurotrophic factor; early onset; Val66Met
7.  N-acetylaspartate normalization in bipolar depression after lamotrigine treatment 
Bipolar disorders  2014;17(4):450-457.
To examine N-acetylaspartate (NAA), a general marker of neuronal viability, and total NAA (tNAA), the combined signal of NAA and N-acetylaspartylglutamate, in bipolar depression before and after lamotrigine treatment. Given that NAA is synthesized through direct acetylation of aspartate by acetyl-coenzyme A-L-aspartate-N-acetyltransferase, we hypothesized that treatment with lamotrigine would be associated with an increase in NAA level.
Patients with bipolar depression underwent two-dimensional proton magnetic resonance spectroscopy of the anterior cingulate at baseline (n = 15) and after 12 weeks of lamotrigine treatment (n = 10). A group of age-matched healthy controls (n = 9) underwent scanning at baseline for comparison.
At baseline, patients with bipolar depression had significantly lower NAA [mean standard deviation (SD) = 1.13 (0.21); p = 0.02] than controls [mean (SD) = 1.37 (0.27)]. Significant increases in NAA [mean (SD) = 1.39 (0.21); p = 0.01] and tNAA [mean (SD) = 1.61 (0.25); p = 0.02] levels were found after 12 weeks of lamotrigine treatment.
These data suggest an NAA deficit in bipolar depression that is normalized after lamotrigine treatment. Future research is warranted to evaluate whether baseline NAA level is a potential biomarker for identifying lamotrigine response patterns and whether this functional brain change has an associated clinical response.
PMCID: PMC4655601  PMID: 25495884
bipolar depression; bipolar disorder; lamotrigine; N-acetylaspartate; neuroprotection; two-dimensional proton magnetic resonance spectroscopy
8.  Ketamine: stimulating antidepressant treatment? 
BJPsych open  2016;2(3):e5-e9.
The appeal of ketamine – in promptly ameliorating depressive symptoms even in those with non-response – has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine’s potential as an option for treating depression and provide a synthesis of perspectives – derived from evidence and clinical experience – and to consider strategies for future investigations.
Declaration of interests
G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker’s Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; ‘paid-for’ ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse’s employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998–2013.
Copyright and usage
© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
PMCID: PMC4995167  PMID: 27703782
9.  The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample 
BMC Psychiatry  2016;16:129.
Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response.
This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response.
Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30–40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost.
Trial registration
Identifier: NCT01272531
Registered: January 6, 2011
PMCID: PMC4857276  PMID: 27150464
Bipolar disorder; Lithium; Mood stabilizer; Pharmacogenetics; GWAS; Prospective trial; Personalized medicine; Precision medicine
10.  Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients 
Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression.
Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22).
Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = −0.67, P = 0.002).
This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-d-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.
PMCID: PMC4772340  PMID: 26925576
NMDA receptor; Cytokines; ECT; Quinolinic acid; Inflammation; IL-6; Kynurenic acid; Treatment-resistant depression
11.  An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents 
Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents.
Methods: Twenty-four adolescents (aged 11–18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx].
Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs).
Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.
PMCID: PMC5127083  PMID: 27965544
transcranial magnetic stimulation; proton magnetic resonance spectroscopy; depression; child and adolescent; cortical excitability; glutamate
12.  Gender Differences in the Relationship between Depressive Symptoms and Cravings in Alcoholism 
This study examines the clinical correlates of alcohol craving in men and women self-referred for addiction treatment. Admission clinical data from patients participating in the Mayo Clinic 1-month Intensive Addictions Program were evaluated. Women had higher BDI and PACS scores compared with men in both the entire cohort and Dual Diagnoses group. Alcohol-dependent females had the most marked correlation between BDI and PACS (ρ =0.78). Further prospective study is encouraged to evaluate whether depressive symptoms and concomitant alcohol cravings in women are a marker for relief cravings and, as such, a target symptom for treatment intervention.
PMCID: PMC4671371  PMID: 20653643
13.  Neurons Forming Optic Glomeruli Compute Figure–Ground Discriminations in Drosophila 
The Journal of Neuroscience  2015;35(19):7587-7599.
Many animals rely on visual figure–ground discrimination to aid in navigation, and to draw attention to salient features like conspecifics or predators. Even figures that are similar in pattern and luminance to the visual surroundings can be distinguished by the optical disparity generated by their relative motion against the ground, and yet the neural mechanisms underlying these visual discriminations are not well understood. We show in flies that a diverse array of figure–ground stimuli containing a motion-defined edge elicit statistically similar behavioral responses to one another, and statistically distinct behavioral responses from ground motion alone. From studies in larger flies and other insect species, we hypothesized that the circuitry of the lobula—one of the four, primary neuropiles of the fly optic lobe—performs this visual discrimination. Using calcium imaging of input dendrites, we then show that information encoded in cells projecting from the lobula to discrete optic glomeruli in the central brain group these sets of figure–ground stimuli in a homologous manner to the behavior; “figure-like” stimuli are coded similar to one another and “ground-like” stimuli are encoded differently. One cell class responds to the leading edge of a figure and is suppressed by ground motion. Two other classes cluster any figure-like stimuli, including a figure moving opposite the ground, distinctly from ground alone. This evidence demonstrates that lobula outputs provide a diverse basis set encoding visual features necessary for figure detection.
PMCID: PMC4429157  PMID: 25972183
feature detection; figure–ground discrimination; optomotor
14.  Randomized, placebo-controlled, adjunctive study of armodafinil for bipolar I depression: implications of novel drug design and heterogeneity of concurrent bipolar maintenance treatments 
Some, but not all, prior investigations suggest armodafinil may have utility as an adjunctive treatment in bipolar I depression.
Multicenter, randomized, double-blind study in patients aged 18 to 65 years experiencing a depressive episode despite maintenance therapy for bipolar I disorder. Patients were randomized to receive adjunctive armodafinil 150 mg/day or adjunctive placebo for 8 weeks. Primary efficacy outcome was change from baseline in 30-Item Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C30) total score at week 8. Safety and tolerability were monitored.
Of 656 patients screened, 399 were randomized, of whom 308 (77 %) were taking a protocol-allowed mood stabilizer as monotherapy. The primary efficacy outcome did not reach statistical significance; however, several secondary efficacy outcomes demonstrated statistically significant advantages for adjunctive armodafinil (n = 197) over adjunctive placebo (n = 196), including Clinical Global Impression of Severity of Illness for depression (weeks 6, 8, and endpoint; all P < 0.05), Global Assessment of Functioning (weeks 4, 8, and endpoint; all P < 0.02), IDS-C30 remitter rates (week 8 and endpoint; both P < 0.02), and mean change from baseline in IDS-C30 total score at week 7 (P < 0.05). Adjunctive armodafinil and adjunctive placebo were generally well tolerated. Although adjunctive armodafinil compared with adjunctive placebo yielded a higher headache rate (15 vs 8 %), it yielded similar (generally favorably low) rates of all-cause discontinuation (16 vs 16 %), adverse event discontinuation (4 vs 5 %), nausea (6 vs 4 %), ≥7 % weight gain (2 vs 5 %), anxiety (4 vs 3 %), insomnia (3 vs 2 %), sedation/somnolence (1 vs 1 %), and hypomania (0 vs <1 %).
In this study, adjunctive armodafinil compared with adjunctive placebo in bipolar I depression did not separate in the primary efficacy outcome but demonstrated advantages for several secondary efficacy outcomes and was generally well tolerated. Additional research is warranted and necessary to better identify clinical predictors (e.g., atypical depressive symptoms, specific anti-manic/mood-stabilizing agents used) that would provide optimized, individualized therapeutics for bipolar depression.
Trial registration NCT01305408
PMCID: PMC4556715  PMID: 26330288
Armodafinil; Bipolar I disorder; Major depressive episode
15.  An electronic health record driven algorithm to identify incident antidepressant medication users 
We validated an algorithm designed to identify new or prevalent users of antidepressant medications via population-based drug prescription records.
Patients and methods
We obtained population-based drug prescription records for the entire Olmsted County, Minnesota, population from 2011 to 2012 (N=149 629) using the existing electronic medical records linkage infrastructure of the Rochester Epidemiology Project (REP). We selected electronically a random sample of 200 new antidepressant users stratified by age and sex. The algorithm required the exclusion of antidepressant use in the 6 months preceding the date of the first qualifying antidepressant prescription (index date). Medical records were manually reviewed and adjudicated to calculate the positive predictive value (PPV). We also manually reviewed the records of a random sample of 200 antihistamine users who did not meet the case definition of new antidepressant user to estimate the negative predictive value (NPV).
161 of the 198 subjects electronically identified as new antidepressant users were confirmed by manual record review (PPV 81.3%). Restricting the definition of new users to subjects who were prescribed typical starting doses of each agent for treating major depression in non-geriatric adults resulted in an increase in the PPV (90.9%). Extending the time windows with no antidepressant use preceding the index date resulted in only modest increases in PPV. The manual abstraction of medical records of 200 antihistamine users yielded an NPV of 98.5%.
Our study confirms that REP prescription records can be used to identify prevalent and incident users of antidepressants in the Olmsted County, Minnesota, population.
PMCID: PMC4147111  PMID: 24780720
16.  Mood Stability in Parkinson’s Disease Status Post Deep Brain Stimulation: A 6-Month Prospective Follow-up Study 
Psychosomatics  2013;55(5):478-484.
Deep brain stimulation (DBS) for Parkinson’s disease (PD) has been associated with psychiatric adverse effects (PAEs) including anxiety, depression, mania, psychosis and suicide. The purpose of this study was to evaluate safety of DBS in a large PD clinical practice.
Patients approved for surgery by Mayo Clinic DBS clinical committee participated in a 6 month prospective naturalistic follow-up study. In addition to the Unified Parkinson’s Disease Rating Scale (UPDRS), stability and psychiatric safety was measured using: Beck Depression Inventory (BDI-II), Hamilton Depression Rating Scale (HAMD-17), and Young Mania Rating scale (YMRS). Outcomes were compared in PD patients with past psychiatric history to PD patients with no comorbid psychiatric history.
Forty-nine of 54 patients completed the study. Statistically significant 6-month baseline to endpoint improvement was found in motor and mood scales. No significant differences were found in psychiatric outcomes based on presence or absence of psychiatric comorbidity.
Our study suggests PD patients with a history of psychiatric comorbidity can safely respond to DBS with no greater risk of PAE occurrence. A multi-disciplinary team approach including careful psychiatric screening ensuring mood stabilization and psychiatric follow-up should be viewed as standard of clinical care to optimize psychiatric outcome in the course of DBS treatment.
PMCID: PMC4063889  PMID: 24360528
17.  Development of a bipolar disorder biobank: differential phenotyping for subsequent biomarker analyses 
We aimed to establish a bipolar disorder biobank to serve as a resource for clinical and biomarker studies of disease risk and treatment response. Here, we describe the aims, design, infrastructure, and research uses of the biobank, along with demographics and clinical features of the first participants enrolled.
Patients were recruited for the Mayo Clinic Bipolar Biobank beginning in July 2009. The Structured Clinical Interview for DSM-IV was used to confirm bipolar diagnosis. The Bipolar Biobank Clinical Questionnaire and Participant Questionnaire were designed to collect detailed demographic and clinical data, including clinical course of illness measures that would delineate differential phenotypes for subsequent analyses. Blood specimens were obtained from participants, and various aliquots were stored for future research.
As of September 2014, 1363 participants have been enrolled in the bipolar biobank. Among these first participants, 69.0 % had a diagnosis of bipolar disorder type I. The group was 60.2 % women and predominantly white (90.6 %), with a mean (SD) age of 42.6 (14.9) years. Clinical phenotypes of the group included history of psychosis (42.3 %), suicide attempt (32.5 %), addiction to alcohol (39.1 %), addiction to nicotine (39.8 %), obesity (42.9 %), antidepressant-induced mania (31.7 %), tardive dyskinesia (3.2 %), and history of drug-related serious rash (5.7 %).
Quantifying phenotypic patterns of illness beyond bipolar subtype can provide more detailed clinical disease characteristics for biomarker research, including genomic-risk studies. Future research can harness clinically useful biomarkers using state-of-the-art research technology to help stage disease burden and better individualize treatment selection for patients with bipolar disorder.
PMCID: PMC4478187  PMID: 26105627
Biobank; Bipolar disorder; Phenotype
18.  Association of GATA4 sequence variation with alcohol dependence 
Addiction biology  2012;19(2):312-315.
To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis (PCA). Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene-level (p=0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.
PMCID: PMC3504631  PMID: 22862823
GATA4; Alcohol dependence; Genetic association; Gene level test
19.  Olfactory Neuromodulation of Motion Vision Circuitry in Drosophila 
Current Biology  2015;25(4):467-472.
It is well established that perception is largely multisensory [1]; often served by modalities such as touch, vision, and hearing that detect stimuli emanating from a common point in space [2, 3]; and processed by brain tissue maps that are spatially aligned [4]. However, the neural interactions among modalities that share no spatial stimulus domain yet are essential for robust perception within noisy environments remain uncharacterized. Drosophila melanogaster makes its living navigating food odor plumes. Odor acts to increase the strength of gaze-stabilizing optomotor reflexes [5] to keep the animal aligned within an invisible plume, facilitating odor localization in free flight [6–8]. Here, we investigate the cellular mechanism for cross-modal behavioral interactions. We characterize a wide-field motion-selective interneuron of the lobula plate that shares anatomical and physiological similarities with the “Hx” neuron identified in larger flies [9, 10]. Drosophila Hx exhibits cross-modal enhancement of visual responses by paired odor, and presynaptic inputs to the lobula plate are required for behavioral odor tracking but are not themselves the target of odor modulation, nor is the neighboring wide-field “HSE” neuron [11]. Octopaminergic neurons mediating increased visual responses upon flight initiation [12] also show odor-evoked calcium modulations and form connections with Hx dendrites. Finally, restoring synaptic vesicle trafficking within the octopaminergic neurons of animals carrying a null mutation for all aminergic signaling [13] is sufficient to restore odor-tracking behavior. These results are the first to demonstrate cellular mechanisms underlying visual-olfactory integration required for odor localization in fruit flies, which may be representative of adaptive multisensory interactions across taxa.
•Small-field motion detection neurons are required for odor-tracking behavior•Responses of a directional wide-field interneuron (Hx) increase with paired odor•Odor activates octopaminergic (OA) neurons that innervate the visual system•OA cells contact Hx; OA vesicle trafficking is required for odor-tracking behavior
Wasserman et al. report that a directionally selective wide-field motion-detecting neuron (Hx) in the fly increases response gain with paired odor. This multimodal interaction is dependent upon vesicle trafficking from octopaminergic neurons, which are themselves responsive to odor and make cell-cell contact with Hx.
PMCID: PMC4331282  PMID: 25619767
20.  Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals 
Biological psychiatry  2013;74(12):917-926.
Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome (TS). Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS.
The combination of DBS and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. Using a with-in subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n=5).
Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS.
Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of TS as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.
PMCID: PMC3910443  PMID: 23993641
Deep brain stimulation (DBS); Tourette syndrome; centromedian; parafascicular; functional magnetic resonance imaging (fMRI); swine model; neural circuitry
21.  Feasibility Evaluation of an Interpersonal and Social Rhythm Therapy Group Delivery Model 
Archives of psychiatric nursing  2013;27(6):271-277.
The effectiveness of psychotherapies, such as interpersonal and social rhythm therapy (IPSRT), is supported by randomized controlled trials. These trials provide minimal direction regarding feasibility of psychotherapy delivery models. The study purpose was to identify factors facilitating implementation and sustainability of an IPRST group for patients with bipolar disorder. Qualitative data were assessed by the normalization process model (NPM). The results demonstrate feasibility of implementation with experienced clinicians, program coordination, and leadership support. Sustainability challenges include aftercare groups, space, and clinician time. The NPM provides a useful framework for evaluation of factors influencing the feasibility of psychotherapy delivery models.
PMCID: PMC4020708  PMID: 24238006
22.  Every reason to discontinue lithium 
Lithium as a gold standard therapy for bipolar disorder is well known to have a number of medical comorbidities that impact renal, parathyroid, and thyroid function. Despite these medical comorbidities, there remains a group of lithium-responsive lithium-treated patients who have maintained mood stability for decades. The risk/benefit ratio of end organ toxicity/mood stability must be evaluated in each individual case.
PMCID: PMC4477477  PMID: 26092398
Lithium; Toxicity; Efficacy
23.  Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB 
Journal of affective disorders  2014;165:151-158.
Bipolar disorder (BD) is a highly heritable disease. While genome-wide association (GWA) studies have identified several genetic risk factors for BD, few of these studies have investigated the genetic etiology of specific disease subtypes. In particular, BD is positively associated with eating dysregulation traits such as binge eating behavior (BE), yet the genetic risk factors underlying BD with comorbid BE have not been investigated.
Utilizing data from the Genetic Association Information Network study of BD, which included 729,454 single nucleotide polymorphisms (SNPs) genotyped in 1001 European American bipolar cases and 1034 controls, we performed GWA analyses of bipolar subtypes defined by the presence or absence of BE history, and performed a case-only analysis comparing BD subjects with and without BE history. Association signals were refined using imputation, and network analysis was performed with Ingenuity Pathway Analysis software. Based on these results, candidate SNPs were selected for replication in an independent sample of 855 cases and 857 controls.
Top ranking SNPs in the discovery set included rs6006893 in PRR5, rs17045162 in ANK2, rs13233490 near PER4, rs4665788 and rs10198175 downstream of APOB, rs2367911 in CACNA2D1, and rs7249968 near ZNF536. Rs10198175 in APOB also demonstrated evidence of association in the replication sample and a meta-analysis of the two samples.
Without information of BE history in controls, it is not possible to determine whether the observed association with APOB reflects a risk factor for BE behavior in general or a risk factor for a subtype of BD with BE. Further longitudinal and functional studies are needed to determine the causal pathways underlying the observed associations.
This study identified new potential BD-susceptibility genes, highlighting the advantages of phenotypic sub-classification in genetic research and clinical practice.
PMCID: PMC4224146  PMID: 24882193
Bipolar disorder; Binge eating; Phenotypic subtypes; Network analysis; Genome-wide association study (GWAS); APOB
24.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
PMCID: PMC4091043  PMID: 24030475

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