Antidepressant-induced Mania Research Articles

Mood regulation in euthymic patients with a history of antidepressant-induced mania.

The use of antidepressants in bipolar disorder (BD) remains contentious, in part due to the risk of antidepressant-induced mania (AIM). However, there is no information on the architecture of mood regulation in patients who have experienced AIM. We compared the architecture of mood regulation in euthymic patients with and without a history of AIM. Eighty-four euthymic participants were included. Participants rated their mood, anxiety and energy levels daily using an electronic (e-) visual analog scale, for a mean (SD) of 280.8(151.4) days. We analyzed their multivariate time series by computing each variable's auto-correlation, inter-variable cross-correlation, and composite multiscale entropy of mood, anxiety, and energy. Then, we compared the data features of participants with a history of AIM and those without AIM, using analysis of covariance, controlling for age, sex, and current treatment. Based on 18,103 daily observations, participants with AIM showed significantly stronger day-to-day auto-correlation and cross-correlation for mood, anxiety, and energy than those without AIM. The highest cross-correlation in participants with AIM was between mood and energy within the same day (median (IQR), 0.58 (0.27)). The strongest negative cross-correlation in participants with AIM was between mood and anxiety series within the same day (median (IQR), -0.52 (0.34)). Patients with a history of AIM have a different underlying mood architecture compared to those without AIM. Their mood, anxiety and energy stay the same from day-to-day; and their anxiety is negatively correlated with their mood.

A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression.

Antidepressants are commonly used to treat bipolar depression but may increase the risk of mania. The evidence from randomized controlled trials, however, is limited by short treatment durations, providing little evidence for the long-term risk of antidepressant-induced mania. The authors performed a target trial emulation to compare the risk of mania among individuals with bipolar depression treated or not treated with antidepressants over a 1-year period. The authors emulated a target trial using observational data from nationwide Danish health registers. The study included 979 individuals with bipolar depression recently discharged from a psychiatric ward. Of these, 358 individuals received antidepressant treatment, and 621 did not. The occurrence of mania and bipolar depression over the following year was ascertained, and the intention-to-treat effect of antidepressants was analyzed by using Cox proportional hazards regression with adjustment for baseline covariates to emulate randomized open-label treatment allocation. The fully adjusted analyses revealed no statistically significant associations between treatment with an antidepressant and the risk of mania in the full sample (hazard rate ratio=1.08, 95% CI=0.72-1.61), in the subsample concomitantly treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.63-2.13), and in the subsample not treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.65-2.07). Secondary analyses revealed no statistically significant association between treatment with an antidepressant and bipolar depression recurrence. These findings suggest that the risk of antidepressant-induced mania is negligible and call for further studies to optimize treatment strategies for individuals with bipolar depression.

Genetic variant associated with antidepressant-induced mania

Genetic variant associated with antidepressant-induced mania

Antidepressant-induced mania in panic disorder: a single-case study of clinical and functional connectivity characteristics.

Mental health issues, including panic disorder (PD), are prevalent and often co-occur with anxiety and bipolar disorders. While panic disorder is characterized by unexpected panic attacks, and its treatment often involves antidepressants, there is a 20-40% risk of inducing mania (antidepressant-induced mania) during treatment, making it crucial to understand mania risk factors. However, research on clinical and neurological characteristics of patients with anxiety disorders who develop mania is limited. In this single case study, we conducted a larger prospective study on panic disorder, comparing baseline data between one patient who developed mania (PD-manic) and others who did not (PD-NM group). We enrolled 27 patients with panic disorder and 30 healthy controls (HCs) and examined alterations in amygdala-based brain connectivity using a seed-based whole-brain approach. We also performed exploratory comparisons with healthy controls using ROI-to-ROI analyses and conducted statistical inferences at a threshold of cluster-level family-wise error-corrected p < 0.05, with the cluster-forming threshold at the voxel level of uncorrected p < 0.001. The patient with PD-mania showed lower connectivity in brain regions related to the default mode network (left precuneous cortex, maximum z-value within the cluster = -6.99) and frontoparietal network (right middle frontal gyrus, maximum z-value within the cluster = -7.38; two regions in left supramarginal gyrus, maximum z-value within the cluster = -5.02 and -5.86), and higher in brain regions associated with visual processing network (right lingual gyrus, maximum z-value within the cluster = 7.86; right lateral occipital cortex, maximum z-value within the cluster = 8.09; right medial temporal gyrus, maximum z-value within the cluster = 8.16) in the patient with PD-mania compared to the PD-NM group. One significantly identified cluster, the left medial temporal gyrus (maximum z-value within the cluster = 5.82), presented higher resting-state functional connectivity with the right amygdala. Additionally, ROI-to-ROI analysis revealed that significant clusters between PD-manic and PD-NM groups differed from HCs in the PD-manic group but not in the PD-NM group. Here, we demonstrate altered amygdala-DMN and amygdala-FPN connectivity in the PD-manic patient, as reported in bipolar disorder (hypo) manic episodes. Our study suggests that amygdala-based resting-state functional connectivity could serve as a potential biomarker for antidepressant-induced mania in panic disorder patients. Our findings provide an advance in understanding the neurological basis of antidepressant-induced mania, but further research with larger cohorts and more cases is necessary for a broader perspective on this issue.

A genome-wide association study of antidepressant-induced mania

Antidepressant-induced mania (AIM) is a side effect of antidepressant treatment that is characterized by mania or hypomania after the start of medication. It is likely polygenic, but its genetic component remains largely unexplored. We aim to conduct the first genome-wide association study of AIM in 814 bipolar disorder patients of European ancestry. We report no significant findings from our single-marker or gene-based analyses. Our polygenic risk score analyses also did not yield significant results with bipolar disorder, antidepressant response, or lithium response. Our suggestive findings on the hypothalamic-pituitary-adrenal axis and the opioid system in AIM require independent replications.

Severe olanzapine-induced liver function test elevation.

Dear Editor:We read with great interest the case report1 on identifying olanzapine-induced liver injury in the setting of acute hepatitis C. We wanted to bring to the attention of the Mental Health Clinician readers our similar case report entitled “Olanzapine-induced elevated liver function tests in an older person with antidepressant-induced mania”, who similarly experienced significant liver function test (LFT) elevation thought to be related to olanzapine that was published in The Senior Care Pharmacist in September 2022.2Although an increase in LFTs is a known adverse effect of antipsychotics including olanzapine, this is an underappreciated adverse effect, especially as the LFT elevation can be severe. Furthermore, there is no standard of care for monitoring LFTs at baseline or how frequently during antipsychotic treatment LFTs should be monitored.Brelje et al1 cites that olanzapine-induced liver injury has been shown to occur anywhere from 12 days to 8 years after initiating olanzapine, which is similar to what we found in published reports.1,2 In the case that Brelje et al reported, LFT elevation occurred after 6 days of olanzapine therapy and ALT peaked at 1510 IU/L.1 This is similar to the case recently published in The Senior Care Pharmacist of a 67-year-old male where LFT elevation began on day 6 of olanzapine treatment and peaked on day 8 with an AST of 2024 IU/L and ALT of 1508 IU/L.2If drug-induced liver injury or adverse effects of antipsychotics are topics of interest to the reader, we encourage you to read the Brelje et al1 article in the Mental Health Clinician as well as the Reid et al2 article in The Senior Care Pharmacist. The latter article reviews potential mechanisms of olanzapine-induced LFT elevation such as via a toxic intermediary metabolite or in relation to nonalcoholic fatty liver disease.2 Reid et al2 also summarizes 9 additional cases of olanzapine-induced LFT elevation.Brelje et al1 cites “large psychiatric professional societies have refrained from recommending widespread asymptomatic testing”(p213) of hepatic enzymes. However, both articles highlight how significantly elevated LFTs can become within 1 week of starting olanzapine treatment. We encourage readers to incorporate baseline monitoring and consider rechecking within 1 to 2 weeks of initiation with continued monitoring of LFTs in patients treated with antipsychotics including olanzapine into their routine practice.

Brain Neural Activity Patterns in an Animal Model of Antidepressant-Induced Manic Episodes.

Background: In the treatment of patients with bipolar disorder (BP), antidepressant-induced mania is usually observed. The rate of phase switching (from depressive to manic) in these patients exceeds 22%. The exploration of brain activity patterns during an antidepressant-induced manic phase may aid the development of strategies to reduce the phase-switching rate. The use of a murine model to explore brain activity patterns in depressive and manic phases can help us to understandthe pathological features of BP. The novel object recognition preference ratio is used to assess cognitive ability in such models.Objective: To investigate brain Ca2+ activity and behavioral expression in the depressive and manic phases in the same murine model, to aid understanding of brain activity patterns in phase switching in BP.Methods: In vivo two-photon imaging was used to observe brain activity alterations in a murine model in which induce depressive-like and manic-like behaviors were induced sequentially. The immobility time was used to assess depressive-like symptoms and the total distance traveled was used to assess manic-like symptoms.Results: In vivo two-photon imaging revealed significantly reduced brain Ca2+ activity in temporal cortex pyramidal neurons in the depressive phase in mice exposed to chronic unpredictable mild stress compared with naïve controls. The brain Ca2+ activity correlated negatively with the novel object recognition preference ratio within the immobility time. Significantly increased brain Ca2+ activity was observed in the ketamine-induced manic phase. However, this activity did not correlate with the total distance traveled. The novel object recognition preference ratio correlated negatively with the total distance traveled in the manic phase.

Homicide attempt due to medication induced mania

Bipolar disorders are a group of mental disorders characterized by fluctuations in mood, with depressive symptoms generally dominating the course of disorder. Research on the efficacy of serotonergic antidepressants in bipolar depression is controversial and as a result, treatment of depressive symptoms in bipolar disorder is difficult. A particularly difficult situation arises when bipolar disorder is unrecognized and the depressive state is treated as major depressive disorder with the use of serotonergic antidepressants, which can result in the phenomenon of antidepressant induced mania (AIM). In this report, we present a case of antidepressant induced mania (AIM) with homicidal ideation after initiation of serotonergic antidepressants. Here, we discuss the importance of monitoring for bipolar disorder after prescribing serotonergic antidepressant therapy as well as medico-legal considerations.

Treating Depression in the Context of Mania or Mania Risk in Youth

Bipolar disorder (BD) is a heritable and episodic psychiatric disorder that is increasingly being recognized to take onset in childhood or adolescence. Youth with a parent or sibling with BD may also be at risk for mania, but frequently present with depression. In a busy clinical practice, treating depression in the context of mania or risk for mania can be obfuscated by a number of factors, including clinical heterogeneity and co-occurring conditions, changes in symptom presentation over the course of development, and treatment-emergent affective switching. In this review, we critically appraise recently published literature pertinent to the use of nonpharmacological and pharmacological strategies for the treatment of depression in youth with or at familial risk for BD. We used available data and extrapolate from adult studies to present reasonable treatment options in the context of a limited evidence base. Initial consideration of nonpharmacologic approaches such as psychotherapy, engaging in resilience-promoting strategies, and using omega-3 fatty acid supplementation is suggested given the low risk involved in implementation. Pharmacological treatment is guided by a combination of presenting symptoms, response to previous treatment trials or family history of previous responses, reported adverse effects, and patient and family preference. We conclude with a research update on emerging evidence-based treatment of bipolar I depression in youth. High-risk youth are more susceptible to developing antidepressant-induced mania (AIM), but the risks may be cautiously managed by starting at low doses, slow titrations, close monitoring for emerging adverse effects, and consideration of mood stabilizers and atypical antipsychotics with any emergence of persistent hypomania or mania that is not reversed by lowering or discontinuing antidepressant dosing.

SA80 - ASSOCIATION OF CYP2D6 METABOLIZER STATUS WITH ANTIDEPRESSANT INDUCED MANIA

Background Bipolar Disorder (BD) is a mood disorder characterized by alternating periods of depression and mania/hypomania. It affects approximately 1% of the population and is considered one of the top 20 leading causes of disability. Although mood stabilizers are currently the frontline treatment for BD, antidepressants still play a valuable role in treating the depressive symptoms. However, 20–40% of these individuals will experience Antidepressant-Induced Mania (AIM). There are several clinical factors that have been suggested to contribute to this phenomenon, such as BD type I, age of onset, and number and severity of manic episodes prior to the start of the antidepressant. The serotonin transporter gene has also been thoroughly studied in this context. Studies suggest that individuals with the short allele of this gene have a greater risk of experiencing AIM. More recently, it's been suggested that individuals that are slow metabolizers of the CYP2D6 liver enzyme gene are also at a greater risk of experiencing AIM when given an antidepressant that acts on that enzyme. We sought to extend these findings. Methods Using a subset of the Toronto Bipolar sample (N=52), we investigated whether being a slow or intermediate metabolizers for any of five liver enzyme genes (CYP2D6, CYP2C9, CYP2C19, CYP1A2 and CYP3A4) would make one more susceptible to experiencing AIM. Individuals who were part of this sample met the DSM-IV criteria for a BD diagnosis and were of European descent. Results Our preliminary data (N=40) showed a trend of association with CYP2D6 metabolizer status. Individuals that were either poor or intermediate metabolizers of this liver enzyme were more likely to have experienced AIM when given serotonergic antidepressants (x2=3.14, p=0.077). Discussion Our findings provide preliminary support to the earlier observation of association of poor and intermediate metabolizer status of CYP2D6 with AIM. This is presumably because the drug has more time to build up in the system of those who are poor or intermediate metabolizers than extensive metabolizers, who are able to better break down the drug. The data suggests that in addition to the potential clinical factors, pharmacogenetic components may need to be considered prior to prescribing antidepressants to individuals with BD.

CYP2D6 metabolizer status and HTTLPR variant of SLC6A4 associated with antidepressant-induced mania in bipolar disorder

IntroductionApproximately 12% of individuals with bipolar disorder (BD) treated with an antidepressant experience antidepressant-induced mania (AIM). Numerous clinical risk factors have been identified but the only genetic risk factor found is the “S” allele or “SS” genotype of HTTLPR, a polymorphism in the promoter region of SLC6A4. We sought to investigate whether metabolizer status of five Cytochrome P450 genes, which encode for enzymes involved in the degradation of medications in the liver played a role in AIM. Methods26 AIM+/25AIM− individuals were identified from the Toronto BD sample, via a blind retrospective analysis of two questionnaires and life charts. Genotyping was performed using pre-plated Taqman assays and metabolizer status was assigned based on the Clinical Pharmacogenetics Implementation Consortium guidelines. ResultsConcurrent use of mood stabilizer had a protective effect against AIM (p = 0.0001). No significant association between metabolizer status and AIM for the CYP genes was observed. When we grouped poor metabolizers (PM) and intermediate metabolizers (IM) we identified a nominal trend (p = 0.14) towards them being at a greater risk of experiencing AIM. In an additive model, combining CYP2D6 metabolizer status and HTTLPR, PM and IM with the “S” allele were 9× more likely to experience AIM (p = 0.002). DiscussionOur results provide further support for concurrent mood stabilizers having a protective effect against AIM. They also suggest that PM and IM of CYP2D6 may be at a greater risk of AIM. Lastly, combining the risk-allele of the HTTLPR with the risk metabolizer statuses increases the overall risk of AIM.

A Dynamical Bifurcation Model of Bipolar Disorder Based on Learned Expectation and Asymmetry in Mood Sensitivity.

Bipolar disorder is a common psychiatric dysfunction characterized by recurring episodes of mania and depression. Despite its prevalence, the causes and mechanisms of bipolar disorder remain largely unknown. Recently, theories focusing on the interaction between emotion and behavior, including those based on dysregulation of the so-called behavioral approach system (BAS), have gained popularity. Mathematical models built on this principle predict bistability in mood and do not invoke intrinsic biological rhythms that may arise from interactions between mood and expectation. Here we develop and analyze a model with clinically meaningful and modifiable parameters that incorporates the interaction between mood and expectation. Our nonlinear model exhibits a transition to limit cycle behavior when a mood-sensitivity parameter exceeds a threshold value, signaling a transition to a bipolar state. The model also predicts that asymmetry in response to positive and negative events can induce unipolar depression/mania, consistent with clinical observations. We analyze the model with asymmetric mood sensitivities and show that large unidirectional mood sensitivity can lead to bipolar disorder. Finally, we show how observed effects of lithium- and antidepressant-induced mania can be explained within the framework of our proposed model.

Risk Factors Associated With Antidepressant Exposure and History of Antidepressant-Induced Mania in Bipolar Disorder.

Despite their widespread use in bipolar disorder, there is controversy surrounding the inclusion of antidepressant medications in the disorder's management. We sought to identify which demographic, socioeconomic, and clinical factors are associated with antidepressant exposure in bipolar disorder and which bipolar disorder patients are most likely to report a history of antidepressant-induced mania (AIM) when exposed to antidepressants. Our study included subjects with bipolar I disorder (n = 309), bipolar II disorder (n = 66), and bipolar disorder not otherwise specified (n = 27) and schizoaffective disorder, bipolar type (n = 14), from a longitudinal, community-based study. Subjects were evaluated using the Diagnostic Interview for Genetic Studies, modified for DSM-IV criteria. We applied multivariate logistical regression modeling to investigate which factors contribute to antidepressant exposure in bipolar disorder patients. We also used a logistic regression modeling approach to determine which clinical factors in bipolar disorder patients are associated with a history of AIM. Data were gathered from February 2006 through December 2010. Our results suggest that the risk factors most strongly associated with antidepressant exposure are female sex (OR = 2.73, P = .005), older age (OR = 1.03, P = .04), greater chronicity of illness (OR = 2.29, P = .04), and, to a lesser extent, white race (OR = 0.44, P = .051). Factors associated with reduced antidepressant exposure include history of affective psychosis (OR = 0.36, P = .01) and a greater number of previous manic episodes (OR = 0.98, P = .03). In subjects who reported a history of AIM, regression analysis revealed that the only statistically significant factor associated with AIM history was female sex (OR = 3.74, P = .02). These data suggest that there are certain identifiable factors associated with antidepressant exposure in bipolar disorder patients, and some of these, specifically female sex, are also associated with a history of AIM. These data may be useful in designing prospective trials to identify interventions that can reduce the risk of this adverse outcome.

Serotonin Transporter Gene Polymorphisms and Selective Serotonin Reuptake Inhibitor Tolerability: Review of Pharmacogenetic Evidence.

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5-HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability. This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes. Four online databases (PubMed, Cochrane CENTRAL, PsycINFO, and PharmGKB) were searched for articles on polymorphisms of SLC6A4 including 5-HTTLPR and STin2 by using a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references. Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5-HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant-induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings. In conclusion, the S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence include assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs.

Bipolar spectrum – A helpful concept?

IntroductionMany patients seen in clinical practice have a mood disorder not well described by the existing diagnostic categories. Formally, they would be called “not otherwise specified” but this creates a huge single category for many patients that belies the richness and complexity of their symptoms.ObjectivesReview the existing information regarding the bipolar spectrum concept and reflect about its importance and utility.MethodsNonsystematic review of the literature – scientific publications from Pubmed and Psychiatry Textbooks.ResultsThe “bipolar spectrum disorder”, designating those patients who fall in the middle of the mood spectrum between the classic unipolar and type I bipolar extremes, would represent recurrent severe depression, but with a family history of bipolar disorder or antidepressant-induced mania or a number of other features of bipolarity in addiction to depressive symptoms, course, or treatment response. The presence of hyperthymic or cyclothymic mood temperaments has also been suggested as part of this bipolar spectrum concept. Several arguments can be found supporting the existence of this spectrum. A validated bipolar spectrum concept will allow a decrease in the diagnostic underestimation of bipolar disease and a more differentiated investigation and treatment model. Bipolar spectrum concepts will help identify those patients to whom antidepressants are not the best therapeutic approach, in relation to mood stabilizers and/or neuroleptics.DiscussionThe bipolar spectrum concept has considerable supporting evidence and utility, theoretical as well as practical. Its development and diagnostic acceptance shall allow new discriminated investigation and better patient outcomes.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Antidepressant-induced Dopamine Receptor Dysregulation: A Valid Animal Model of Manic-Depressive Illness.

Background: Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2 receptors may be responsible of antidepressant-induced mania. This review aims to report the experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation can be considered an animal model of bipolar disorder.Methods: We reviewed papers reporting preclinical and clinical studies on the role of DA in the mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders.Results: A number of preclinical and clinical evidence suggests that mania could be associated with an increased DA activity, while a reduced function of this neurotransmission might underlie depression. Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system, followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST.Conclusion: We suggest that chronic treatment with antidepressants induces a behavioural syndrome that mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover the observation that memantine prevents the “bipolar-like” behavior, suggests that the drug may have an antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.

Pharmacogenomics of Antidepressant Induced Mania

Identifying clinical and genetic risk factors associated with antidepressant-induced mania (AIM) may improve individualized treatment strategies for bipolar depression. Several small studies have investigated the association of variation in the serotonin transporter gene (SLC6A4) with AIM. Here we extend these studies using a new sample from the Mayo Clinic Bipolar Disorder Biobank, and perform the first genome wide association study (GWAS) of AIM. Bipolar patients, confirmed by structured interview were retrospectively screened for AIM. AIM cases reported a manic/hypomanic episode within 60 days of starting or changing dose of antidepressant, while control had an adequate (≥60 days) exposure to an antidepressant with no associated manic/hypomanic episode. The sample with genome-wide genotyping included 525 Caucasian bipolar patients (174 AIM cases and 351 controls). No genome-wide significant associations were observed in our GWAS of AIM. The SNP with strongest evidence of association (rs10093489; p=5.79E-07) maps to an intron of ZMAT4. Another top signal represents a cluster of SNPs that map to the DVL1 (Dishevelled -1) gene region (top SNP rs307364; P = 1.25E-06). A set of candidate variants selected based on association with treatment response in prior antidepressant pharmacogenomics studies in major depressive disorder did not show evidence of association in the AIM GWAS, suggesting that different variants may contribute to antidepressant response in unipolar and bipolar depression. Ongoing analyses using polygenic methods are being used to further investigate this question. The potential role of DVL1 warrants further investigation, as the gene encodes a cytoplasmic scaffolding protein involved in Wnt signaling, which has been implicated in antidepressant effects in rodents. Further work is encouraged to better delineate the potential role of Wnt signaling in antidepressant response in mood disorders.

Pharmacogenomics of Mood Disorders

Overall Abstract Single gene and GWAS analyses of pharmacological treatment response in depression and bipolar disorder have had varying success in identifying functionally relevant genes associated with pharmacological treatment response such as response to SSRI in depression and lithium in bipolar disorder. Hence, the need to better understand the complex genetic underpinnings of pharmacoresponse may include methodologies such as RNA-seq and microarray analyses. Such approaches contribute to a more in in-depth functional characterization of risk loci related to treatment response and to characterize the genetic underpinnings of both adverse events (e.g. induction of mania by antidepressants) and of medical comorbidity contributing to poor treatment response. In addition, gene expression profile and eQTLs can assist an improved understanding of the functional genomics of mood disorders. Specifically, recent large-scale GWAS meta-analyses (ConLiGen) have implicated multiple novel loci, two of which met the threshold for genome-wide significance: GADL1 (Chen et al., 2014) and an intergenic locus on chromosome 21 (Hou et al., 2016). The functional implications of the related genes remain to be described. In a first presentation, results will be presented from whole blood RNA-seq-data in a subsample of ConLiGen to validate and characterize these associations with clinical lithium treatment response and how these loci impact gene function and lithium response (David Stacey). Addressing the need to investigate the genetic underpinning of a broader range of treatment outcomes and adverse events, the genetic contribution of a potential induction of mania by antidepressants will be discussed in a second presentation, that shows results from a GWAS of antidepressant-induced mania (Joanna Biernacka). Among other factors, the co-morbidity of depression with other psychiatric and cardiometabolic disorders may negatively influence antidepressants treatment outcome. Moreover, response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. Hence, use of polygenic scores (PGS) could be a better alternative to estimate the overall effect of genetic factors on treatment response and assess the importance of co-morbidities and related phenotypes. To investigate this further, we evaluated whether PGS derived from 25 recognized comorbid cardiometabolic and psychiatric disorders, personality traits and educational attainment predict treatment outcome to SSRIs in major depressive disorder using the ISPC data (Bernhard Baune). Previous studies aiming to identify the transcriptome signature of depression are inconsistent with low replicability at the single gene level in both brain and peripheral tissues. In a fourth presentation, results from analyses of whole blood transcriptomes of 521 elderly people from the general population (The Sydney Memory and Age Study, MAS, Sydney) are shown to describe molecular networks involved in geriatric depression. Functional characterisation of two out of 29 modules of the co-expression network indicated that abnormalities in structural constituents of ribosome may be involved in the pathophysiology of geriatric depression. In addition, results of pathway analyses using Ingenuity Pathway Analysis software will be shown (Liliana Ciobanu).

From obsessivity to bipolarity and vice versa. A literature review

IntroductionThe prevalence of obsessive symptoms in bipolar patients is currently under discussion. Last years, different cases of antidepressant-induced mania and hypomania in patients with OCD have been described.Several authors have reported that patients with OCD and bipolar disorder have more depressive episodes than patients with only OCD.ObjectiveTo know the relationship between OCD and other bipolar spectrum disorders.MethodBibliographical review on comorbidity between obsessive symptoms and bipolarity.ResultsSome longitudinal analysis have shown that patients firstly diagnosed with OCD have an increased risk for subsequent diagnosis of all other conditions, especially for bipolar and schizoaffective disorder, for those whose risk is of up to 13 times higher. The handling of a patient with bipolar disorder and OCD implies some difficulty, because of the main treatment of anxiety disorders, the antidepressants, alters the course of manic-depressive illness, accelerating cycles.ConclusionsOCD is etiologically related to bipolar spectrum disorders and schizophrenia. Therefore, it is necessary to continue the investigation of possible involved genes and approaches for clinical practice.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Development of a bipolar disorder biobank: differential phenotyping for subsequent biomarker analyses.

BackgroundWe 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.MethodsPatients 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.ResultsAs 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 %).ConclusionsQuantifying 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.