Antidepressant-associated diagnostic change from major depressive to bipolar disorder.

BACKGROUND: Anticipating diagnostic change from major depressive (MDD) to bipolar disorder (BD) can support better prognosis and treatment, especially of depression but is challenging and reported research results are inconsistent. We therefore assessed clinical characteristics associated with diagnostic change from MDD to BD with antidepressant treatments. METHODS: We compared characteristics of 3212 initially MDD patients who became (hypo)manic during antidepressant treatment to those with stable MDD diagnoses as well as with cases of stable, spontaneous BD, using standard bivariate and multivariate statistics. RESULTS: Among MDD patients, 6.69% [CI: 5.85-7.61] changed to BD, mostly type II (BD2, 76.7%). BD-converters had higher rates of familial mood disorders (74.1% vs. 57.1%) or BD (33.7% vs. 21.0%) and 2.8-years younger onset than stable MDD patients. They also had more prior depressive recurrences/year, years-of-illness, mood-stabilizer treatment, divorces, fewer children, more suicide attempts and drug-abuse, and higher intake cyclothymia, YMRS and MDQ scores. Predictors independently associated with diagnostic conversion were: more familial BD, depressions/year, unemployment, cyclothymic temperament, suicidal ideation or acts, and fewer children. BD-converters vs. spontaneous BD cases had significantly more suicide attempts, BD2 diagnoses, and affected relatives. Converting to vs. spontaneous BD1 was associated with more ADHD, more suicidal ideation or behavior, MDI course, and younger onset; converting to vs. spontaneous BD2 had more episodes/year, unemployment, ADHD, substance abuse, suicidal ideation or attempts, and more relatives with BD. CONCLUSIONS: Few (6.69%) initially MDD subjects converted to BD, most (76.7%) to BD2. Independent predictive associations with diagnostic change included: familial BD, more depressions/year, unemployment, cyclothymic temperament, suicidal behavior and fewer children. Notably, several characteristics were stronger among those changing to BD during antidepressant treatment vs. others with spontaneous BD.

Pharmacokinetic Markers of Clinical Outcomes in Severe Mental Illness: A Systematic Review.

The term severe mental illness (SMI) encompasses those psychiatric disorders exerting the highest clinical burden and socio-economic impact on the affected individuals and their communities. Pharmacogenomic (PGx) approaches hold great promise in personalizing treatment selection and clinical outcomes, possibly reducing the burden of SMI. Here, we sought to review the literature in the field, focusing on PGx testing and particularly on pharmacokinetic markers. We performed a systematic review on PUBMED/Medline, Web of Science, and Scopus. The last search was performed on the 17 September 2022, and further augmented with a comprehensive pearl-growing strategy. In total, 1979 records were screened, and after duplicate removal, 587 unique records were screened by at least 2 independent reviewers. Ultimately, forty-two articles were included in the qualitative analysis, eleven randomized controlled trials and thirty-one nonrandomized studies. The observed lack of standardization in PGx tests, population selection, and tested outcomes limit the overall interpretation of the available evidence. A growing body of evidence suggests that PGx testing might be cost-effective in specific settings and may modestly improve clinical outcomes. More efforts need to be directed toward improving PGx standardization, knowledge for all stakeholders, and clinical practice guidelines for screening recommendations.

Risk factors for early recurrence after discontinuing lithium in bipolar disorder.

BACKGROUND: Time to a new episode of bipolar disorder (BD) is shorter after discontinuing lithium rapidly. We now address this and other factors associated with the risk of early illness after discontinuing lithium. METHODS: We compared factors for association with recurrences of BD within 12 months of discontinuing long-term lithium treatment, using bivariate and multivariable analyses, as well as survival analysis to evaluate latency to new episodes versus rate of lithium-discontinuation and prior treatment duration. RESULTS: Among 227 BD subjects who received lithium for 4.47 [CI: 3.89-5.04] years and then discontinued, rapid treatment-discontinuation, and stopping for medical reasons were strongly associated with new illness-episodes within 12 months, as were diagnosis (BD-I > BD-II), greater morbidity during lithium-treatment, and less education, but neither longer treatment nor serum lithium concentrations. Discontinuation rate was strongly associated with shorter median latency to a new episode (rapid: 3.50; gradual [≥2 weeks]: 10.6 months), even with very early recurrences excluded to avoid potential contributions of emerging illness to treatment-discontinuation. Early recurrence was not associated with treatment-duration of ≥2 or ≥5 years or less. In multivariable logistic regression, rapid discontinuation, stopping for medical reasons, and BD-I diagnosis remained significantly, independently associated with early illness after lithium-discontinuation, with no effect of treatment duration. CONCLUSIONS: Early recurrence risk was again much greater after rapid discontinuation of lithium and discontinuing for medical reasons, somewhat greater with BD-I than BD-II, and following greater morbidity during lithium-treatment, but not related to dose or duration of preceding treatment exposure.

Nanoparticle anisotropy induces sphere-to-cylinder phase transition in block copolymer melts.

Block copolymer nanocomposites including anisotropic nanoparticles have been previously found to co-assemble into complex structures with nanoparticle alignment. Anisotropic nanoparticles with large aspect ratios are found to modify the morphology of block copolymers at modest concentrations, inducing a sphere-to-cylinder phase transition by breaking the local symmetry in the vicinity of a solid particle. This transition takes place over a wide range of NP lengths comparable with the BCP spacing. Controlling the orientation of uniaxial nanoparticles provides additional control over the global orientation of the block copolymer, as previously reported by experiments.

Suicidal risk factors in major affective disorders.

BACKGROUND: Rates and risk factors for suicidal behaviour require updating and comparisons among mood disorders.AimsTo identify factors associated with suicidal risk in major mood disorders. METHOD: We considered risk factors before, during and after intake assessments of 3284 adults with/without suicidal acts, overall and with bipolar disorder (BD) versus major depressive disorder (MDD), using bivariate comparisons, multivariable regression modelling and receiver operating characteristic (ROC) analysis. RESULTS: Suicidal prevalence was greater in BD versus MDD: ideation, 29.2 versus 17.3%; attempts, 18.8 versus 4.78%; suicide, 1.73 versus 0.48%; attempts/suicide ratio indicated similar lethality, 10.9 versus 9.96. Suicidal acts were associated with familial BD or suicide, being divorced/unmarried, fewer children, early abuse/trauma, unemployment, younger onset, longer illness, more dysthymic or cyclothymic temperament, attention-deficit hyperactivity disorder (ADHD), substance misuse, mixed features, hospital admission, percentage time unwell, less antidepressants and more antipsychotics and mood stabilisers. Logistic regression found five independent factors: hospital admission, more depression at intake, BD diagnosis, onset age ≤25 years and mixed features. These factors were more associated with suicidal acts in BD than MDD: percentage time depressed/ill, alcohol misuse, >4 pre-intake depressions, more dysthymic/cyclothymic temperament and prior abuse/trauma. ADHD and total years ill were similar in BD and MDD; other factors were more associated with MDD. By ROC analysis, area under the curve was 71.3%, with optimal sensitivity (76%) and specificity (55%) with any two factors. CONCLUSIONS: Suicidal risks were high in mood disorders: ideation was highest with BD type II, attempts and suicides (especially violent) with BD type I. Several risk factors for suicidal acts differed between BD versus MDD patients.Declaration of interestNo author or immediate family member has financial relationships with commercial entities that might appear to represent potential conflicts of interest with the information presented.

Large scale three dimensional simulations of hybrid block copolymer/nanoparticle systems.

Block copolymer melts self-assemble in the bulk into a variety of nanostructures, making them perfect candidates to template the position of nanoparticles. The morphological changes of block copolymers are studied in the presence of a considerable filling fraction of colloids. Furthermore, colloids can be found to assemble into ordered hexagonally close-packed structures in a defined number of layers when softly confined within the phase-separated block copolymer. A high concentration of interface-compatible nanoparticles leads to complex long-lived block copolymer morphologies depending on the polymeric composition. Macrophase separation between the colloids and the block copolymer can be induced if colloids are unsolvable within the matrix. This leads to the formation of ellipsoid-shaped polymer-rich domains elongated along the direction perpendicular to the interface between block copolymer domains.

Co-assembly of Janus nanoparticles in block copolymer systems.

Block copolymer are ideal matrices to control the localisation of colloids. Furthermore, anisotropic nanoparticles such as Janus nanoparticles possess an additional orientational degree of freedom that can play a crucial role in the formation of highly ordered materials made of block copolymers. This work presents a mesoscopic simulation method to assert the co-assembly of Janus nanoparticles in a block copolymer mixture, finding numerous instances of aggregation and formation of ordered configurations. Comparison with chemically homogeneous neutral nanoparticles shows that Janus nanoparticles are less prone to induce bridging along lamellar domains, thus being a less destructive way to segregate nanoparticles at interfaces. The combination of asymmetric block copolymer and asymmetric Janus nanoparticles can result in assembly of colloids with an even number of layers within the minority domain.

The effect of amidation on the behaviour of antimicrobial peptides.

Aurein 2.6-COOH and aurein 3.1-COOH were studied along with their naturally occurring C-terminally amidated analogues. Circular dichroism (CD) and molecular dynamic (MD) simulations were used to study the effects of amidation on the interaction of antimicrobial peptides (AMPs) with lipid bilayers. CD measurements and MD analysis suggested that both peptide analogues were predominantly random coil and adopted low levels of α-helical structure in solution (<30%) and in the presence of a lipid bilayer the peptides formed a stable α-helical structure. In general, amidated analogues have a greater propensity than the non-amidated peptides to form a α-helical structure. MD simulations predicted that aurein 2.6-COOH and aurein 3.1-CHOOH destabilised lipid bilayers from 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phosphoserine via angled bilayer penetration. They also showed that aurein 2.6-CONH2 and aurein 3.1-CONH2 formed a helix horizontal to the plane of an asymmetric interface.

The cooperative behaviour of antimicrobial peptides in model membranes.

A systematic analysis of the hypothesis of the antimicrobial peptides' (AMPs) cooperative action is performed by means of full atomistic molecular dynamics simulations accompanied by circular dichroism experiments. Several AMPs from the aurein family (2.5,2.6, 3.1), have a similar sequence in the first ten amino acids, are investigated in different environments including aqueous solution, trifluoroethanol (TFE), palmitoyloleoylphosphatidylethanolamine (POPE), and palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayers. It is found that the cooperative effect is stronger in aqueous solution and weaker in TFE. Moreover, in the presence of membranes, the cooperative effect plays an important role in the peptide/lipid bilayer interaction. The action of AMPs is a competition of the hydrophobic interactions between the side chains of the peptides and the hydrophobic region of lipid molecules, as well as the intra peptide interaction. The aureins 2.5-COOH and 2.6-COOH form a hydrophobic aggregate to minimize the interaction between the hydrophobic group and the water. Once that the peptides reach the water/lipid interface the hydrophobic aggregate becomes smaller and the peptides start to penetrate into the membrane. In contrast, aurein 3.1-COOH forms only a transient aggregate which disintegrates once the peptides reached the membrane, and it shows no cooperativity in membrane penetration.

In Situ X-ray Absorption Spectroscopy Study of the Deactivation Mechanism of a Ni-SrTiO3 Photocatalyst Slurry Active in Water Splitting.

We used in situ X-ray absorption spectroscopy (XAS) to investigate the composition-performance correlation of Ni-SrTiO3 photocatalysts active for water splitting. After preparation and exposure to ambient conditions, the Ni particles on SrTiO3 consist of Ni(0) and Ni(II) phases, with a 4:1 at % ratio, in a metal/oxide core/shell configuration, as confirmed by XPS and TEM-EDX. In situ XAS experiments using an aqueous slurry of the Ni-SrTiO3 photocatalyst and simultaneous continuous exposure to 365 nm light with a power density of 100 mW cm-2 and the X-rays do not reveal significant changes in oxidation state of the Ni particles. Contrarily, when the X-rays are discontinuously applied, UV excitation leads to oxidation of a significant fraction of Ni(0) to Ni(II), specifically to NiO and Ni(OH)2 phases, along with cocatalyst restructuring. Ni dissolution or oxidation to higher valence states (e.g., Ni(III)) was not observed. The UV light-induced oxidation of Ni(0) causes the hydrogen evolution rate to drop to similar rates as observed for pristine SrTiO3, suggesting that Ni(0) is the active phase for H2 generation. Our results underscore the importance of assessing the effects of (continuous) X-ray exposure to (photo)catalyst-containing aqueous slurries during in situ XAS experiments, which can significantly influence the observation of compositional and structural changes in the (photo)catalysts. We ascribe this to X-ray induced water photolysis and formation of free electrons, which in this study quench SrTiO3 photoholes and prevent Ni oxidation.

Enhanced Photocatalytic Paracetamol Degradation by NiCu-Modified TiO2 Nanotubes: Mechanistic Insights and Performance Evaluation.

Anodic TiO2 nanotube arrays decorated with Ni, Cu, and NiCu alloy thin films were investigated for the first time for the photocatalytic degradation of paracetamol in water solution under UV irradiation. Metallic co-catalysts were deposited on TiO2 nanotubes using magnetron sputtering. The influence of the metal layer composition and thickness on the photocatalytic activity was systematically studied. Photocatalytic experiments showed that only Cu-rich co-catalysts provide enhanced paracetamol degradation rates, whereas Ni-modified photocatalysts exhibit no improvement compared with unmodified TiO2. The best-performing material was obtained by sputtering a 20 nm thick film of 1:1 atomic ratio NiCu alloy: this material exhibits a reaction rate more than doubled compared with pristine TiO2, enabling the complete degradation of 10 mg L-1 of paracetamol in 8 h. The superior performance of NiCu-modified systems over pure Cu-based ones is ascribed to a Ni and Cu synergistic effect. Kinetic tests using selective holes and radical scavengers unveiled, unlike prior findings in the literature, that paracetamol undergoes direct oxidation at the photocatalyst surface via valence band holes. Finally, Chemical Oxygen Demand (COD) tests and High-Resolution Mass Spectrometry (HR-MS) analysis were conducted to assess the degree of mineralization and identify intermediates. In contrast with the existing literature, we demonstrated that the mechanistic pathway involves direct oxidation by valence band holes.

Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study.

BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses. METHOD: We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications. RESULTS: Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

Effects of acute vasodilation on the hemodynamic response to muscle metaboreflex.

The aim of the present study was to test the contribution of stroke volume (SV) in hemodynamic response to muscle metaboreflex activation in healthy individuals. We hypothesized that an acute decrease in cardiac afterload and preload due to the administration of a vasodilating agent could reduce postexercise muscle ischemia (PEMI)-induced SV response. Ten healthy males (age 33.6 ± 1.3 yr) were enrolled and randomly assigned to the following study protocol: 1) PEMI session, 2) control exercise recovery (CER) session, 3) PEMI after sublingual administration of 5 mg of isosorbide dinitrate (ISDN), and 4) CER after ISDN. Central hemodynamics were evaluated by means of impedance cardiography. The main findings were a blunted SV response during metaboreflex following acute arterial and venous vasodilation, associated with a reduction in cardiac diastolic time and filling, and a decrement of systemic vascular resistance. These hemodynamic changes restrain blood pressure response during metaboreflex activation. Our results indicate that hemodynamic response to metaboreflex activation is a highly integrated phenomenon encompassing complex interplay between heart rate, cardiac performance, preload, and afterload and that impairment of one or more of these parameters leads to altered hemodynamic response to metaboreflex.

Suicidal risk and protective factors in major affective disorders: A prospective cohort study of 4307 participants.

BACKGROUND: Suicidal behavior is strongly associated with major affective disorders, but there is a need to quantify and compare specific risk and protective factors in bipolar disorder (BD) and major depressive disorder (MDD). METHODS: In 4307 extensively evaluated major affective-disorder participants with BD (n = 1425) or MDD (n = 2882) diagnosed by current international criteria, we compared characteristics among those with versus without suicidal acts from illness-onset through 8.24 years of follow-up. RESULTS: Suicidal acts were identified in 11.4 % of participants; 25.9 % were violent and 6.92 % (0.79 % of all participants) were fatal. Associated risk factors included: diagnosis (BD > MDD), manic/psychotic features in first-episodes, family history of suicide or BD, separation/divorce, early abuse, young at illness-onset, female sex with BD, substance abuse, higher irritable, cyclothymic or dysthymic temperament ratings, greater long-term morbidity, and lower intake functional ratings. Protective factors included marriage, co-occurring anxiety disorder, higher ratings of hyperthymic temperament and depressive first episodes. Based on multivariable logistic regression, five factors remained significantly and independently associated with suicidal acts: BD diagnosis, more time depressed during prospective follow-up, younger at onset, lower functional status at intake, and women > men with BD. LIMITATIONS: Reported findings may or may not apply consistently in other cultures and locations. CONCLUSIONS: Suicidal acts including violent acts and suicides were more prevalent with BD than MDD. Of identified risk (n = 31) and protective factors (n = 4), several differed with diagnosis. Their clinical recognition should contribute to improved prediction and prevention of suicide in major affective disorders.

Characteristics of rapid cycling in 1261 bipolar disorder patients.

BACKGROUND: Rapid-cycling (RC; ≥ 4 episodes/year) in bipolar disorder (BD) has been recognized since the 1970s and associated with inferior treatment response. However, associations of single years of RC with overall cycling rate, long-term morbidity, and diagnostic subtypes are not clear. RESULTS: We compared descriptive and clinical characteristics in 1261 BD patients with/without RC, based on history and prospective follow-up for several years. RC in any previous year was identified in 9.36% of BD subjects (3.74% in BD1, 15.2% BD2), and somewhat more among women than men. RC-BD subjects had 3.21-fold greater average prospective annual rates of recurrence but not hospitalizations, had less difference in %-time-ill, received more mood-stabilizing treatments, and had greater suicidal risk, lacked familial psychiatric illnesses, had more cyclothymic temperament, were more likely to be married, had more siblings and children, experienced early sexual abuse, but were less likely to abuse drugs (not alcohol) or smoke. In multivariable regression modeling, older age, mood-switching with antidepressants, and BD2 > BD1 diagnosis, as well as more episodes/year were independently associated with RC. Notably, prospective mean recurrence rates were below 4/year in 79.5% of previously RC patients, and below 2/year in 48.1%. CONCLUSIONS: Lifetime risk of RC in BD was 9.36%, more likely in women, with older age, and in BD2 > BD1. With RC, recurrence rates were much higher, especially for depression with less effect on %-time ill, suggesting shorter episodes. Variable associations with unfavorable outcomes and prospective recurrence rates well below 4/year in most previously RC patients indicate that RC was not a sustained characteristic and probably was associated with use of antidepressants.

Comparison of bipolar disorder type II and major depressive disorder.

OBJECTIVE: Compare patients diagnosed as DSM-5 type II bipolar disorder (BD2) vs. major depressive disorder (MDD). METHODS: We compared characteristics of 3246 closely and repeatedly evaluated, consenting, adult patient-subjects (n = 706 BD2, 2540 MDD) at a specialty clinic using bivariate methods and multivariable modeling. RESULTS: Factors more associated with BD2 than MDD included: [a] descriptors (more familial psychiatric, mood and bipolar disorders and suicide; younger at onset, diagnosis and first-treatment; more education; more unemployment; fewer marriages and children; higher cyclothymic, hyperthymic and irritable temperament ratings, lower anxious); [b] morbidity (more hypomanic, mixed or panic first episodes; more co-occurring general medical diagnoses, more Cluster B personality disorder diagnoses and ADHD; more alcohol and drug abuse and smoking; shorter depressive episodes and interepisode periods; lower intake ratings of depression and anxiety, higher for hypomania; far more mood-switching with antidepressants; lower %-time depressed; DMI > MDI course-pattern in BD2; more suicide attempts and violent suicidal behavior); [c] item-scores with intake HDRS21 higher for suicidality, paranoia, anhedonia, guilt, and circadian variation; lower somatic anxiety, depressed mood, insight, hypochondriasis, agitation, and insomnia; and [d] treatment (more lithium, mood-stabilizing anticonvulsants and antipsychotics, less antidepressants and benzodiazepines). CONCLUSIONS: BD2 and MDD subjects differed greatly in many descriptive, psychopathological and treatment measures, notably including more familial risk, earlier onset, more frequent recurrences and greater suicidal risk with BD2. Such differences can contribute to improving differentiation of the disorders and planning for their treatment.

Early sexual or physical abuse in female and male mood disorder patients.

Early abuse has been associated with psychiatric morbidity but comparisons of bipolar (BD) and major depressive (MDD) disorder subjects with versus without early sexual or physical abuse are rare. Patients (n = 684) diagnosed with a DSM-5-TR major mood disorder were evaluated and followed for several years at mood disorder centers to compare details of history and clinical status in participants with versus without early sexual or physical abuse. Early history of sexual (16.2%) or physical abuse (11.9%) was prevalent; 5.15% reported both. Both types of abuse were much more prevalent with BD than MDD. Sexual abuse was associated with younger illness-onset and somewhat younger menarche in females; both abuse-types were associated with familial mood disorders, especially BD. Prospective, long-term illness episode-frequency, depressions or [hypo]manias/year and %-time [hypo]manic all were greater following sexual abuse but morbidity measures did not differ following physical abuse. Prevalence of suicidal behavior ranked: double (48.5%) > physical (32.1%) > sexual (30.3%) abuse, and with BD > MDD (OR = 2.31). Recall bias and not using psychometric instruments to define abuse severity or type may limit interpretation of findings. Early sexual (more than physical) abuse, led to greater morbidity and both abuses were strongly associated with familial mood disorders and greater suicidal risk, especially with double-abuse and BD diagnosis. We support a bilateral relationship between abuse and diagnosis of BD: abuse may facilitate early appearance of BD but also may result from the actions of abusive BD family members.

Affective temperaments mediate aggressive dimensions in bipolar disorders: A cluster analysis from a large, cross-sectional, international study.

BACKGROUND: Affective temperaments show potential for aggressive behavior (AB) preventive strategies in bipolar disorder (BD). We aim to define intra-diagnostic subgroups of patients with BD based on homogeneous behaviors related to AB. Subsequently, to assess whether affective temperament dimensions may contribute to the presence and severity of AB. METHODS: Patients with BD were recruited. AB was evaluated through the modified overt aggression scale (MOAS); affective temperaments were assessed with the TEMPS-A. A cluster analysis was conducted based on TEMPS-A and MOAS scores. Stepwise backward logistic regression models were used to identify the predictive factors of cluster membership. RESULTS: 799 patients with BD were enrolled. Three clusters were determined: non-aggressive (55.5 %), self-aggressive (18 %), and hetero-aggressive (26.5 %). Depressive, irritable, and anxious temperament scores significantly increased from the non-aggressive (lower) to the self-aggressive (intermediate) and the hetero-aggressive group (highest). A positive history of a suicide attempt (B = 5.131; OR = 169.2, 95 % CI 75.9; 377) and rapid cycling (B = -0.97; OR = 0.40, 95 % CI 0.17; 0.95) predicted self-aggressive cluster membership. Atypical antipsychotics (B = 1.19; OR = 3.28, 95 % CI 2.13; 5.06) or SNRI treatment (B = 1.09; OR = 3, 95 % CI 1.57; 5.71), psychotic symptoms (B = 0.73; OR = 2.09, 95 % CI 1.34; 3.26), and history of a suicide attempt (B = -1.56; OR = 0.20, 95 % CI 0.11; 0.38) predicted hetero-aggressive cluster membership. LIMITATIONS: Recall bias might have affected the recollection of AB. CONCLUSIONS: Clinical factors orientate the prevention of different ABs in BD. Affective temperaments might play a role in preventing AB since patients with more pronounced affective temperaments might have an increased risk of showing AB, in particular hetero-AB.

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.

An integrated precision medicine approach in major depressive disorder: a study protocol to create a new algorithm for the prediction of treatment response.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients' empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance.