Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis.

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.

The Development of Temperament Evaluation of Memphis, Pisa, Paris, and San Diego - Auto-questionnaire for Adolescents (A-TEMPS-A) in a Serbian Sample.

BACKGROUND: Previous studies suggest that temperament features of adolescents may be good predictors of the development of future psychopathology in this population. The aim of the study was to adapt the content and validate the psychometric properties of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego - Auto-questionnaire in a sample of Serbian adolescents. SUBJECTS AND METHODS: The sample included 2113 adolescents, 56% girls and 44% boys, average age 16.73±0.47, attending 48 Serbian secondary schools. The base for the development of this scale included Serbian standardised versions as well as the TEMPS-I, Interview version. RESULTS: The final scale is comprised of 36 items, with six factors (depressive, cyclothymic, hyperthymic, irritable, and anxious-cognitive/somatic) explaining 39.9% of the total variance, the internal consistency coefficient α=0.77, and the average test-retest coefficient (rho=0.84). The correlations among the temperaments ranged from weak to moderate, with the highest positive correlations between the depressive, cyclothymic and anxious scales. The highest values were detected on hyperthymic and the lowest on depressive temperament. Significantly higher scores of depressive, cyclothymic and anxious temperaments were detected in girls, whereas boys had higher scores on the hyperthymic scale. CONCLUSIONS: The scale has shown good psychometric properties, which encourages its further use in adolescent population. The results show certain specific features of this population, such as higher scores on all temperament types than the ones in student and adult population and a tendency of socially desirable answers.

Lifetime mania is related to post-traumatic stress symptoms in high school students exposed to the 2009 L'Aquila earthquake.

BACKGROUND: Bipolar patients seem to be at high risk of trauma exposure and, when exposed, of PTSD. When comorbid, PTSD has shown a negative impact on the course of the bipolar illness. Conversely, a correlation between even manic symptoms and an increased risk for suicide has also been reported in PTSD patients. The aim of this study was to investigate the relationships between lifetime mood spectrum symptoms and PTSD in a sample of earthquake survivors. METHODS: A total of 475 young adults who survived the L'Aquila 2009 earthquake, 21months earlier, were assessed by the Moods Spectrum-Self Report (MOODS-SR) and the Trauma and Loss Spectrum Self Report (TALS-SR). RESULTS: Significantly higher MOODS-SR and TALS-SR domain scores were found in PTSD survivors compared to those without. The mood depressive (O.R.=1.17, 95% CI: 1.10-1.25), cognition depressive (O.R.=1.07, 95% CI: 1.01-1.14) and energy manic (O.R.=1.13, 95% CI: 1.02-1.25) MOODS-SR domains were significantly associated with an increased likelihood of PTSD. CONCLUSIONS: Our data corroborate the strong relationship between mood disorder and PTSD highlighting a relationship between lifetime depressive and manic symptoms and PTSD, with a particular impact of the latter on the number of traumatic exposures and maladaptive behaviors.

Standardization of the NEO-PI-3 in the Greek general population.

BACKGROUND: The revised NEO Personality Inventory (NEO-PI-3) includes 240 items corresponding to the Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience) and subordinate dimensions (facets). It is suitable for use with adolescents and adults (12 years or older). The aim of the current study was to validate the Greek translation of the NEO-PI-3 in the general Greek population. MATERIAL AND METHODS: The study sample included 734 subjects from the general Greek population of whom 59.4% were females and 40.6% males aged 40.80 ± 11.48. The NEO-PI-3 was translated into Greek and back-translated into English, and the accuracy of the translation was confirmed and established. The statistical analysis included descriptive statistics, confirmatory factorial analysis (CFA), the calculation of Cronbach's alpha, and the calculation of Pearson product-moment correlations. Sociodemographics groups were compared by ANOVA. RESULTS: Most facets had Cronbach's alpha above 0.60. Confirmatory factor analysis showed acceptable loading of the facets on their own hypothesized factors and very good estimations of Cronbach's alphas for the hypothesized factors, so it was partially supportive of the five-factor structure of the NEO-PI-3.The factors extracted with Procrustes rotation analysis can be considered reasonably homologous to the factors of the American normative sample. Correlations between dimensions were as expected and similar to those reported in the literature. DISCUSSION: The literature suggests that overall, the psychometric properties of NEO-PI-3 scales have been found to generalize across ages, cultures, and methods of measurement. In accord with this, the results of the current study confirm the reliability of the Greek translation and adaptation of the NEO-PI-3. The inventory has comparable psychometric properties in its Greek version in comparison to the original and other national translations, and it is suitable for clinical as well as research use.

Temperaments mediate suicide risk and psychopathology among patients with bipolar disorders.

BACKGROUND: Several studies have demonstrated that bipolar II (BD-II) disorder represents a quite common, distinct form of major mood disorders that should be separated from bipolar I (BD-I) disorder. The aims of this cross-sectional study were to assess temperament and clinical differences between patients with BD-I and BD-II disorders and to assess whether temperament traits are good predictors of hopelessness in patients with bipolar disorder, a variable highly associated with suicidal behavior and ideation. METHOD: Participants were 216 consecutive inpatients (97 men and 119 women) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), BD who were admitted to the Sant'Andrea Hospital's psychiatric ward in Rome (Italy). Patients completed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego--Autoquestionnaire, the Beck Hopelessness Scale (BHS), the Mini International Neuropsychiatric Interview (MINI), and the Gotland Scale of Male Depression. RESULTS: Patients with BD-II had higher scores on the BHS (9.78 ± 5.37 vs 6.87 ± 4.69; t(143.59) = -3.94; P < .001) than patients with BD-I. Hopelessness was associated with the individual pattern of temperament traits (ie, the relative balance of hyperthymic vs cyclothymic-irritable-anxious-dysthmic). Furthermore, patients with higher hopelessness (compared with those with lower levels of hopelessness) reported more frequently moderate to severe depression (87.1% vs 38.9%; P < .001) and higher MINI suicidal risk. CONCLUSION: Temperaments are important predictors both of suicide risk and psychopathology and may be used in clinical practice for better delivery of appropriate care to patients with bipolar disorders.

Clinical presentations of substance abuse in bipolar heroin addicts at time of treatment entry.

BACKGROUND: Studies on the 'self-medication hypothesis' have focused on substance abuse as an attempt to alleviate emotional suffering. METHODS: We have investigated concomitant substances of abuse in 150 bipolar heroin addicts clustered according to their clinical presentation at treatment entry (depressive episode, hypomanic episode, manic episode and mixed episode). Bipolar heroin addicted patients were chosen because they tend to have a concomitant poly-substance abuse and because, as compared with patients suffering for other mental illnesses, they more clearly reveal a variety of identifiable affective states. RESULTS: Patients with a depressive episode more frequently used non-prescribed anxiolytic-hypnotics. They were found to use cocaine-amphetamines more frequently during a hypomanic episode, whereas the use of cannabis and cocaine-amphetamines occurred more frequently during a manic episode. The associated use of alcohol, cocaine-amphetamines and cannabinoids was more frequently encountered during a mixed episode. LIMITATIONS: apart from the difficulty in determining whether the substance use modifies the mood or the mood state determines the substance used, this is a report on a retrospective analysis, rather than a study specifically designed to elucidate the issue; in addition, no information was available on the temperament of our subjects. Assessments of the same subject in various clinical presentations would have provided a better level of information. CONCLUSIONS: Besides one expected result - the prominent use of CNS stimulants during a depressive phase of bipolar patients - this study supports the hypothesis that mood elation is a pleasurable, rewarding experience that, in bipolar patients, can be started or prolonged by means of CNS stimulant drugs. Stimulant use was, therefore, more prevalent during the 'up' rather than the 'down' phase of the illness.

Could hypomanic traits explain selective migration? Verifying the hypothesis by the surveys on sardinian migrants.

INTRODUCTION: A recent survey put forward the hypothesis that the emigration that occurred from Sardinia from the 1960's to the 1980's, selected people with a hypomanic temperament. The paper aims to verify if the people who migrated from Sardinia in that period have shown a high risk of mood disorders in the surveys carried out in their host countries, and if the results are consistent with this hypothesis. METHODS: This is systematic review. RESULTS: In the 1970's when examining the attitudes towards migration in Sardinian couples waiting to emigrate, Rudas found that the decision to emigrate was principally taken by males. Female showed lower self-esteem than male emigrants. A study on Sardinian immigrants in Argentina carried out in 2001-02, at the peak of the economic crisis, found a high risk of depressive disorders in women only. These results were opposite to the findings recorded ten years earlier in a survey on Sardinian immigrants in Paris, where the risk of Depressive Episode was higher in young men only. DISCUSSION: Data point to a bipolar disorder risk for young (probably hypomanic) male migrants in competitive, challenging conditions; and a different kind of depressive episodes for women in trying economic conditions. The results of the survey on Sardinian migrants are partially in agreement with the hypothesis of a selective migration of people with a hypomanic temperament. Early motivations and self-esteem seem related to the ways mood disorders are expressed, and to the vulnerability to specific triggering situations in the host country.

Are migraine and bipolar disorders comorbid phenomena?: findings from a pharmacoepidemiological study using the Norwegian Prescription Database.

OBJECTIVES: Clinical, epidemiological, and, recently, genome-wide linkage and genome-wide association studies suggest migraine and bipolar disorder are comorbid phenomena. The objective of this study was to determine whether there is also evidence that this comorbidity exists by virtue of there being a positive relationship between the prescription of medications used to treat migraine and mood-stabilizing agents using the National Norwegian Prescription Database. METHODS: Data allowing ascertainment of the concurrence of prescriptions for migraine and mood-stabilizing agents were gleaned from the Norwegian Prescription Database for calendar year 2006, covering the total population (N = 4,640,219). Results were obtained using logistic regression analyses and were expressed by odds ratios (ORs). RESULTS: A total of 81,225 persons (1.8% of the population) received medications for migraine and 19,517 (0.45%) received a mood-stabilizing agent for a bipolar disorder; 843 persons received both types of medications. The OR expressing the relationship between the concurrent use of both categories of medications was 2.55 (95% confidence interval [CI], 2.38-2.73, P < 0.001, z score = 26.44), significant for all mood stabilizers (lithium: OR = 1.82 [95% CI, 1.58-2.10], P < 0.001, z score = 8.31; carbamazepine: OR = 2.48 [95% CI, 2.01-3.06], P < 0.001, z score = 8.42; valproic acid: OR = 2.26 [95% CI, 1.89-2.70], P < 0.001, z score = 8.96; and lamotrigine: OR = 3.50 [95% CI, 3.14-3.90], P < 0.001, z score = 22.68). The association was significantly higher for men (OR = 3.16 [95% CI, 2.74-3.66], P < 0.001, z score = 15.53) than for women (OR = 2.21 [95% CI, 2.04-2.39], P < 0.001, z score = 19.61) and was most pronounced in younger age groups and for lamotrigine. CONCLUSIONS: There was a strong positive association between the prescription of medications used to treat migraine and mood-stabilizing agents. This is compatible with the hypothesis that migraine and bipolar disorders are associated with one another.

Pharmacological response in juvenile bipolar disorder subtypes: A naturalistic retrospective examination.

This study reports on the naturalistic pharmacotherapy of 266 youths with bipolar disorder (BP), manic or hypomanic episode (158 males and 108 females, 13.8+/-2.8 years), first treated with monotherapy on valproic acid (VPA) (n=158, 59.4%), lithium (n=90, 33.8%) or atypical antipsychotics (n=18, 6.8%). Among the patients receiving mood stabilizers, 59.5% of those treated with VPA and 47.8% of those receiving lithium did not need other antimanic agents (mood stabilizers and/or atypical antipsychotics). Lower severity was associated with a greater persistence of both VPA and lithium monotherapy. Factors associated with greater persistence of VPA monotherapy were BP II and co-occurring generalized anxiety disorder, separation anxiety disorder and simple phobias. On the contrary, BP I and co-occurring psychotic symptoms and/or conduct disorder were associated with a lower persistence of VPA monotherapy. Factors associated with lower persistence of lithium monotherapy were younger age and the association with attention deficit hyper-activity disorder (ADHD). Type of BP and presence of psychotic symptoms and conduct disorder did not affect the lithium monotherapy. Overall, predictors of non-response (multiple stepwise logistic regression) in both VPA and lithium groups were baseline Clinical Global Impression (CGI) Severity score and comorbid conduct disorder; while psychotic symptoms and absence of comorbid generalized anxiety disorder were predictors of poorer treatment response only in the VPA group, and chronic course, comorbid ADHD and absence of comorbid panic disorder were predictors only in the lithium group. Such naturalistic data from an ordinary clinical setting have relevance to clinical practice.

Mood stabilizers in the treatment of substance use disorders.

Individuals suffering from drug addiction may also manifest features of bipolar spectrum disorders. Hyperthymic and cyclothymic temperaments may render individuals vulnerable to later development of substance abuse. Bipolar disorders themselves may be altered or precipitated by substance use, most notably by stimulants (amphetamines), alcohol, and cannabinoids. The clinical usefulness of mood stabilizers, particularly antiepileptics, has been established as safe and effective in substance abusers with and without comorbid mood disorders. Most studies on this issue have been of short duration and focused on the resolution of a currently manifest period of illness. Few studies have been conducted on the usefulness of these drugs on the long-term longitudinal course of these diseases, such as frequently encountered recurrent relapses into states of agitation, impulsivity, and/or dissatisfaction. As opposed to the clinical experience with traditional antidepressants and neuroleptics, antiepileptics do not induce counter-polar states (depressed patients abruptly turning manic or hypomanic; nor patients currently hypomanic or manic turning abruptly depressed). Many clinicians consider antiepileptic mood stabilizers to be the preferred category of medications for the treatment of such patients. Valproate appears to be a potentially fruitful medication to study in these dual diagnosis patients due to preliminary evidence demonstrating its anticraving efficacy.