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.

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.

Adjunctive valproate in panic disorder patients with comorbid bipolar disorder or otherwise resistant to standard antidepressants: a 3-year "open" follow-up study.

The aim of the study was to report on the clinical utility of naturalistic adjunctive treatment with valproate (VPA) in a group of panic disorder (PD) patients with comorbid bipolar disorder (BD) or otherwise resistant to antidepressants. The hypothesis was that these patients might not respond because of coexisting low-grade mood instability and adjunctive VPA treatment might ameliorate PD symptoms. A group of 47 patients with lifetime comorbid BD (n = 35, 74.5%) or otherwise resistant to antidepressants (n = 12, 25.6%), from a population of 326 consecutive outpatients with PD-Agoraphobia evaluated and treated at the Psychiatric Institute of the University of Pisa from 1991 to 1995, and followed for a period of 3 years. All patients were evaluated at baseline and at least every 2 months by means of an intensive interview including semi-structured and structured instruments (SCID, Life-Up, and Panic Disorder/Agoraphobia Interview). Mean dosage was 687 (SD = 234) mg/day (min 400, max 1,500 mg/day). Adjunctive treatment with VPA was well tolerated by all subjects, and there was no treatment interruption because of side effects or adverse events. All antidepressants-resistant subjects and 31 of 35 (88.6%) patients with bipolar comorbidity achieved symptomatological remission. During the observation period, 7 (58.3%) among resistant subjects and 17 (48.6%) of bipolar patients had a relapse of panic disorder after remission. Survival analysis of remission durations and onset relapses for PD and Agoraphobia did not show significant differences between the two groups. Relapses of Agoraphobia were less frequent and more delayed than those for panic. According to the results, VPA seems to be an effective and a well-tolerated adjunctive treatment in PD patients who were resistant to antidepressant therapy or had BD in comorbidity. The results of the study support the hypothesis of resistance to antidepressant treatment being related to mood instability.

A naturalistic exploratory study of the impact of demographic, phenotypic and comorbid features in pediatric obsessive-compulsive disorder.

BACKGROUND: Few studies have examined the impact of gender, age at onset, phenotype and comorbidity in pediatric obsessive-compulsive disorder (OCD) in children. In this naturalistic study we consider these characteristics of OCD in the framework of the 4 OCD phenotypes (contamination/cleaning, order/symmetry, obsessions/checking and hoarding) proposed by Leckman et al. SAMPLING AND METHODS: A consecutive series of 257 patients aged 13.6 +/- 2.8 years, diagnosed using a DSM-IV-based clinical interview (Schedule for Affective Disorders and Schizophrenia for School Age Children - Present and Lifetime Version), were included. RESULTS: Patients with OCD onset before 12 years of age presented a higher frequency of comorbid tic disorder and disruptive behavior disorders. The type of obsession varied with gender: order/symmetry was more frequent in males, contamination/cleaning in females. Order/symmetry had the highest comorbidity with tics, contamination/cleaning was the least severe according to the Clinical Global Impression Severity, and was associated with a high rate of comorbid anxiety and depression, similarly to sexual-religious obsessions. Hoarding was the severest according to the Clinical Global Impression Severity, and was associated with a high comorbidity with social phobia and bipolar disorder. Tic comorbidity was more prevalent in males, had an earlier onset, and a heavier comorbidity with attention deficit hyperactivity disorder and other disruptive behavior disorders. A comorbid attention deficit hyperactivity disorder was associated with an earlier onset of OCD and a poorer response to treatments. CONCLUSIONS: OCD phenotypes and comorbidities may have marked clinical and prognostic implications. Tertiary care population results may not generalize to less impaired juvenile populations.

Six-year stability of affective temperaments as measured by TEMPS-A.

BACKGROUND: A number of psychopathological and neurobiological studies on affective temperament have been conducted based on the assumption that temperament is a stable trait. However, few studies have actually assessed the long-term stability of affective temperament. The objective of this study is to evaluate the 6-year stability of affective temperaments as measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego--Autoquestionnaire version (TEMPS-A) in a non-clinical adult population. SAMPLING AND METHODS: Study participants consisted of 178 Japanese white-collar workers (103 males and 75 females; mean age = 38.5 years, SD = 7.8) who completed the Japanese version of TEMPS-A twice over a 6-year interval, and who did not have either past or current DSM-IV affective, anxiety or psychotic disorders, as diagnosed with the Mini-International Neuropsychiatric Interview. The long-term stability of affective temperaments as measured by TEMPS-A was assessed by analyzing Pearson correlation coefficients for temperament scores over a 6-year period. RESULTS: Temperament scores were moderately to highly correlated over the 6-year period (depressive temperament, r = 0.59; cyclothymic temperament, r = 0.68; hyperthymic temperament, r = 0.82; irritable temperament, r = 0.66; anxious temperament, r = 0.74; p < 0.01 for all values). Pearson coefficients were in the range of 0.61-0.83 for males and 0.51-0.79 for females, while they were 0.56-0.85 for younger and 0.63-0.77 for older participants. All correlations were significant at p < 0.01, irrespective of temperament type, gender and age. CONCLUSIONS: Affective temperaments as measured by TEMPS-A exhibited good long-term stability and were robust, irrespective of temperament type, gender and age. Affective temperaments as measured by TEMPS-A may be considered to be stable traits, providing a sound basis for psychopathological and neurobiological studies. Limitations of this study include the fact that our sample was not drawn from the general community, it was entirely composed of Japanese participants and the size was not large.

How possible is the development of an operational psychometric method to assess the presence of the 5-HTTLPR s allele? Equivocal preliminary findings.

OBJECTIVE: The s allele of the 5-hydroxytryptamine transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene has been found to be associated with neuroticism-related traits, affective temperaments and response to selective serotonin reuptake inhibitor (SSRI) treatment. The aim of the current study was to develop a psychometric tool that could at least partially substitute for laboratory testing and could predict the presence of the s allele. METHODS: The study included 138 women of Caucasian origin, mean 32.20 +/- 1.02 years old. All subjects completed the Hungarian standardised version of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) instrument and were genotyped for 5-HTTLPR using PCR. The statistical analysis included the calculation of the Index of Discrimination (D), Discriminant Function Analysis, creation of scales on the basis of the above and then item analysis and calculation of sensitivity and specificity. RESULTS: Four indices were eventually developed, but their psychometric properties were relatively poor and their joint application did not improve the outcome. CONCLUSIONS: We could not create a scale that predicts the 5-HTTLPR genotype with sufficient sensitivity and specificity, therefore we could not substitute a psychometric scale for laboratory genetic testing in predicting genotype, and also possibly affective disorder characterisation and treatment.

Association of the s allele of the 5-HTTLPR with neuroticism-related traits and temperaments in a psychiatrically healthy population.

INTRODUCTION: Research concerning the genetic background of traits, temperaments and psychiatric disorders has been rapidly expanding. One of the most frequently studied genetic polymorphisms in the background of psychological and psychiatric phenomena is the 5-HTTLPR polymorphism of the serotonin transporter gene which has earlier been found to be associated with neuroticism and neuroticism-related traits and disorders. However, both the neuroticism trait and psychiatric disorders are complex and composed of several subfacets. The aim of our study was to investigate the association of the 5-HTTLPR polymorphism with several smaller, distinct and better characterisable phenomena related to the neuroticism trait. METHODS: 169 healthy females participated in the study. All participants completed the Buss-Durkee Hostility Inventory (BDHI), the State-Trait Anxiety Inventory (STAI), The Zung Self-rating Depression Scale (ZSDS), the Beck Hopelessness Scale, the SCL-51, the Temperament and Character Inventory (TCI) and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) questionnaire. All subjects were genotyped for the 5-HTTLPR using PCR. Data were analysed with ANOVA and MANCOVA with age as a covariate. RESULTS: We found that the presence of the s allele was significantly associated with anxiety, depression, hopelessness, guilt, hostility, aggression, presence of neurotic symptoms, self-directedness and affective temperaments carrying a depressive component even when controlling for age. CONCLUSIONS: Our study is the first that confirms that traits and characteristics related to neuroticism, such as increased anxiety, depression, hopelessness, somatization, feeling of guilt, hostility, aggression, lack of self-directedness and affective temperament are consistently and independently associated with the 5-HTTLPR polymorphism of the serotonin transporter gene. Our study therefore suggests that neuroticism can be considered a unified construct not only from a phenotypical but also from a genetic point of view and 5HTTLPR can be considered one component of its polygenic background. Our results thus yield further insight into the role of the 5-HTTLPR in the background of neuroticism and neuroticism-related psychiatric disorders.

Is a family history of bipolar disorder a risk factor for migraine among affectively ill patients?

AIMS: The aim was to determine whether having a family history of bipolar disorder (BPD) or unipolar major depressive disorder (MDD) is associated with an increased likelihood of having migraine headaches. METHODS: Latino adults received structured diagnostic interviews. Family history was determined by live interview of first-degree relatives or interview by proxy. All patients met the criteria for major depressive episode (MDE) at the time of assessment. The method of diagnosing migraine had sensitivity and specificity of 87 and 50%, respectively. Logistic regression was used to test for associations and control for confounding. RESULTS: In total, 153 patients met the criteria for MDD and 87 for BPD. Patients with MDD who had a family history of BPD were 4.3 times more likely to have migraine headaches than those who did not (OR=4.34, z=3.02, p=0.003, 95% CI=1.67-11.27). Patients with BPD who had a family history of BPD were 3 times more likely to have migraine than those who did not (OR=2.99, z=2.45, p=0.014, 95% CI=1.25-7.19). Within the entire group of patients, those with a family history of BPD were 4.4 times more likely to have migraine headaches than those who did not (OR = 4.38, p<0.0001, z=4.72, 95% CI=2.37-8.09). A family history of MDD was not associated with an increased risk of having migraine. CONCLUSION: Regardless of a patient's polarity, having a family history of BPD is associated with an increased risk of having migraine headache.

Psychopathological correlates of lifetime anxiety comorbidity in bipolar I patients: findings from a French national cohort.

BACKGROUND: Despite numerous studies on the comorbidity of bipolar and anxiety disorders, there is no satisfactory psychopathological model for their overlap. METHOD: 1,090 hospitalized patients meeting DSM-IV criteria for a manic episode of bipolar I disorder were subtyped according to the presence or not of lifetime anxiety comorbidity and assessed for demographic, illness course, clinical, associated condition, temperament, and treatment characteristics. RESULTS: Lifetime anxiety comorbidity, defined as presence of at least one anxiety disorder in lifetime, was found in 27.2% (n = 297) of the sample. Compared to patients without such a comorbidity (n = 793), those who had it experienced a higher number of mood episodes and suicide attempts in the previous year, more stressors, organic disorders and less free intervals; furthermore, they showed more temperaments with depressive features and complex treatment. At study entry, they also experienced manic episodes with higher levels of depression, psychosis and hostility. The following independent variables were associated with lifetime anxiety comorbidity: higher scores on the Montgomery-Asberg Depression Rating Scale, depressive temperament, irritable temperament, higher scores on the Scale for the Assessment of Positive Symptoms, episodes without free intervals and at least one stressor before the index episode. CONCLUSIONS: Factors associated with lifetime anxiety comorbidity in bipolar I patients may be integrated into a comprehensive diathesis-stress model emphasizing the role of irritable temperament as a source of mood instability and stress, and interacting with other temperamental characteristics to trigger the outbreak of both anxiety and bipolar symptoms.

Suicide risk and personality traits in physically and/or sexually abused acute psychiatric inpatients: a preliminary study.

The aim of the present study was to analyze hopelessness and the affective temperament profile and MMPI characteristics among suicidal and nonsuicidal psychiatric inpatients with or without childhood physical and sexual abuse. The participants were 62 acute psychiatric inpatients (14 men, 48 women) admitted to the Sant'Andrea Hospital's psychiatric ward in Rome. Participants were administered the Italian versions of the Childhood Trauma Questionnaire, the Mini-International Neuropsychiatric Interview (MINI), the Italian Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire version (TEMPS-A-Rome), the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), and the Beck Hopelessness Scale. The suicide risk was evaluated by 6 items of the MMPI-2 assessing suicidal intent. Patients with physical/sexual abuse reported high Hopelessness and differed from nonabused patients on several temperamental and personality traits. Patients who reported bruises or marks caused by physical abuse by family members were 9 times more likely to be at higher risk for suicide; those who reported having been punished with a belt or other hard objects were 20 times more likely to be at higher risk for suicide, and those who reported having been insulted by family members were 6 times more likely to be at higher risk for suicide than patients who denied such abuse experiences. Results suggest that clinicians who identify suicide attempts and suicidal tendencies among patients should routinely be assessed for sexual or physical abuse.

Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication.

CONTEXT: There is growing recognition that bipolar disorder (BPD) has a spectrum of expression that is substantially more common than the 1% BP-I prevalence traditionally found in population surveys. OBJECTIVE: To estimate the prevalence, correlates, and treatment patterns of bipolar spectrum disorder in the US population. DESIGN: Direct interviews. SETTING: Households in the continental United States. PARTICIPANTS: A nationally representative sample of 9282 English-speaking adults (aged >or=18 years). MAIN OUTCOME MEASURES: Version 3.0 of the World Health Organization's Composite International Diagnostic Interview, a fully structured lay-administered diagnostic interview, was used to assess DSM-IV lifetime and 12-month Axis I disorders. Subthreshold BPD was defined as recurrent hypomania without a major depressive episode or with fewer symptoms than required for threshold hypomania. Indicators of clinical severity included age at onset, chronicity, symptom severity, role impairment, comorbidity, and treatment. RESULTS: Lifetime (and 12-month) prevalence estimates are 1.0% (0.6%) for BP-I, 1.1% (0.8%) for BP-II, and 2.4% (1.4%) for subthreshold BPD. Most respondents with threshold and subthreshold BPD had lifetime comorbidity with other Axis I disorders, particularly anxiety disorders. Clinical severity and role impairment are greater for threshold than for subthreshold BPD and for BP-II than for BP-I episodes of major depression, but subthreshold cases still have moderate to severe clinical severity and role impairment. Although most people with BPD receive lifetime professional treatment for emotional problems, use of antimanic medication is uncommon, especially in general medical settings. CONCLUSIONS: This study presents the first prevalence estimates of the BPD spectrum in a probability sample of the United States. Subthreshold BPD is common, clinically significant, and underdetected in treatment settings. Inappropriate treatment of BPD is a serious problem in the US population. Explicit criteria are needed to define subthreshold BPD for future clinical and research purposes.

How best to identify a bipolar-related subtype among major depressive patients without spontaneous hypomania: superiority of age at onset criterion over recurrence and polarity?

BACKGROUND: History of high depressive recurrence (without history of mania/hypomania) has been proposed as a mood subtype close to bipolar disorders. Herein we test whether this is the best approach to this question. METHODS: We systematically evaluated consecutive 224 Major Depressive (MDD) and 336 Bipolar II Disorders (BP-II) outpatients in a private practice, by the SCID for DSM-IV (modified for better probing hypomania by Akiskal and Benazzi [Akiskal, H.S., Benazzi, F., 2005. Optimizing the detection of bipolar II disorder in outpatient private practice: toward a systematization of clinical diagnostic wisdom. J. Clin. Psychiatry 66, 914-921]). We conducted univariate and multivariate analyses on such putative bipolar validators as early age at onset of first major depressive episode (before 21 years), high recurrence, family history for bipolar disorders, and depressive mixed states (mixed depression, i.e. depression plus concurrent hypomanic symptoms), in order to identify an MDD subgroup close to BP-II. RESULTS: All bipolar validators were independent predictors of BP-II. Early onset was the only variable which identified an MDD subgroup significantly associated with all bipolar validators. This MDD subgroup was similar to BP-II on age at onset and bipolar family history, and had a high frequency of mixed depression. A dose-response relationship was found between number of bipolar validators present in MDD, and bipolar family history loading among MDD relatives. LIMITATIONS: Study limited to outpatients. CONCLUSIONS: From among the bipolar validators, early age at onset of first major depression (<21 years) was superior to high recurrence (>4 depressive episodes) in identifying an MDD subgroup close to BP-II, which might be subsumed under the broad bipolar spectrum. Implications of unipolar-bipolar boundaries and genetic investigations are discussed.

Non-right-handedness is associated with migraine and soft bipolarity in patients with mood disorders.

BACKGROUND: There is a substantial body of data showing differences in the functioning of the two hemispheres in unipolar depressive and bipolar disorders. Migraine is a frequent co-morbid disorder in these patients, and it has been proposed that migraine may be associated with left-handedness. It would therefore be interesting to study migraine and handedness in a population of patients with mood disorders. METHODS: A total of 201 patients with an index episode of either major depression or mania were interviewed with a semi-structured interview based partly on DSM-IV criteria and partly on TEMPS-I for affective temperaments. The criteria of the Headache Classification Committee of the International Headache Society were used to establish the diagnosis of migraine. Hand preference was assessed using the Edinburgh inventory, and the patients were classified as having right-, left-, or mixed-handedness. RESULTS: In the whole group 117 patients had migraine (58%) and 59 (29%) were classified as having non-right hand preference. There was a significant increased prevalence of non-right-handedness in the migraine group (37% vs. 19%, p=0.021, Chi-square test; OR 2.5; 95% CI 1.3 -4.8, p=0.007). In patients with cyclothymic, hyperthymic or irritable temperaments the prevalence of non-right-handedness (42%) was significantly higher (p=0.013, Chi-square test; OR 2.2, 95% CI 1.2-4.3) compared to patients with a depressive or no affective temperament (24%). The prevalence of non-right-handedness was also significantly higher both in patients with co-morbid eating disorders (48% vs. 26%, p=0.008 Chi-square test; OR 2.7, 95% CI 1.3-5.9, p=0.01) and asthma (45% vs. 26%, p=0.026 Chi-square test; OR 2.3, 95% CI 1.1-5.1, p=0.029). LIMITATIONS: Non-blind evaluation of affective diagnosis, migraine and handedness. CONCLUSIONS: Our main finding supports the hypothesis that non-right-handedness is associated with migraine and bipolar affective temperaments ("soft bipolarity") in a sample of patients with major affective disorders.

A case series on the hypothesized connection between dementia and bipolar spectrum disorders: bipolar type VI?

BACKGROUND: The concept of bipolar spectrum disorders has opened therapeutic opportunities for patients with atypical and complex affective conditions. The literature has recently described several commonalities in pathophysiological processes of bipolar disorders and dementia. However, this connection has been insufficiently appreciated at the clinical level, in part because affective dysregulation in the elderly and, particularly in the dementia setting, is typically attributed either to secondary depressive states or otherwise relegated to a neurologically understandable behavioral complication resulting from cerebral disease. METHODS: We selected a case series of 10 elderly patients with late-onset mood and related behavioral symptomatology and cognitive decline without past history of clear-cut bipolar disorder. Clinical features, temperament, cognition, family history and pharmacological response were assessed to identify prototypical patients to illustrate the complexities of the dementia-bipolar interface. RESULTS: Mixed and depressive mood symptoms were most commonly observed and all patients had been premorbidly of hyperthymic, cyclothymic and/or irritable temperaments. Most patients had a family history of bipolar disorder or disorders related to the bipolar diathesis. Symptoms were often refractory to or aggravated by antidepressants and acetylcholinesterase inhibitors, whereas mood stabilizers and/or atypical antipsychotics were beneficial, promoting behavioral improvement in all treated patients and marked cognitive recovery in five. LIMITATIONS: Case series with retrospective methodology. CONCLUSION AND CLINICAL IMPLICATIONS: Patients with cognitive decline and frequent mood lability might be manifesting a late-onset bipolar spectrum disorder, which we posit as type VI. We further posit that dementia and/or other biopsychosocial challenges associated with aging might release latent bipolarity in such individuals. Antidepressants, even drugs targeting dementia, might aggravate the behavioral dysregulation in these patients. Evaluation of premorbid temperament and/or family history of bipolarity and related disorders might help in broadening the clinical and biological understanding of such patients, providing a rationale for better customized treatment along the lines of mood stabilization and avoidance of antidepressants.

TEMPS-A (Rome): psychometric validation of affective temperaments in clinically well subjects in mid- and south Italy.

BACKGROUND: Our aim was to study the psychometrics and factor structure replicability of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) in its Italian (Rome) Version. The questionnaire is a self-report 110-item measure that postulates five affective temperaments-the depressive, cyclothymic, irritable, hyperthymic, and anxious-which embody both strengths and liabilities along affective reactivity. In Italian, the TEMPS has previously been validated in its original 32-item version, the TEMPS-I (Pisa), one which did not yet include an anxious subscale. METHODS: The present sample consisted of 948 nonclinical subjects (27.39 years+/-8.22 S.D.). There were 476 men (50.2%: 28.56 years+/-8.63 S.D.) and 472 women (49.8%: 26.21 years+/-7.61 S.D.). Reliability and validity were assessed by standard psychometric tests. RESULTS: Principal Components Analysis with Varimax rotation resulted in a 3-factor solution: the first with highest explained variance (8.84%) represents Dysthymic, Cyclothymic and Anxious (Dys-Cyc-Anx) temperaments combined; the second identifies Irritable temperament (5.65% of variance); and the third Hyperthymic temperament (5.16% of variance). Cronbach Alpha coefficients for the three subscales were respectively .89, .77 and .74. The rates for the Dys-Cyc-Anx were 2.7%, and for the Irritable 3.1%. Despite the low rate of the Hyperthymic temperament (.2%), nonetheless 16% were between 1st and 2nd SD. Exploratory factor analysis revealed a positive loading combining Dys-Cyc-Anx with the Irritable; the Hyperthymic loaded negatively on this factor. In terms of dominant temperaments, based on z-scores, 2.7% were dysthymic, 1.7% cyclothymic, .7% hyperthymic, 3.5% irritable and 3% anxious. LIMITATION: Although developed for self-rated use, the Italian authors nonetheless administered the TEMPS-A in an interview format. It is uncertain in what ways this procedure could have influenced our results, if any. Another limitation is that we did not assess test-retest reliability. CONCLUSIONS: These data identify at least 3-factors, Dys-Cyc-Anx and Irritable (which are correlated), and Hyperthymic, which is uncorrelated with the others. Though our data are reminiscent of the neuroticism-extraversion distinction, importantly traits are operationalized in affective terms. Beyond the well-known relationship between the Dysthymic and Cyclothymic subscales and that between the Dysthymic and Anxious, the present data reveal a strong relationship between the Cyclothymic and Anxious as well, which is of great relevance for bipolar II. It is also provocative that much of hyperthymia (16%) in the +SD is between the 1st and 2nd SD, thereby "normalizing" this temperament in Italy, as previously reported by TEMPS-I (Pisa) from Northern Italy (and TEMPS-A from Lebanon and Argentina).