Robert Gonzalez

Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety☆

BACKGROUND The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder. Although second generation antipsychotics are being used with increasing frequency in bipolar patients, their anxiolytic effects have not been well studied in this population. METHODS The anxiolytic effect of risperidone 0.5-4 mg/day was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder (GAD). The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale (CGI-21 Anxiety). Secondary measures included the Hamilton Anxiety Scale (HAM-A) and the Sheehan Panic Disorder Scale. RESULTS On the last-observation-carried forward analysis of repeated measures analysis of variance (ANOVA), risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures. Risperidone was well tolerated, with only two patients withdrawing because of adverse events. LIMITATIONS The risperidone treated group had more patients with mixed states and lifetime panic disorder at randomization than the placebo group. The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD. The results may not be applicable to risperidone as an add-on treatment to mood stabilizers, or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD. CONCLUSIONS Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5-4 mg/day over 8 weeks of treatment. The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind, placebo-controlled studies.

A single blind comparison of lithium and lamotrigine for the treatment of bipolar II depression

BACKGROUND Treatment studies are lacking for patients with bipolar II disorder (BDII). The objective of this study was to compare lamotrigine (LTG) and lithium (Li) monotherapy for the treatment of BDII depression. METHODS Patients with BDII acute depression were randomized to open-label monotherapy with LTG or Li, and evaluated by trained raters blinded to treatment. Patients were titrated to 200 mg/day of LTG over 8 weeks or at least 900 mg/day of Li over 2 weeks (serum level 0.6-1.2 mEq/L), and seen biweekly for 16 weeks. The primary outcome variable was change in the Hamilton Depression Rating Scale 17-item (Ham-D(17)), evaluated using mixed effects random regression. RESULTS Both groups showed significant improvement from baseline to endpoint on the Ham-D(17) (p<0.0001), with no between group differences (p=0.95). Seventy-two percent of the population was rapid cycling by DSM-IV criteria. No differences in response were noted between rapid cyclers and non-rapid cyclers. Early termination for any cause was 42%. The Li group reported significantly more side effects, although drop-out due to side effects did not differ between groups. LIMITATIONS This study was limited by an open treatment design, a lack of placebo arm, and uneven treatment groups. CONCLUSIONS Lamotrigine and lithium were effective monotherapy for BDII depression, with comparable response and remission rates. Naturalistic design and lack of placebo limit conclusions, though patient history indicated long standing depression unlikely to be alleviated by time. Patients who received Li reported more side effects, but this did not appear to impact drop-out rates.

The relationship between bipolar disorder and biological rhythms.

BACKGROUND Rhythm disruption is a core feature of bipolar disorder and it has been hypothesized that disturbances of the circadian timing system play a fundamental role in the etiology of the disorder. OBJECTIVE We sought to investigate (1) theoretical models for biological rhythm disruptions in bipolar disorder, (2) physiological disturbances of biological rhythms in bipolar disorder, (3) clinical and therapeutic implications of biological rhythm disturbances in bipolar disorder, and (4) associations between circadian gene variations and bipolar disorder. DATA SOURCES PubMed database was searched systematically for articles that were published on or before May 5, 2013, and were written in English using the terms bipolar disorder, clock genes, endogenous clock, molecular clock, biological rhythms, circadian, suprachiasmatic nucleus, circadian rhythm, melatonin, and sleep. STUDY SELECTION Seventy-four articles highlighting the objectives were included in the review. DATA EXTRACTION Data regarding exploring the association between bipolar disorder and circadian and chronobiological phenomena were reviewed and findings summarized. RESULTS The literature reviewed suggests that circadian rhythm disturbance may be a feature of bipolar disorder. CONCLUSIONS In toto, the literature suggests that circadian rhythm disturbances may be a feature of bipolar disorder. This area of research has received theoretical consideration as playing a significant role in the pathophysiology of the illness but has been understudied to this point. Further research in the field is warranted.

The relationship between affective state and the rhythmicity of activity in bipolar disorder.

OBJECTIVE The aim of this study was to test the relationships between mood state and rhythm disturbances as measured via actigraphy in bipolar disorder by assessing the correlations between manic and depressive symptoms as measured via Young Mania Rating Scale (YMRS) and 30-item Inventory for Depressive Symptomatology, Clinician-Rated (IDS-C-30) scores and the actigraphic measurements of rhythm, the 24-hour autocorrelation coefficient and circadian quotient. METHOD The research was conducted at the University of Texas Southwestern Medical Center at Dallas from February 2, 2009, to March 30, 2010. 42 patients with a DSM-IV-TR diagnosis of bipolar I disorder were included in the study. YMRS and the IDS-C-30 were used to determine symptom severity. Subjects wore the actigraph continuously for 7 days. The 24-hour autocorrelation coefficient was used as an indicator of overall rhythmicity. The circadian quotient was used to characterize the strength of a circadian rhythm. RESULTS A greater severity of manic symptoms correlated with a lower degree of rhythmicity and less robust rhythms of locomotor activity as indicated by lower 24-hour autocorrelation (r = -0.3406, P = .03) and circadian quotient (r = -0.5485, P = .0002) variables, respectively. No relationship was noted between the degree of depression and 24-hour autocorrelation scores (r = -0.1190, P = .45) or circadian quotient (r = 0.0083, P = .96). Correlation was noted between the 24-hour autocorrelation and circadian quotient scores (r = 0.6347, P < .0001). CONCLUSIONS These results support the notion that circadian rhythm disturbances are associated with bipolar disorder and that these disturbances may be associated with clinical signatures of the disorder. Further assessment of rhythm disturbances in bipolar disorder is warranted.

Comparison of objective and subjective assessments of sleep time in subjects with bipolar disorder

INTRODUCTION Sleep disturbance is a core feature of bipolar disorder. To date there are a limited number of studies that compare subjective and objective measures of sleep in populations of subjects with mood disorders. This study evaluated the relationship between subjective and objective measurements of total sleep time (TST) in a bipolar type I disorder (BD I) population. METHODS Thirty-nine subjects diagnosed with BD I participated in the study. Mood symptoms were assessed via YMRS and IDS-30-C. Subjects wore an actigraph device and maintained a sleep diary for seven consecutive days. Differences between TST as estimated via sleep diaries and actigraphy were calculated. RESULTS Objective and subjective measures of TST were significantly correlated (r=0.5151, p=0.0008). Secondary analysis revealed that the severity of depressive symptoms did correlate to this discrepancy (t=2.65, p=0.01). LIMITATIONS The impact that medications have on the accuracy of TST reported was not investigated. Also, sleep diaries may have acted to prompt subjects to pay closer attention to their sleep habits and therefore more accurately report TST than in the average clinical setting. CONCLUSION The results of the current study demonstrate a significant correlation between the estimation of TST as measured objectively via actigraphy and subjectively via sleep diaries in BD patients. Mood symptomotology might impact the accuracy of TST reported. Further study is warranted.

First controlled treatment trial of bipolar II hypomania with mixed symptoms: Quetiapine versus placebo

OBJECTIVES To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

Identification of circadian gene variants in bipolar disorder in Latino populations

BACKGROUND Variations in circadian genes can impact biological rhythms. Given the rhythm disturbances that characterize bipolar disorder (BD), genes encoding components of molecular clocks are good candidate genes for the illness. METHODS A family based association analysis of circadian gene single nucleotide polymorphisms (SNPs) and BD was conducted in Latino pedigrees. 884 individuals from 207 pedigrees (473BP phenotype and 411 unaffected family members) were genotyped. Family based single marker association testing was performed. Ancestral haplotypes (SNPs found to be in strong LD defined using confidence intervals) were also tested for association with BD. RESULTS Multiple suggestive associations between circadian gene SNPs and BD were noted. These included CSNK1E (rs1534891, p=0.00689), ARNTL (rs3789327, p=0.021172), CSNK1D (rs4510078, p=0.022801), CLOCK (rs17777927, p=0.031664). Individually, none of the SNPs were significantly associated with BD after correction for multiple testing. However, a 4-locus CSNK1E haplotype encompassing the rs1534891 SNP (Z-score=2.685, permuted p=0.0076) and a 3-locus haplotype in ARNTL (Z-score=3.269, permuted p=0.0011) showed a significant association with BD. LIMITATIONS Larger samples are required to confirm these findings and assess the relationship between circadian gene SNPs and BD in Latinos. CONCLUSIONS The results suggest that ARNTL and CSKN1E variants may be associated with BD. Further studies are warranted to assess the relationships between these genes and BD in Latino populations.

The relationships between clinical characteristics, alcohol and psychotropic exposure, and circadian gene expression in human postmortem samples of affective disorder and control subjects

Circadian abnormalities may be related to mood disorders. Circadian gene expression was measured in postmortem brain tissue from individuals with affective disorders and controls. Relationships between circadian gene expression, clinical characteristics, and alcohol and psychotropic medication use were noted. Further study is warranted to characterize these relationships.

Circadian Rhythm and the Prediction of Relapse in Bipolar Disorder

aDepartment of Psychiatry, Texas Tech University Health Sciences Center El Paso, El Paso, Texas bDepartment of Psychiatry & Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico *Corresponding author: Robert Gonzalez, MD, Department of Psychiatry, Texas Tech University Health Sciences Center El Paso, 4615 Alameda, El Paso, TX 79905 (Robert99.Gonzalez@ttuhsc.edu). J Clin Psychiatry 2018;79(1):17com11821

Relationship between temperament and character traits, mood, and medications in bipolar I disorder

INTRODUCTION Bipolar I disorder is an illness causing mood shifts that can result in personality and character trait alterations. The relationship between mood and personality and character traits in bipolar I disorder is unclear at this time. METHODS We conducted a study from February 2009 to March 2010 that included 42 subjects with bipolar I disorder, which was confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders. Mood was assessed via the Young Mania Rating Scale (YMRS) and the 30-item Clinician-rated Inventory of Depressive Symptomatology (IDS-C). Temperament and character traits were assessed via the Temperament and Character Inventory (TCI). Multivariate analysis was used to test relationships between mood and temperament and character traits with the effects of possible cofactors taken into account (eg, age, gender, medications). RESULTS We noted a positive correlation between YMRS scores and persistence (P = .046) and a trend toward positive correlation with novelty seeking (P = .054). There was a positive correlation between higher IDS-C scores and harm avoidance (P < .001) and a negative correlation with self-directedness scores (P < .001). Antipsychotic use was positively correlated with the character trait self-directedness (P = .008), with a trend toward a positive correlation with reward dependence (P = .056). Lithium was negatively correlated with reward dependence (P = .047) and self-transcendence (P = .028), with a trend toward a negative correlation with novelty seeking (P = .053). CONCLUSIONS The findings of our study suggest that some personality and character traits may vary according to mood state and medications in patients with bipolar I disorder. Prospective and longitudinal studies are required to fully characterize the relationships between personality and character traits and mood state in bipolar I disorder.