Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.     

Altered [3H]imipramine and 5-HT2 but not [3H]paroxetine binding sites in platelets from depressed patients.

BACKGROUND: Serotonergic system alterations were studied in 51 depressed patients classified according to DSM-III-R criteria for major depression with melancholia compared to 31 healthy controls. METHOD: [3H]Imipramine and [3H]paroxetine binding sites and the 5HT2 receptor were simultaneously determined in blood platelet membranes. RESULTS: A significantly lower maximum binding in [3H]imipramine binding was observed in depressed patients compared to controls (1134+/-74 vs. 1712+/-106 fmol/mg protein, P<0.0001) without changes in the equilibrium dissociation constant (1.10+0.05 vs. 1.25-/+0.09 nM). [3H]Paroxetine binding did not differ between the two groups (Bmax, 1441+/-55 vs. 1280+/-81 fmol/mg protein; Kd, 0.060+/-0.002 vs. 0.062+/-0.002 nM). The K(d) value of 5HT2 binding was lower in depressed patients than controls (0.95+/-0.04 vs. 1.15+/-0.09 nM, P<0.039) without changes in maximum binding (140+/-11 vs. 127+/-14 fmol/mg protein). CONCLUSIONS: Taken together, these results suggest that [3H]imipramine and 5HT2 receptors may be good biological markers for serotonergic dysfunction in depressive disorders.     

Olanzapine in the treatment of adolescent acute mania: a report of seven cases.

BACKGROUND: Clozapine may be effective in adults and adolescents with treatment-resistant bipolar disorder. Olanzapine has a receptor affinity profile similar to that of clozapine. METHODS: The responses of seven consecutive adolescents (ages 12-17) with DSM-IV bipolar disorder, manic episode, treated with olanzapine were evaluated. Response to olanzapine was rated as marked, moderate, minimal, none or worse. RESULTS: Five (71%) adolescents showed a marked or moderate response. The mean+/-SD olanzapine dose was 0.146+/-0.086 mg/kg/day (11+/-6 mg/day). CONCLUSION: Olanzapine may have antimanic effects in some adolescents with acute mania. Controlled studies of olanzapine in adolescent bipolar disorder appear to be warranted.     

Is adjunctive open-label zonisamide effective for bipolar disorder?

OBJECTIVE: To assess the effectiveness and safety of zonisamide in bipolar disorder. METHODS: A chart review was conducted of naturalistic treatment with zonisamide in 35 outpatients meeting DSM-IV criteria for bipolar disorder (9 males, 26 females; mean +/- SD age = 29.2 +/- 12.7; 14 with bipolar disorder type I, 6 with bipolar disorder type II, and 14 with bipolar disorder not otherwise specified). Patients received zonisamide adjunctive therapy between January 1994 and December 2004. Treatment response was defined as a Clinical Global Impressions - Improvement (CGI-I) scale score of +2 (much improved) or + 3 (very much improved). RESULTS: Zonisamide was moderately to markedly effective in 9 subjects (26%). Indication for treatment included depressive (34.3%, [12/35]), manic/hypomanic (28.6%, [10/35]), or mixed (31.4%, [11/35]) symptoms. The mean zonisamide dose was 130 mg/d for a mean duration of treatment of 27.0 +/- 32.3 weeks. Sedation (25%, [4/16]) was the most common side effect; 19/35 (54.3%) reported no side effects. 17/35 (49%) patients terminated early, mostly due to adverse effects (6/35). Using a multivariable model, predictors of response, concurrent mood stabilizers, dose and bipolar subtype (bipolar type I > type II/NOS), were controlled for in this sample. CONCLUSIONS: In 35 persons with bipolar disorder taking standard mood stabilizers and other psychotropic agents, adjunctive zonisamide appears to have modest benefit in global improvement when added to a pre-existing complex medication regimen in patients with bipolar spectrum disorder. These pilot data support the need for larger studies to test the potential efficacy of zonisamide for treatment in mood disorders.     

A change in the density of [(3)H]flumazenil, but not [(3)H]muscimol binding, in Brodmann's Area 9 from subjects with bipolar disorder

BACKGROUND: This study examines the hypothesis that there are changes in cortical serotonergic, GABAergic and glutamatergic systems in bipolar disorder and schizophrenia. METHODS: In situ radioligand binding and autoradiography were used to measure neurochemical markers in Brodmann's Area (BA) 9 from control subjects and subjects with bipolar disorder or schizophrenia (n=8 per group). RESULTS: Compared to tissue from schizophrenic (mean+/-S.E.M, 385+/-44 fmol/mg ETE) and control (383+/-44 fmol/mg ETE) subjects, there was an increase in the density of [(3)H]flumazenil binding to the benzodiazepine binding site on the GABA(A) receptor in subjects with bipolar disorder (451+/-17 fmol/mg ETE; P<0.05). There was no difference in the density of [(3)H]muscimol binding to the GABA(A) receptor or in the density of the serotonin(1A) receptor, serotonin(2A) receptor, ionotropic glutamate receptors or the serotonin transporter between the three cohorts. There was an age-related decrease in NMDA receptor density in control subjects that was absent in schizophrenia and bipolar disorder. An age-related increase in [(3)H]flumazenil binding in schizophrenia was absent in control and bipolar disorder subjects. LIMITATIONS: This study involved a relatively small number of individuals. CONCLUSIONS: An increase in the gamma2-receptor sub-unit in the GABA(A) receptor has been shown to increase benzodiazepine but not [(3)H]muscimol binding, this is the mismatch in binding we have shown in BA 9 from subjects with bipolar disorder. Thus, a change in the assembly of receptor subunits into GABA(A) receptors may be involved in the neuropathology of bipolar disorder. There may also be differences in age-related changes in cortical receptor density between bipolar disorder and schizophrenia.     

Binding of yohimbine and imipramine to platelets in depressive illness

Radioligand binding to intact platelets was carried out in antidepressant-free patients and the 1 mg dexamethasone suppression test (DST) was performed. There were no differences in binding characteristics between patients and controls for either [3H]yohimbine or [3H]imipramine. There were no differences in binding between patients classified as endogenous using the Newcastle Scale, compared with non-endogenous patients, and no difference between DST suppressors and non-suppressors. The severity of depression did not affect binding values. After 4-6 weeks antidepressant treatment [3H]yohimbine binding was significantly reduced but [3H]imipramine binding was unaffected.     

Platelet [3H]paroxetine binding to 5-HT uptake sites in Alzheimer's disease.

Platelet serotonin (5-hydroxytryptamine, 5-HT) uptake sites were studied in a control group (n = 30) and an Alzheimer group (n = 40) using [3H]paroxetine as radioligand. The maximum number of binding sites (Bmax) for control (1250 +/- 60 fmol/mg protein) was not different from the Alzheimer group (1280 +/- 40 fmol/mg protein). There were no differences in apparent binding affinity (Kd): 0.046 (0.024-0.062) nM for control and 0.040 (0.027-0.061) nM for Alzheimer. Thus even though several previous studies have demonstrated marked atrophy of 5-HT containing neurites and 5-HT uptake sites in Alzheimer's disease, these findings are not found in the periphery on platelets. The platelet 5-HT uptake site cannot be used as a peripheral marker of Alzheimer's disease.     

Neuropsychological impairment among manic, depressed, and mixed-episode inpatients with bipolar disorder

Previous research has demonstrated broad neurobehavioral abnormalities in bipolar affective disorder (cf. G. Cassens, L. Wolfe, & M. Zola, 1990). However, there have been no comparisons of neuropsychological function across patients with manic, depressed, or mixed subtypes. In the present study, 37 manic, 24 mixed-episode, and 25 depressed bipolar I inpatients and 34 control subjects were administered a brief battery of neuropsychological tests. The multivariate and univariate effects of participant group on the neuropsychological measures were uniformly significant (p < .05). Planned contrasts revealed that the bipolar participants performed worse than the controls, and few differences existed between the 3 patient groups. Additionally, the bipolar groups were impaired on 50% of the test battery. These abnormalities were unlikely attributable to differences in psychiatric symptomatology, medical illness, comorbid psychiatric diagnoses, or medication status. Findings imply that acute mood disturbance during bipolar disorder yields significant neurobehavioral dysfunction.     

三种常见精神疾病心肌酶及心电图对比分析

目的：对比不同精神科疾病患者心肌酶及心电图情况,探讨心肌酶变化在不同精神科疾病患者诊断治疗方面的意义.方法：通过随机抽取既往1年住我院某病区的精神分裂症患者、双相情感障碍-躁狂发作、躁狂发作、双相情感障碍-抑郁发作、抑郁发作患者病历,对其入院次日清晨心肌酶检测结果,包括肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）、天门冬氨酸氨基转移酶（AST）的水平以及患者的心电图情况进行对比分析.结果：精神分裂症、躁狂发作及双相障碍-躁狂发作患者的心肌酶及心率有不同程度升高,并与抑郁发作和双相障碍-抑郁发作患者对比有统计学意义.结论：心肌酶的增高对于精神疾病诊断有一定临床参考意义.     

Effect of lithium carbonate on serotonin uptake in blood platelets of patients with affective disorders

Lithium carbonate treatment for 2-3 weeks produced a significant decrease in the maximum velocity (Vmax) of serotonin (5-HT) uptake, a measure of the number of 5-HT uptake sites in blood platelets from bipolar patients. The decrease was more pronounced in bipolar manic patients than bipolar depressed patients. There was no significant affect on the affinity for 5-HT (Km) of the uptake sites in the platelets of manic or depressed bipolar patients although Km did decrease (indicating increased affinity) in the majority of subjects from both groups of patients. However, lithium treatment of at least 1 year duration was associated with significant increases in Vmax without affecting Km. Lithium in vitro, at concentrations up to 1 mM, had no effect on the Km or Vmax of 5-HT uptake in blood platelets of normal controls. The possible mechanisms of the inhibitory and stimulatory effect of lithium carbonate treatment on platelet 5-HT uptake are discussed.     

Effect of symptoms on executive function in bipolar illness

BACKGROUND: The relationship between cognitive function and symptomatology in bipolar disorder is unclear. This study assessed executive function during the manic, depressed and remitted stages of bipolar I disorder. METHOD: Tasks assessing phonological and semantic verbal fluency, the Hayling Sentence Completion Test, the Stroop Neuropsychological Screening Test and the Cognitive Estimates Test were administered to manic (n = 15), depressed (n = 15), and remitted (n = 15) bipolar I patients, and to healthy controls (n = 30). Multiple regression analyses and analyses of covariance were used to identify potential determinants of executive dysfunction in the three bipolar groups. RESULTS: Executive function deficits were particularly associated with the manic state. In general, manic patients performed less accurately than the remitted and depressed groups, and their performance deficit was related to the severity of positive thought disorder. The depressed and remitted bipolar groups showed a less widespread pattern of impairment. Deficits in response initiation, strategic thinking and inhibitory control were evident in all the bipolar groups. CONCLUSIONS: Executive function deficits in bipolar I disorder are most evident during mania, and are particularly associated with formal thought disorder. However, deficits in response initiation, strategic thinking and inhibitory control may be more related to the underlying disorder than a particular symptom profile.     

Trait impulsivity in patients with mood disorders

BACKGROUND: Impulsivity is a key component of the manic behavior of bipolar disorder and is reported to occur in bipolar patients as a stable characteristic, i.e. a trait. Nevertheless, impulsivity has not been widely studied in depressed bipolar patients. We assessed impulsivity in depressed and euthymic bipolar and unipolar patients and healthy controls. We hypothesized that bipolar subjects would have higher levels of trait impulsivity than the comparison groups. METHODS: Twenty-four depressed bipolar, 24 depressed unipolar, 12 euthymic bipolar, and 10 euthymic unipolar patients, as well as 51 healthy subjects were evaluated with the Barratt Impulsiveness Scale (BIS). Analysis of covariance with age and sex as covariates was used to compare mean group differences. RESULTS: Depressed bipolar, euthymic bipolar, and depressed unipolar patients did not differ, and showed greater impulsivity than healthy controls on all of the BIS scales. Euthymic unipolar patients scored higher than healthy controls only on motor impulsivity. LIMITATIONS: Higher number of past substance abusers in the bipolar groups, and no control for anxiety and personality disorders, as well as small sample sizes, limit the reach of this study. CONCLUSIONS: This study replicates prior findings of stable trait impulsivity in bipolar disorder patients, and extends them, confirming that this trait can be demonstrated in depressed patients, as well as manic and euthymic ones. Trait impulsivity may be the result of repeated mood episodes or be present prior to their onset, either way it would influence the clinical presentation of bipolar disorder.     

Endogenous digoxin-like immunoreactive factor (DLIF) serum concentrations are decreased in manic bipolar patients compared to normal controls.

BACKGROUND: A decrease in sodium pump activity in erythrocytes has been associated with manic episodes of bipolar illness relative to euthymic moods. Since red blood cells are long-lived and lack a nucleus, it is likely that a plasma factor is responsible for the observed decrease in sodium pump activity. METHODS: Utilizing a radioimmunoassay, we examined the serum concentrations of the digoxin-like immunoreactive factor (DLIF) in ill and well bipolar patients and compared the values to those of normal controls. RESULTS: DLIF was significantly decreased in manic individuals as compared to normal controls (143.6+/-S.E.M. 20.94 vs. 296.6+/-12.76 pg digoxin equivalents/ml, respectively, F = 4.77, P<0.05), but not compared to euthymic bipolar subjects 213.8+/-86.92, P = 0.77). There were no significant differences in DLIF concentrations between manic and euthymic bipolar individuals (P = 0.8). Since relapse in bipolar patients appears to display a seasonal pattern, we also measured the plasma concentration of this factor over a 12-months period. Normal controls exhibited a seasonal pattern of change in serum DLIF concentrations with a nadir in the winter months. Plasma concentrations of DLIF in bipolar patients did not show a seasonal pattern and maintained low levels throughout the year. LIMITATIONS: Due to the nonspecificity of our antibody, we could measure only total DLIF. Furthermore, it is unclear what the role of circulating DLIF, if any, may be on brain function. CONCLUSION: DLIF may be involved in the pathophysiology of mania.     

Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: post hoc analyses of 47-week data

BACKGROUND: Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania. METHODS: A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5-20 mg/day) to divalproex sodium (500-2500 mg/day) for bipolar manic or mixed episodes (N=251). Young Mania Rating Scale (YMRS) scores > or = 20 were required for inclusion. Patients were classified at study entry as "rapid cyclers" if they experienced > or = 4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline. RESULTS: A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p=0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p<0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific. LIMITATIONS: Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account. CONCLUSIONS: Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment.     

不同临床相双相障碍患者血液NMDA受体NR1亚基mRNA的表达

目的:探讨谷氨酸(Glu)能神经递质及传递功能异常在双相障碍病理机制中的作用。方法:选取符合ICD-10诊断标准的双相障碍抑郁发作期患者35例,躁狂发作期患者33例,缓解期患者28例及40例正常对照,用汉密顿抑郁量表(HAMD-17)、汉密顿焦虑量表(HAMA)、贝克-拉范森躁狂量表(BRMS)评估被试临床症状,以酶联免疫吸附法测定血清Glu水平,以RT-PCR技术检测NR1亚基mRNA表达水平。结果:抑郁发作期组、躁狂发作期组血清Glu水平[(35.3±6.1) mg/L,(35.8±6.3) mg/L vs.(27.8±5.4) mg/L,(28.6±5.7) mg/L,P<0.01]及NR1亚基mRNA水平[(1.6±0.4),(1.4±0.3) vs.(0.7±0.4),(0.6±0.5),P<0.01]高于缓解期组及对照组;抑郁发作期组血清Glu水平与HAMD总分呈正相关(r=0.58,P<0.05),躁狂发作期组NR1亚基mRNA水平与BRMS总分呈正相关(r=0.42,P<0.05)。结论:双相障碍疾病发作期可能存在Glu能神经递质水平紊乱及NR1...     

Platelet serotonin uptake and 3H-imipramine binding in panic disorder

Platelet serotonin uptake and 3H-imipramine binding were measured in eight patients with panic disorders and nine controls. The Vmax of serotonin uptake was significantly elevated in patients compared to controls (77 +/- 14 vs. 50 +/- 4 pmol/10(8) platelets/min; P less than 0.05) while Km values were not different (1.46 +/- 0.41 vs. 1.24 +/- 0.20 microM). 3H-Imipramine binding to ruptured platelet membranes was not significantly different between patients and controls for either Bmax (395 +/- 71 vs. 412 +/- 107 fmol/mg protein) or Kd (0.90 +/- 0.18 vs. 1.09 +/- 0.30 nM). The implications for a serotonergic dysfunction in panic disorders are discussed.     

Gender differences in bipolar affective disorder

We report a study of gender differences in a sample of 111 manic patients. Female manics (N = 78) exhibited fewer manic and more depressive symptoms than males (N = 33). Although male manics had a more frequent history of delayed landmarks, the two groups did not differ in cortical function as measured by EEG and neuropsychological testing. There were no significant differences between male and female relatives of male and female probands for unipolar or bipolar affective disorder, alcoholism or sociopathy. Female relatives of both groups were at greater risk for total affective disorder and male relatives were at greater risk for alcoholism. Familial illness patterns indicated that male and female manics shared the same genetic liability for affective disorder and that X-linked transmission was unlikely.     

Clinical importance of inter-episode symptoms in patients with bipolar affective disorder

A literature review was performed to determine whether inter-episode symptoms are of clinical importance in the management of bipolar disorder. Inter-episode symptoms are easy to miss but observational studies confirm that they are related to impaired function and reduced survival to full relapse. Randomised, controlled trials with lithium carbonate, and two studies exploring psychological treatments to recognise and treat prodromal symptoms of manic or depressive relapse, suggest some inter-episode symptoms are worth recognising because they are associated with reduced manic relapse and improved function. A classification is proposed to inform attempts at management of inter-episode symptoms in bipolar disorder patients, both clinically, and for future research. However, promotion of well-being in bipolar disorder patients does not require all symptoms to be treated. In other patients, the presence of inter-episode symptoms may be a marker of resistance to treatment. Finally, the mechanism by which inter-episode symptoms might lead to relapse, or even lead directly to functional impairment, awaits convincing explanation and empirical support.     

Stability and course of neuropsychological deficits in manic and depressed bipolar patients compared to patients with Major Depression

BACKGROUND: Neuropsychological functioning varies across different subgroups of patients with affective disorders; yet there have only been a few studies pointing out distinctive neuropsychological profiles and following-up possible changes in this functioning. The aim of this study was to compare neuropsychological functioning across remitted manic or depressed patients with bipolar disorder compared to remitted patients with Major Depression and to explore the course of their cognitive functioning. METHODS: 30 patients with Major Depression, 17 manic bipolar patients, and 22 depressed bipolar patients were assessed for memory, attention, and executive functions using the Auditory Verbal Learning Test (AVLT), the Modified Card Sorting Test (MCST), the Attention Network Test (ANT), and Stop-Signal Task. Neuropsychological assessment was performed at discharge and seven weeks after discharge. RESULTS: The three groups showed different neuropsychological performance at discharge. Regarding selective attention and speed of responding the manic bipolar patients displayed poorer performance than the other two groups. Furthermore, follow-up assessment revealed that although all patient groups demonstrated an overall improvement, some deficits (especially in executive functions) remain. Manic bipolar patients showed again the worst performance. Depressed bipolar patients, however, were not observed to show a poorer outcome than depressed unipolar patients. CONCLUSIONS: This study provides further evidence for distinct neuropsychological functioning in patients with affective disorders depending on their state of illness. Furthermore, it supports the hypothesis that especially manic bipolar patients stay impaired in certain cognitive functions after remission. These findings may be of clinical relevance regarding treatment and prevention programs and emphasize the need of further research investigating stability and course of patients with mood disorders.     

Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder

BACKGROUND: This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder. METHODS: Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N=516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed. RESULTS: Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-rapid cycling (p<0.01 for each subpopulation); in men and women (p=0.001 for both); in patients in the 18-40 and 41-55 year age groups (por=5% of patients aged 18-40 years receiving aripiprazole were similar to those reported for the overall population. LIMITATIONS: This post hoc analysis utilized pooled data from two short-term studies. CONCLUSION: Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.