The impact of response to previous mood stabilizer therapy on response to olanzapine versus placebo for acute mania

Objectives: A clinically important question for any new treatment for bipolar disorder is whether its efficacy extends to patients who have both responded and failed to respond to other mood stabilizers. In this secondary analysis of a placebo-controlled trial demonstrating olanzapine's efficacy for acute mania, we explore whether its usefulness extends to those patients with a history of poor response to other mood stabilizers.

Methods: This 4-week, double-blind, placebo-controlled trial studied olanzapine monotherapy 5–20 mg/day for hospitalized patients in acute manic or mixed bipolar episodes. The primary outcome variable was beginning to endpoint change in the Young-Mania Rating Scale (Y-MRS) total score. We investigated whether prospectively identified history of recent failure to respond to other mood stabilizers predicted response to olanzapine.

Results: As previously reported, olanzapine-treated patients experienced significantly greater improvement in Y-MRS total score and higher remission rates relative to placebo-treated patients. The current analysis compared these outcome parameters in patients with known poor prior response to lithium and/or valproate with all other patients and found no significant group by treatment interactions, i.e., treatment effects were not significantly diminished in non-responders to older mood stabilizing agents.

Conclusions: Olanzapine has been shown to be superior to placebo for the treatment of mania. This secondary analysis suggests that olanzapine monotherapy is similarly effective for patients whether or not they previously have failed to respond to another mood stabilizer for mania. A study limitation is that response to lithium or valproate was determined retrospectively.     

Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment

Objective: During the last decade, much attention has been given to the role of signal transduction pathways in affective disorders. This review describes the possible role of the cAMP signaling in such disorders.

Methods: Among the components of cAMP signaling, this review focuses on the cAMP-dependent phosphorylation system. We analyzed the basic components of the cAMP-dependent phosphorylation system and the preclinical evidence supporting their involvement in the biochemical action of antidepressants and mood stabilizers. The clinical data available until now, concerning the possible link between the cAMP-dependent phosphorylation system and the pathophysiology of affective disorders, are also reviewed.

Results: The studies herein presented demonstrated that the levels and the activity of cAMP-dependent protein kinase are altered by antidepressants and mood stabilizers. Furthermore, these medications are able to modify the phosphorylation state, as well as the levels of some of the cAMP-dependent protein kinase substrates. More recently, clinical studies have reported abnormalities in the cAMP-dependent phosphorylation system in both peripheral cells and the postmortem brain of patients with affective disorders.

Conclusions: Overall, these studies support an involvement of cAMP signaling in affective disorders. The precise knowledge of the findings has the potential to improve the understanding of pharmacotherapy and to provide directions for the development of novel biochemical and genetic research strategies on the pathogenesis of affective disorders.     

The Internal State Scale: replication of its discriminating abilities in a multisite, public sector sample

Objective: The Internal State Scale (ISS) is a self-report instrument that has been validated for discriminating mood states in patients with bipolar disorder. This study a) extends investigation to a multisite public sector sample and b) tests a revised scoring algorithm that formally identifies patients in mixed states.

Methods: Eighty-six patients with bipolar disorder from four Veterans Affairs medical centers were assessed in a cross-sectional design. Physician-conducted semi-structured interviews used DSM-IV criteria to identify subjects as meeting criteria for euthymia, mania or hypomania, depression, or mixed state (mania or hypomania plus depression). A revised ISS scoring algorithm independently assigned mood state. Mean subscale scores were analyzed across groups. Receiver-operating characteristic (ROC) curve analysis was conducted to determine optimal algorithm structure.

Results: Analysis of mean scores for the ISS subscales replicated original results for Activation, Well-Being, and Perceived Conflict, but indicated differences from the original results for the Depression Index. The ROC curve analysis identified optimal cut-off scores for the revised algorithm. The overall kappa score indicated moderate agreement between ISS and physician ratings of mood state, including mixed states.

Limitations: The study used a sample consisting primarily of male veterans. Mood state was assigned by experts using expert clinician diagnosis, not structured interviews.

Conclusion: The performance of the ISS in this multisite, public sector sample was similar to the performance in the initial research clinic sample. This finding confirms the validity of the ISS as a discriminator of mood states in bipolar disorder. The development of a revised scoring algorithm makes feasible formal identification of mixed episodes with the ISS.     

Onset of action of antipsychotics in the treatment of mania

Introduction: An important consideration in treating acute mania is the promptness with which a chosen therapy can bring symptom amelioration. This article reviews the available published data from controlled, blinded studies regarding the latency of responses to antipsychotics in patients with acute mania.

Methods: Articles for this review were obtained from a search of the Medline database (1966–1999), using the following keywords and phrases: antipsychotic, atypical, bipolar disorder, mania, neuroleptic, typical. The bibliographic sections of articles gleaned from this search were used to direct further inquiries.

Results: Although information regarding the onset of action of antipsychotics is limited, we discovered data for four typical and three atypical antipsychotics. Drugs with the fastest onsets include haloperidol, risperidone, and olanzapine, with onsets appearing in 2–6 days. Chlorpromazine and thiothixene were at the slowest end of the continuum, with onsets of 2 weeks or longer. Data regarding pimozide are mixed, with some studies showing an onset equivalent to that of the 'fast' compounds and others showing one similar to that of the 'slow' compounds.

Conclusions: Choice of therapy should consider not only efficacy and safety, but also onset speed. Atypical antipsychotics appear to offer safer, faster, and more effective therapies.     

Repetitive transcranial magnetic stimulation: perspectives for application in the treatment of bipolar and unipolar disorders

Objectives: Transcranial magnetic stimulation (TMS) affects the brain by non-invasively stimulating the cerebral cortex and inducing electrical currents in neurons. The powerful magnetic field acts as a vector that passes across the scalp and the skull, and then converts into an electrical energy within the brain. Originally used in neurophysiology, TMS has since been applied in a variety of neuropsychiatric conditions, including mood disorders. Imaging studies in mood-disordered patients have pointed to dysfunctional limbic and prefrontal cortex activity. TMS researchers have thus postulated that dorsolateral prefrontal cortex (DLPFC) stimulation might change brain activity both locally and in paralimbic areas through transynaptic connections, and alter mood.

Methods: We will describe the technology of TMS, its applications to date, and explore its mechanisms of action.

Results: Several clinical trials have demonstrated TMS effects on mood in health and disease. There is a growing consensus that TMS has antidepressant effects, although little is known about the role played by a variety of stimulation parameters such as the intensity or frequency of stimulation. One study has found an antimanic effect of right prefrontal TMS.

Conclusion: TMS is relatively safe; however, much more research is needed before TMS can be integrated into routine clinical practice.     

Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder

Objectives: The primary purpose of this study was to describe the clinical presentation of bipolar I disorder (BP-I) as it occurs in children and adolescents and to assess whether the manifestations of BP-I were similar in both age groups.

Method: Ninety youths between the ages of 5 and 17 years meeting full diagnostic symptom criteria for BP-I were included in this study. The diagnosis of BP-I was established for these youths based on the results of a semi-structured diagnostic interview and a clinical assessment by a child and adolescent psychiatrist. The course of a subset of these youngsters' illnesses was assessed using the Life Charting Method (LCM). Data regarding the clinical presentation, longitudinal history, psychiatric co-morbidities and parental psychopathology were also obtained.

Results: The clinical presentation of BP-I was similar in children and adolescents. Youths meeting diagnostic criteria for BP-I developed an average of approximately 5.8 of the 7 symptoms of mania during periods of elevated or irritable mood. BP-I was found to be a cyclic disorder characterized by high rates of rapid cycling (50%) with almost no inter-episode recovery. Almost 75% of these subjects also met diagnostic symptom criteria for a disruptive behavior disorder. High rates of mood disorders were found in fathers.

Conclusions: These data suggest that the presentation of juvenile BP-I is a cyclic and valid clinical condition with manifestations on a continuum with the later-onset forms of this illness.     

Glycogen synthase kinase-3beta,mood stabilizers,and neuroprotection

Objectives: This paper reviews results of our studies examining the regulation of endoplasmic reticulum (ER) stress proteins by valproate (VPA), and discusses the possible implications in bipolar disorder.

Methods: Our previous studies in the field are reviewed along with relevant literature.

Results: Using differential display PCR, we identified GRP78 as a VPA-regulated gene in rat cerebral cortex. We also showed that other members of the ER stress proteins family, GRP94 and calreticulin, are also upregulated by VPA. Immunohistochemistry identified that ER stress proteins are increased in frontal and parietal cortex, as well as regions of the hippocampus in rat brain following chronic treatment with VPA.

Conclusions: Regulation of ER stress proteins by VPA may prove to be important to the mechanism of action of the drug. The neuroprotective role of these proteins may also prove to be involved in the pathophysiology of bipolar disorder.     

An open study of methylphenidate in bipolar depression

Background: The treatment of bipolar depression is problematic. Mood stabilizing agents are often inadequate, while antidepressants may induce mania or mood destabilization. Methylphenidate has been advocated as an effective antidepressant agent in unipolar depression, and depression secondary to medical illness. Amphetamine administration has been shown to reduce manic behavior. These independent observations suggest that methylphenidate may be a safe and effective agent in bipolar depression.

Methods: Fourteen depressed subjects with DSM-IV bipolar illness and a Hamilton-depression (HAM-D) scale score of at least 15 had methylphenidate added to a stable mood stabilizer regiment. Patients were followed weekly for 4 weeks and then biweekly for an additional 8 weeks.

Results: HAM-D scores dropped from 16.9±1.79 SD at baseline to 9.4±9.73 on week 12 (p=0.12, t=1.84, df=6) and 9.8±7.56 on last observation carried forward (LOCF) (p=0.019, t=2.8, df=10). Psychiatric symptom assessment scale (PSAS) scores dropped from 17.9±5.63 at baseline to 4.8±7.47 at week 12 (p=0.016, t=4.02, df=4) and 6.3±6.75 on LOCF (p=0.007, t=3.74, df=7). Three individuals stopped secondary to anxiety, agitation, and hypomania, respectively.

Conclusion: In this brief, open study, methylphenidate was effective and relatively safe in depressed bipolar subjects.     

Choline, myo-inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex

Objectives: Alterations in choline and myo-inositol metabolism have been noted in bipolar disorder, and the therapeutic efficacy of lithium in mania may be related to these effects. We wished to determine the relationship between anterior cingulate cortex choline and myo-inositol levels, assessed using proton magnetic resonance spectroscopic imaging (MRSI), and mood state in subjects with bipolar disorder.

Methods: Serial assessments of anterior cingulate cortex choline and myo-inositol metabolism were performed in nine subjects with bipolar disorder, taking either lithium or valproate, and 14 controls. Each bipolar subject was examined between one and four times (3.1±1.3). On the occasion of each examination, standardized ratings of both depression and mania were recorded.

Results: In the left cingulate cortex, the bipolar subjects' depression ratings correlated positively with MRSI measures of Cho/Cr-PCr. In the right cingulate cortex, the Cho/Cr-PCr ratio was significantly higher in subjects with bipolar disorder compared with control subjects. In addition, bipolar subjects not taking antidepressants had a significantly higher right cingulate cortex Cho/Cr-PCr ratio compared with patients taking antidepressants or controls. No clinical or drug-related changes were observed for the Ino/Cr-PCr ratio.

Conclusions: The results of this study suggest that bipolar disorder is associated with alterations in the metabolism of cytosolic, choline-containing compounds in the anterior cingulate cortex. As this resonance arises primarily from phosphocholine and glycerophosphocholine, both of which are metabolites of phosphatidylcholine, these results are consistent with impaired intraneuronal signaling mechanisms.     

Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents

The evidence for the involvement of cholinergic muscarinic receptors in mania and depression is reviewed. Small pilot trials with cholinesterase inhibitors and muscarinic agonists suggest that stimulation of muscarinic receptors may produce an antimanic effect, possibly by activation of muscarinic M(4) receptors. It is concluded that it is not likely that currently used mood stabilizers, such as lithium, valproic acid and carbamazepine, work directly through muscarinic receptor mechanisms. Furthermore, the evidence indicates that antipsychotic agents used for mania are working through the common mechanism of antagonism of dopamine D(2) receptors, and interactions with muscarinic receptors do not play a key role. Finally, it is hypothesized that olanzapine has robust antimanic activity, due to blockade of dopamine D(2) receptors and antagonism of other monoaminergic receptors. Olanzapine may normalize mood due to antidepressant-like activities, such as 5-HT(2A) receptor antagonism and increasing cortical norepinephrine and dopamine.     

An open longitudinal study of patients with bipolar rapid cycling treated with lithium or lamotrigine for mood stabilization

Objectives: Patients with rapid cycling bipolar disorder are frequently observed to fail conventional treatment. We conducted a preliminary study to explore the potential efficacy of lamotrigine in the treatment of this refractory patient population.

Methods: In an open longitudinal investigation, 14 patients with rapid cycling bipolar disorder were treated for 1 year with either lithium or lamotrigine as mood stabilizer.

Results: Out of the seven patients with lithium, three out of seven (43%) had less than four and four out of seven (57%) had four or more episodes. In the lamotrigine group, six out of seven (86%) had less than four and one out of seven (14%) had more than four affective episodes (depressive, manic, hypomanic or mixed). In fact, three out of seven (43%) of the patients who were on lamotrigine therapy were without any further affective episodes. There was no evidence of a preferential antidepressant versus antimanic efficacy.

Conclusions: Although the study is limited by the small number of patients, the results are in line with other investigations, suggesting efficacy for lamotrigine and a suboptimal response for lithium in rapid cycling bipolar disorder. These preliminary data need to be confirmed with controlled double blind studies.     

The treatment of bipolar depression

Objectives: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management.

Methods: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'.

Results: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate.

Conclusions: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.     

Clinical decision-making using the General Behavior Inventory in juvenile bipolarity

Objective: The General Behavior Inventory (GBI) is a questionnaire that has utility in the assessment of mood disorders in adults. The purpose of this study was to examine how the GBI might optimally be used in the assessment of youths.

Method: Children and adolescents between the ages of 5 and 17 years participated in this study. All youths were evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Based on the K-SADS results, subjects were then assigned to one of four groups: a bipolar spectrum group, a depressive disorders group, a disruptive behaviors disorders group, and a no diagnosis group. Guardians completed a version of the GBI modified for parent reporting. Patients 10 years old or greater also completed the GBI as a self-report measure.

Results: There were 196 subjects who participated. Both parent report and youth self-report assigned patients to the appropriate diagnostic group with better than 74% accuracy. Combining information from multiple informants did not significantly improve diagnostic group assignment.

Conclusions: These data suggest that the GBI may be a useful adjunct in the diagnosis of mood disorders in youths, particularly when diagnostic specificity is more important than sensitivity.     

No evidence of association from transmission disequilibrium analysis of the hKCa3 gene in bipolar disorder

Objective: A recent case–control study has suggested that modest enlargements of a highly polymorphic CAG repeat in exon 1 of the gene encoding potassium channel hKCa3 may be associated with bipolar disorder (BPD). We have examined this hypothesis by genotyping this locus in a family-based association study.

Method: One hundred and twenty-eight parent–offspring trios of British Caucasian origin were examined where the proband was diagnosed with the American Psychiatric Association's Diagnostic and Statistical Manual (DSM)-IV BPD I (n=123) or II (n=5). An improved assay was used, with redesigned polymerase chain reaction (PCR) primers, permitting quicker and higher resolution genotyping. The resultant genotypes were analysed using the extended transmission/disequilibrium test (ETDT).

Results: The experimental data did not provide evidence for the preferential transmission of large alleles to bipolar cases (χ2=11.12, df=10, p=0.349).

Conclusions: Our data provide no support for the hypothesis that variation at the hKCa3 gene contributes to susceptibility to BPD.     

Comorbidity of obsessive-compulsive disorder in recovered inpatients with bipolar disorder

Objective: To determine the frequency of obsessive-compulsive disorder (OCD) in inpatient subjects with bipolar disorder (BD) and to examine the clinical characteristics of BD subjects with OCD.

Method: The sample consisted of 143 inpatient subjects with DSM-III-R BD-I and BD-NOS (BD-II), recovered from a current episode of either depression or mania. Demographic and clinical variables were obtained on the day of admission. Current comorbid conditions including OCD were determined by the Structured Clinical Interview for DSM-III-R following recovery from the acute affective episode.

Results: The frequency of current OCD was 7% (N=10). All BD subjects with OCD were BD-II, were male, and had a diagnosis of current dysthymia. They had fewer episodes and a higher incidence of prior suicide attempts than bipolar subjects without OCD. None of the bipolar subjects with OCD fulfilled criteria for cyclothymia.

Conclusions: Our findings suggest that BD-II, OCD, dysthymia, and suicidality cluster together in some subjects with BD. We discuss the clinical implications of our findings.     

Novel antipsychotics in bipolar and schizoaffective mania

OBJECTIVE: Novel antipsychotics are increasingly used in the treatment of bipolar and schizoaffective mania. This paper presents an overview of the controlled studies in this field. METHOD: Using cross-references, a computerized search was performed on MEDLINE and EMBASE psychiatry covering the period 1990-2002. RESULTS: Olanzapine and risperidone, added to mood stabilizers, and olanzapine as monotherapy enjoy the most evidential support in terms of efficacy and side-effect profile for their use in acute bipolar mania. The use of modern antipsychotics in bipolar prophylaxis and in both the short- and long-term treatment of schizomania has not been widely studied yet. CONCLUSION: More controlled trials are still needed comparing modern antipsychotics as monotherapy and adjunctive to mood stabilizers with conventional antipsychotics, lithium, anticonvulsants and with each other in short-term and, especially, maintenance treatment of (schizo)mania. Partly based on controlled studies, olanzapine, risperidone and other modern antipsychotics could become preferable for these indications.     

Oxcarbazepine treatment of refractory bipolar disorder: a retrospective chart review

Objective: To determine if oxcarbazepine is effective as treatment for refractory bipolar illness in a naturalistic setting.

Methods: All charts of out-patients treated with oxcarbazepine (n=13) were reviewed and clinical response assessed retrospectively using the Clinical Global Impression of Improvement (CGI-I) rating scale. All patients had failed treatment with at least one previous mood stabilizer.

Results: Mild improvement was seen in 46% (n=6) and moderate improvement in 16% (n=2). Fifty-four percent (n=7) of the total sample discontinued treatment because of adverse effects.

Conclusion: Oxcarbazepine may possess mild to moderate mood-stabilizing properties in this refractory, mostly depressed, bipolar sample. This naturalistic study is limited by its uncontrolled nature.     

Response to placebo among bipolar I disorder patients experiencing their first manic episode

Background: The first episode of an illness may respond differently to any treatment compared to multiple episodes of the same illness. This study details the treatment response of six first-episode manic patients who participated in a previously reported study of 139 subjects comparing olanzapine to placebo in bipolar I mania (Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KNR, Daniel DG. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry 1999; 156: 702–709).

Methods: Six first-episode subjects participated in a 3-week double-blind, random assignment, parallel group, placebo-controlled study of olanzapine for bipolar mania. The Young Mania Rating Scale (Y-MRS), Clinical Global Impression, and Hamilton Depression ratings were administered weekly. Lorazepam as rescue medication was permitted for the first 10 days.

Results: Five subjects were randomized to placebo and one to olanzapine. Two subjects (40%) with psychotic mania (who also had their first-illness episode) were assigned to placebo and responded with greater than 50% reduction in the Y-MRS score and also remitted in 3 weeks. Another placebo-assigned subject had a 46% reduction in the Y-MRS scores, and two placebo-assigned subjects worsened. The olanzapine-assigned subject had a 44% reduction in the Y-MRS score. In contrast, 34 of 69 (48.6%) multiple-episode olanzapine subjects responded and 14 of 61 (23.0%) of placebo-treated subjects did.

Conclusions: This preliminary data set suggest there may be differences in treatment response between first-illness episode versus multi-episode bipolar manic subjects. Larger numbers of subjects with these illness characteristics are needed to either confirm or refute this suggestion.     

Cholesterol levels in mood disorders: high or low?

Objectives: To assess cholesterol levels in patients with mood disorders.

Methods: All consecutively admitted patients meeting inclusion criteria (n=50) who were hospitalized in an affective disorders unit received assessments of cholesterol levels. Correlations were made with diagnosis using DSM-IV criteria, current mood states, and other clinical and demographic features of illness. Exclusion criteria included current alcohol abuse, medical illnesses that could influence cholesterol levels, eating disorders, and age greater than 70 years.

Results: Cholesterol levels did not differ based on diagnostic status of unipolar depression or bipolar disorder. In the total sample, cholesterol levels were lower in patients with current manic (170.2±38.9, p=0.05) and depressive (182.0±42.0) than in mixed (226.4±43.3) episodes (p=0.05). In subgroups of patients with bipolar disorder, manic episodes (169.9±38.8, n=9) were associated with lower cholesterol levels than depressive (201.0±49.4) or mixed (226.4±44.4) episodes (p=0.02 for comparison of manic and mixed episodes). Body mass index (BMI), age, alcohol use, and gender did not account for these findings.

Conclusions: Cholesterol levels were lower in manic and depressive than in mixed episodes. No differences were found between diagnoses of unipolar or bipolar mood disorders. Cholesterol may be a state rather than a trait function, and may be influenced by the acute mood state.     

Medication prescribing patterns for patients with bipolar I disorder in hospital settings: adherence to published practice guidelines

Objective: The purposes of this paper were to examine the medication prescribing patterns for bipolar I disorder in hospital settings and to compare them to recently published expert consensus guidelines for medication treatment of bipolar disorder.

Methods: Data were obtained from the 1996–2000 CQI+^SM Outcomes Measurement System, on patients age 18 or older admitted to psychiatric inpatient units from over 100 medical–surgical hospitals. A total of 1864 patients with a primary discharge diagnosis of bipolar I or II disorder were identified from a large cohort of hospitalized patients. Patient characteristics were assessed at hospital admission and medication usage, at discharge. The medication analysis focused on the 1471 individuals with bipolar I mania or bipolar I depression (with or without psychotic features), representing 54% and 25% of admitted bipolar patients, respectively.

Results: At admission, the typical bipolar patient (mean age 57) had experienced a relatively severe and chronic course of illness. The array of psychotropic agents used was broad, with no single prescribing pattern predominant. Only one in three bipolar I ( manic or depressed ) patients with psychotic features was discharged on medications recommended by expert guidelines as preferred or alternate recommended treatment. Absent psychotic features, this dropped to one in six patients. Surprising was the relatively high use of antidepressants for patients with mania, particularly those without psychotic symptoms.

Conclusions: Results suggest that a substantial proportion of patients with bipolar I disorder are discharged from hospitals on medications not generally recommended by current practice guidelines.