Toxoplasma gondii in individuals with schizophrenia: association with clinical and demographic factors and with mortality

BACKGROUND: Increased rates of exposure to Toxoplasma gondii have been found in individuals with schizophrenia as compared with control groups, but the correlates of Toxoplasma exposure in schizophrenia have not been defined. METHODS: We measured IgG class antibodies to Toxoplasma gondii in 358 individuals with schizophrenia. We correlated Toxoplasma antibody status with clinical and demographic variables and examined the effect of Toxoplasma seropositivity on mortality in a follow-up period of up to 5 years. RESULTS: Individuals with schizophrenia who had serological evidence of Toxoplasma infection were more likely to be female but did not differ in age, race, total symptom score, or other demographic or clinical characteristics. However, we found that serological evidence of Toxoplasma was associated with a significantly increased risk of dying of natural causes during the follow-up period (Cox proportional hazard ratio of 4.70; 95% confidence interval, 1.27-17.31, P = .020) adjusted for age, gender, and other clinical and demographic variables. CONCLUSIONS: Toxoplasma infection may confer an increased risk for mortality from natural causes in schizophrenia. An understanding of the pathogenesis of Toxoplasma infections in individuals with schizophrenia might lead to new approaches to the management of this disorder.     

Is preadolescent mania the same condition as adult mania? A British perspective.

Until relatively recently, the prevailing view was that mania was uncommon in preadolescent children. In the past 15 years, however, there has been increasing interest in the idea that mania may be much more common at younger ages than previously recognized. This article is concerned with the issue of whether preadolescent mania represents the same kind of problem as adult mania. It reviews concepts of bipolar disorder and mania in adults and preadolescents, some of the issue that arise in diagnosing mania in children, and the evidence for continuities between preadolescent and adult mania. The diagnosis of mania in preadolescent children often requires that inferences are made about the meaning of some symptoms but it is not always clear that these inferences are valid. It is concluded that the extant evidence does not provide a clear conclusion about the links between preadolescent and adult mania. More work is needed on the phenomenology and diagnosis of mania in children, on its natural history and on its familial correlates.     

De novo mania among elderly people.

De novo mania is defined as the occurrence of a first manic episode in a patient with no history of mood disorder, after exclusion of organic etiologies. Although it is believed to be rare in elderly populations, the authors nonetheless report 6 cases encountered over a 2-year period. The literature regarding mania among elderly people is reviewed, and the authors formulate their recommendations in view of more frequent recognition and better management of these patients.     

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.     

Long-term inter-episode stability of syndromes underlying mania

OBJECTIVE: To explore the stability of diverse manic presentations across manic recurrences. METHOD: A total of 253 bipolar patients who experienced two or more hospitalizations, because of consecutive manic (or mixed) episodes, during a 20-year period were included. All patients had second hospitalizations with an mean interval of 773 days, while 126 and 91 patients had third and fourth hospitalizations with mean intervals of 1559 and 2237 days from the index hospitalization, respectively. Seven symptom scores, previously factor-validated, were calculated. RESULTS: Depressive mood, irritable aggression, psychomotor/thought inhibition, mania, emotional lability/agitation and psychosis were moderately correlated across the index and subsequent hospitalizations. CONCLUSION: A majority of diverse manic presentations were stable across manic recurrences. The stability was not restricted to two consecutive recurrences but appeared widespread over the long-term course of bipolar disorder. The finding may serve for the development of more effective long-term treatment strategies and a clinically more reasonable subtyping of mania.     

Insight into illness in patients with mania,mixed mania,bipolar depression and major depression with psychotic features

Dell'Osso L, Pini S, Cassano GB, Mastrocinque C, Seckinger RA, Saettoni M, Papasogli A, Yale SA, Amador XF. Insight into illness in patients with mania, mixed mania, bipolar depression and major depression with psychotic features. Bipolar Disord 2002: 4: 315–322. © Blackwell Munksgaard 2002 Background: Poor insight into illness is a common feature of bipolar disorder and one that is associated with poor clinical outcome. Empirical studies of illness awareness in this population are relatively scarce with the majority of studies being published over the previous decade. The study reported here sought to replicate previous report findings that bipolar patients frequently show high levels of poor insight into having an illness. We also wanted to examine whether group differences in insight exist among bipolar manic, mixed and unipolar depressed patients with psychotic features. Methods: A cohort of 147 inpatients with DSM‐III‐R bipolar disorder and 30 with unipolar depression with psychotic features, were evaluated in the week prior to discharge using the Structured Clinical Interview for DSM‐III‐R‐Patient Edition (SCID‐P), the Brief Psychiatric Rating Scale (BPRS) and the Scale to assess Unawareness of Mental Disorder (SUMD). Results: Insight into specific aspects of the illness was related to the polarity of mood episode: patients with mania showed significantly poorer insight compared with those with mixed mania, bipolar depression and unipolar depression. A linear regression analysis using SUMD score as the dependent variable and symptoms of mania as the independent variable found that specific manic symptoms did not account for level of insight. Similar results were obtained when the mean insight scores of patients with and without grandiosity were contrasted. Conclusions: We hypothesize that the lack of association between level of insight and total number of manic symptoms or with specific manic symptoms may be related to the persistence of subsyndromal symptoms in patients remitting from a manic episode.     

What symptoms predict the diagnosis of mania in persons with severe/profound intellectual disability in clinical practice?

Background While researchers have attempted to address the difficulties of diagnosing affective disorders in the intellectually disabled population, diagnosing bipolar disorder in an individual with severe intellectual disability (ID) remains a challenge. The aim of this study was to identify what symptoms can predict a diagnosis of mania in the intellectually disabled population. Methods Three groups of persons with ID participated in this study: (1) individuals with a bipolar diagnosis who were currently manic; (2) individuals with an Axis I diagnosis other than bipolar disorder; and (3) individuals without an Axis I diagnosis. Two recognized measures of mania (i.e. Diagnostic Assessment for the Severely Handicapped‐Revised and Parent Version of Young Mania Rating Scale) were used to evaluate symptoms of mania. A logistical regression procedure was conducted on mania items to identify which items correctly identify persons with ID who were currently manic. Results Psychomotor agitation, decreased sleep, changes in mood and aggression were significantly related to the diagnosis of mania. Further, psychomotor agitation and disturbed sleep were significant predictors of a diagnosis of mania. Conclusions Problems of sleep and psychomotor agitation should alert clinicians that further assessment of bipolar symptomatology is warranted. Focusing on observable behaviours based on Diagnostic and Statistical Manual of Mental Disorder‐IV criteria can be useful in formulating a diagnosis of bipolar disorder in persons with ID.     

Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis

Recent studies have linked infectious agents to schizophrenia. The largest number of studies has involved the analysis of Toxoplasma gondii; these studies were subjected to a meta-analysis. Published articles and abstracts were identified by searches of MEDLINE, Ovid, and Google Scholar; by a search of Chinese publications; through letters to researchers; and by visiting China. Published and unpublished controlled studies that used serological methods for measuring T. gondii antibodies to assess inpatients and/or outpatients diagnosed with schizophrenia were selected for analysis, and source documents were translated as needed. Forty-two studies carried out in 17 countries over 5 decades were identified; 23 of these (6 unpublished) met selection criteria. The combined odds ratio (OR) was 2.73 (95% confidence interval, 2.10 to 3.60; chi-square with 1 df 263; P < .000001). Seven studies that included only patients with first-episode schizophrenia (OR 2.54) did not differ significantly from 16 studies that included patients in all clinical phases (OR 2.79). The results suggest that individuals with schizophrenia have an increased prevalence of antibodies to T. gondii. This association is consistent with other epidemiological studies as well as with animal studies. Although the OR of 2.73 is modest, it exceeds that for genetic or other environmental factors identified to date and suggests that Toxoplasma is in some way associated with a large number of cases of schizophrenia. If an etiological association can be proven, it would have implications for the design of measures for the prevention and treatment of this disease.     

Antidepressant-induced mania: an overview of current controversies

Objective:  The prevalence, characteristics, and possible risk factors associated with antidepressant-induced mania remain poorly described. The present review sought to identify published rates of antidepressant-induced mania and describe risk factors for its emergence.
Methods:  A MedLine search was conducted of journals that focused on mania or hypomania associated with recent antidepressant use. Data from published reports were augmented with relevant findings from recent clinical trials presented at scientific conferences.
Results:  Antidepressant-induced manias have been reported with all major antidepressant classes in a subgroup of about 20–40% of bipolar patients. Lithium may confer better protection against this outcome when compared with other standard mood stabilizers, although switch rates have been reported with comparable frequencies on or off mood stabilizers. Evidence across studies most consistently supports an elevated risk in patients with (i) previous antidepressant-induced manias, (ii) a bipolar family history, and (iii) exposure to multiple antidepressant trials.
Conclusion:  About one-quarter to one-third of bipolar patients may be inherently susceptible to antidepressant-induced manias. Bipolar patients with a strong genetic loading for bipolar illness whose initial illness begins in adolescence or young adulthood may be especially at risk. Further efforts are needed to better identify high-vulnerability subgroups and differentiate illness-specific from medication-specific factors in mood destabilization.     

Risperidone in the treatment of bipolar mania

Atypical antipsychotic medications have assumed growing importance for the treatment of bipolar disorder, an illness that affects approximately 1.2%–3.7% of the general population in a given year. Current practice guidelines for the treatment of bipolar mania support the use of atypical antipsychotic medications as monotherapy or as a component of polytherapy, and in clinical settings the use of atypical antipsychotics to treat bipolar disorder is widespread. Risperidone is an atypical antipsychotic, sometimes referred to as a second-generation antipsychotic. The receptor-binding profile of risperidone, which includes potent antagonism of the serotonin 5-HT2_A, dopamine D₂, and alpha-adrenergic receptors, is believed to be related to positive effects on mood. The FDA-approved bipolar indications for risperidone include: 1) monotherapy for short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and 2) combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. This review of risperidone for bipolar mania will address the chemistry, pharmacodynamics, pharmacokinetics, and metabolism of risperidone, use with concomitant medications, clinical trials in bipolar mania, as well as safety and tolerability issues. Finally, dosing and administration are addressed as well as use for bipolar mania in geriatric, child, or adolescent patients.     

Antibodies to the glutamate receptor in mania

Dickerson F, Stallings C, Vaughan C, Origoni A, Khushalani S, Yolken R. Antibodies to the glutamate receptor in mania. Bipolar Disord 2012: 14: 547–553. © 2012 The Authors.Journal compilation © 2012 John Wiley & Sons A/S. Background: There is evidence that the glutamatergic system is involved in the pathophysiology of mania. Antibodies to the NR2 subunits of the N‐methyl‐D‐aspartate (NMDA) receptor have been shown to adversely affect glutamate functioning. Methods: We measured serum antibodies to the NR2 peptide of the NMDA receptor in 60 individuals with different subtypes of mania, including schizoaffective cases, who were assessed at up to three time points. We also measured these antibodies in 295 individuals in other psychiatric groups and in 170 non‐psychiatric controls. NR2 antibody levels were compared among groups by multivariate analyses and within the mania group by repeated measures analysis of variance. Results: Individuals with mania had increased levels of antibodies to the NR2 peptide compared to levels in non‐psychiatric controls when measured at the time of admission (t = 2.99, p = 0.003) and the time of evaluation (t = 2.57, p = 0.010), but not at follow‐up six months later. The levels of antibodies in individuals in other psychiatric groups did not differ significantly from the levels measured in the control population. Within the mania group, there was a significant decrease in antibody levels over the three time points of the study (F = 5.4, df = 2, p = 0.0067). Conclusions: NR2 antibodies are elevated during the acute phase of mania but not at follow‐up. Our findings support a role for antibodies to the NMDA receptor in the pathogenesis of acute mania.     

Asenapine versus olanzapine in acute mania: a double‐blind extension study

Objective: To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. Methods: Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3‐week, double‐blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9‐week, double‐blind extension study. Patients receiving active medication in the 3‐week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per‐protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. Results: A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was ?24.4 (8.7) for asenapine and ?23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment‐emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. Conclusions: Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.     

Dark therapy for mania: a pilot study

BACKGROUND: Recent findings suggest that extended bed rest and darkness could stabilize mood swings in rapid cycling bipolar patients. METHOD: We exposed 16 bipolar inpatients affected by a manic episode to a regimen of 14 h of enforced darkness from 6 p.m. to 8 a.m. each night for three consecutive days [dark therapy (DT)]. Pattern of mood changes were recorded with the Young Mania Rating Scale (YMRS) and compared with a control group of 16 inpatients matched for age, sex, age at onset, number of previous illness episodes and duration of current episode, and were treated with therapy as usual (TAU). RESULTS: Adding DT to TAU resulted in a significantly faster decrease of YMRS scores when patients were treated within 2 weeks from the onset of the current manic episode. When duration of current episode was longer, DT had no effect. Follow-up confirmed that good responders needed a lower dose of antimanic drugs and were discharged earlier from the hospital. CONCLUSIONS: Chronobiological interventions and control of environmental stimuli can be a useful add-on for the treatment of acute mania in a hospital setting.     

A pilot study of rapid lithium administration in the treatment of acute mania

Objectives: The use of rapid lithium dosage administration, a strategy that could lead to rapid improvement in mania, has been largely unexamined. In this open-label, pilot, acute-treatment study, we sought to determine the safety and tolerability of lithium administered at 20 mg/kg/day. A secondary aim was to provide preliminary data regarding the efficacy of this strategy in ameliorating manic, depressive, and psychotic symptoms. Methods: Fifteen patients hospitalized with DSM-IV bipolar disorder, manic or mixed, and who provided written informed consent, received lithium 20 mg/kg/day for up to 10 days. Patients were evaluated for adverse effects daily. Lithium levels were obtained on days 2, 3, 4, 5, 7, and 10 or at study termination. Electrocardiograms (EKGs) were performed at baseline and on days 1–5, 7, and 10 or at study termination. Symptomatic improvement was assessed daily using the Young Mania Rating Scale, 24-item Hamilton Depression Rating Scale, and the Scale for Assessment of Positive Symptoms (SAPS). Results: Five of the 15 patients completed the 10-day study period. Two patients dropped out due to adverse events. Seven patients did not complete the inpatient trial because of improvement sufficient to allow hospital discharge. All patients achieved serum lithium concentrations ≥0.6 mEq/L after 1 day of treatment; the mean±SD concentration on day 5 was 1.1 (±0.1) mEq/L on day 5. There were significant reductions from baseline to endpoint on all rating scales, except the SAPS bizarre behavior subscale. Conclusions: These pilot data suggest that lithium 20 mg/kg/day was well tolerated and that this strategy may produce rapid improvement in affective and psychotic symptoms. These impressions require confirmation in double-blind, randomized trials.     

Decision model for the acute treatment of mania

Decision making in psychiatric diagnosis and treatment has not been evaluated systematically. The authors present a model for treatment of an acute manic episode using a decision analysis software program. Six treatment options were put into the model: lithium, valproate, carbamezepine, electroconvulsive therapy, clonazepam, and neuroleptics. Each treatment was evaluated on three factors, efficacy, tolerability, and cost, using data from the literature and pharmacy and billing information. Output from the computer program identified three top choices among the six options: valproate, carbamazepine, and lithium, with valproate emerging as the first choice using the data we inputted. Depression and Anxiety 4:289–293, 1996/1997.© 1997 Wiley-Liss, Inc.     

Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double‐blind randomized controlled trial

Objective: The purpose of this study was to evaluate the efficacy of adding folic acid to sodium valproate in the acute phase of mania. Method: Following a double‐blind randomized controlled trial, 88 clinically manic patients with diagnosis of type I bipolar disorder (BID) were divided randomly into two groups (case and control). The case group was treated with folic acid and sodium valproate and the control group with sodium valproate and placebo. The severity of mania was assessed using the Young Mania Rating Scale (YMRS) at the beginning and end of the first, second and third weeks of the study. Results: The case group’s mean manic YMRS measurements (SD) before the initiation of therapy and in the first, second and third weeks of treatment were 34.0 ± 7.7, 26.7 ± 2.1, 18.1 ± 2.1 and 7.1 ± 0.9 respectively. The control group’s measurements were 34.7 ± 3.8, 27.3 ± 2.3, 20.7 ± 2.5 and 10.1 ± 1.1. There was a statistically significant difference in YMRS scaling results between the case and control groups after 3 weeks of treatment (7.1 ± 0.9 vs. 10.1 ± 1.1, P = 0.005). Conclusion: Based on our findings, folic acid seems to be an effective adjuvant to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder.