Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Brain functional changes in first-degree relatives of patients with bipolar disorder: evidence for default mode network dysfunction.

BACKGROUND: Relatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia. METHOD: A total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient-relative-matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them. RESULTS: A single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives. CONCLUSIONS: Failure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker.

Clinical features, impulsivity, temperament and functioning and their role in suicidality in patients with bipolar disorder.

OBJECTIVE: Our aim was to analyse sociodemographic and clinical differences between non-suicidal (NS) bipolar patients (BP), BP reporting only suicidal ideation (SI) and BP suicide attempters according to Columbia-Suicide Severity Rating Scale (C-SRSS) criteria. Secondarily, we also investigated whether the C-SRSS Intensity Scale was associated with emergence of suicidal behaviour (SB). METHOD: A total of 215 euthymic bipolar out-patients were recruited. Semistructured interviews including the C-SRSS were used to assess sociodemographic and clinical data. Patients were grouped according to C-SRSS criteria: patients who scored ≤1 on the Severity Scale were classified as NS. The remaining patients were grouped into two groups: 'patients with history of SI' and 'patients with history of SI and SB' according to whether they did or did not have a past actual suicide attempt respectively. RESULTS: Patients from the three groups differed in illness onset, diagnosis, number of episodes and admissions, family history, comorbidities, rapid cycling and medication, as well as level of education, functioning, impulsivity and temperamental profile. CONCLUSION: Our results suggest that increased impulsivity, higher rates of psychiatric admissions and a reported poor controllability of SI significantly increased the risk for suicidal acts among patients presenting SI.

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder.

OBJECTIVE: Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. METHOD: Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM). RESULTS: Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. CONCLUSION: The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder.

Bipolar disorder with comorbid attention-deficit and hyperactivity disorder. Main clinical features and clues for an accurate diagnosis.

OBJECTIVE: To study the prevalence of attention-deficit and hyperactivity disorder (ADHD) in adult patients with bipolar disorder (BD) and identify differential clinical features for a better diagnosis. METHOD: A total of 163 euthymic bipolar out-patients were screened for ADHD with the ASRS.V1 and the WURS at a BD Unit. Patients with a positive screening were assessed with the CAADID, at an ADHD unit. Sociodemographic and clinical features of the groups with and without ADHD were compared. RESULTS: Lifetime prevalence of comorbid ADHD was 17.9% (10.5% for adult ADHD and 7.4% for childhood ADHD). The BD + ADHD group showed more suicidal behaviour although less severe. Comorbidity was also more common, especially regarding substance use disorders. Nevertheless, these patients did not show more affective episodes or hospitalizations and suffered more atypical but less melancholic depression. However, they required more treatment with psychotherapy and valproate. One-third of positive screenings at the ASRS were false; a severe course of BD was the hallmark of this subgroup. CONCLUSION: Adult patients with BD and ADHD show differential clinical features, but not a more severe course of BD. Comorbidity with substance abuse is a big issue, deserving special clinical attention. Better screening tools are necessary to avoid overdiagnosis of comorbid ADHD in BD.

Clinical implications of predominant polarity and the polarity index in bipolar disorder: a naturalistic study.

OBJECTIVE: Predominant polarity (PP) is an important variable in maintenance treatment of bipolar disorder (BD). This study aimed at determining the role of polarity index (PI), a metric indicating antimanic versus antidepressive prophylactic potential of drugs, in clinical decision-making. METHOD: Two hundred and fifty-seven of 604 (43%) of patients with BD-I or II fulfilled criteria for manic (MPP) or depressive PP (DPP). The PI, representing the ratio of number needed to treat (NNT) for depression prevention to NNT for mania prevention, was calculated for patients' current treatment. MPP and DPP groups were compared regarding sociodemographic, clinical and therapeutic characteristics. RESULTS: One hundred and forty-three patients (55.6%) fulfilled criteria for DPP and 114 (44.4%) for MPP. Total PI, Antipsychotics' PI, and mood stabilizers PI were higher, indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of BD-I, male gender, younger age, age at onset and at first hospitalization, more hospitalizations, primary substance misuse, and psychotic symptoms. DP correlated with BD-II, depressive onset, primary life events, melancholia, and suicide attempts. CONCLUSION: The results confirm the usefulness of the PI. In this large sample, clinical differences among these groups justify differential treatment approach. The PI appears to be a useful operationalization of what clinicians do for maintenance therapy in BD.

Risk factors for suicide in schizophrenia: systematic review and clinical recommendations.

OBJECTIVE: To identify risk factors associated with suicide of patients with schizophrenia and provide clinical recommendations, which integrate research findings into a consensus based on clinical experience and evidence. METHOD: A task force formed of experts and clinicians iteratively developed consensus through serial revisions using the Delphi method. Initial survey items were based on systematic literature review published up to June 2013. RESULTS: Various risk factors were reported to be implicated in suicide in schizophrenia. Our findings indicate that suicide risk in schizophrenia is mainly related to affective symptoms, history of a suicide attempt and number of psychiatric admissions. Other risk factors identified are given by younger age, closeness to illness onset, older age at illness onset, male sex, substance abuse and period during or following psychiatric discharge. Integrating the evidence and the experience of the task force members, a consensus was reached on 14 clinical recommendations. CONCLUSION: Identification of risk factors for suicide in individuals diagnosed with schizophrenia is imperative to improve clinical management and develop strategies to reduce the incidence of suicide in this population. This study provides the critical overview of available data and clinical recommendations on recognition and management of the above-mentioned risk factors.

The impact of repeated manic episodes and executive dysfunction on work adjustment in bipolar disorder.

The aim of this study was to study the clinical and neurocognitive variables that best explain poor work adjustment in a sample of bipolar I euthymic patients. Eighty-five euthymic patients at the Hospital Clinic of Barcelona were assessed for this study by means of a comprehensive neuropsychological battery and a work-focused interview to determine work adjustment. Clinical and sociodemographic variables were also collected. Direct logistic regression was performed to assess the impact of demographic, clinical and neuropsychological variables on the likelihood of presenting poor work adjustment. The model that best fitted contained five variables (Hamilton Depression Rating scores, number of manic episodes, number of perseverative errors in the Wisconsin Card Sorting Test (WCST), number of depressive episodes and Trail Making Test-part B). However, only two out of these variables made a unique statistically significant contribution to the model, which were number of manic episodes (OR 1.401; CI 1.05-1.86; p = 0.021) and number of perseverative errors in the WCST (OR 1.062; CI 1.00-1.12; p = 0.044). The model explained up to 36 % of the variance in work adjustment. This study highlights the role of manic relapses and neurocognitive impairment, specifically the role of executive function, in work adjustment.

Brain functional abnormality in schizo-affective disorder: an fMRI study.

BACKGROUND: Schizo-affective disorder has not been studied to any significant extent using functional imaging. The aim of this study was to examine patterns of brain activation and deactivation in patients meeting strict diagnostic criteria for the disorder. METHOD: Thirty-two patients meeting research diagnostic criteria (RDC) for schizo-affective disorder (16 schizomanic and 16 schizodepressive) and 32 matched healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: Controls showed activation in a network of frontal and other areas and also deactivation in the medial frontal cortex, the precuneus and the parietal cortex. Schizo-affective patients activated significantly less in prefrontal, parietal and temporal regions than the controls, and also showed failure of deactivation in the medial frontal cortex. When task performance was controlled for, the reduced activation in the dorsolateral prefrontal cortex (DLPFC) and the failure of deactivation of the medial frontal cortex remained significant. CONCLUSIONS: Schizo-affective disorder shows a similar pattern of reduced frontal activation to schizophrenia. The disorder is also characterized by failure of deactivation suggestive of default mode network dysfunction.

Occupational disability in bipolar disorder: analysis of predictors of being on severe disablement benefit (PREBIS study data).

OBJECTIVE: Patients diagnosed with bipolar disorder (BD) are reported to have significant work impairment during interepisode intervals. This study was carried out to assess potential predictors of occupational disability in a longitudinal follow-up of euthymic patients. METHOD: We included 327 euthymic patients diagnosed with BD type I or type II, 226 of whom were employed and 101 were receiving a severe disablement benefit (SDB). Sociodemographic data were studied and episode recurrence was assessed along a 1-year follow-up. Logistic regression analysis was applied to determine predictors of receiving SDB. Cox regression was built to study recurrences. RESULTS: Predictors of receiving SDB were: axis II comorbidity [Odds Ratio (OR) = 2.94, CI: 1.26-6.86, P = 0.013], number of manic episodes (OR = 1.21, CI: 1.10-1.34, P < 0.001), being without stable partner (OR = 2.44, CI: 1.34-4.44, P = 0.004) and older age (OR = 1.08, CI: 1.05-1.12, P < 0.001). Bipolar patients receiving SDB presented more episodic recurrences regardless of polarity than employed bipolar patients (P = 0.002). The time until recurrence in 25% of the bipolar patients receiving SDB was 6.08 months (CI: 4.44-11.77) being 13.08 months (CI: 9.60 to -) in the employed group. CONCLUSION: Occupational disability in bipolar patients is associated with axis II comorbidity, more previous manic episodes, not having a stable relationship, older age, and more recurrences at 1-year follow-up.

Executive dysfunction and memory impairment in schizoaffective disorder: a comparison with bipolar disorder, schizophrenia and healthy controls.

BACKGROUND: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting. METHOD: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill. RESULTS: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms. CONCLUSIONS: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

Clinical guideline for the treatment of dual pathology in the adult population.

Editorial del vol 28-1.

Group psychoeducation for stabilised bipolar disorders: 5-year outcome of a randomised clinical trial.

BACKGROUND: The long-term efficacy of psychological interventions for bipolar disorders has not been tested. AIMS: This study assessed the efficacy of group psychoeducation to prevent recurrences and to reduce time spent ill for people with bipolar disorders. METHOD: A randomised controlled trial with masked outcome assessment comparing group psychoeducation and non-structured group intervention during 5-year follow-up. One hundred and twenty people with bipolar disorders were included in the study and 99 completed 5-year follow-up. Time to any recurrence, number of recurrences, total number of days spent ill, frequency and length of hospitalisations were the main outcome measures. RESULTS: At the 5-year follow-up, time to any recurrence was longer for the psychoeducation group (log rank=9.953, P<0.002). The psychoeducation group had fewer recurrences (3.86 v. 8.37, F=23.6, P<0.0001) of any type and they spent less time acutely ill (154 v. 586 days, F=31.66, P=0.0001). The median number of days of hospitalisation per hospitalised participant was also lower for the psychoeducation group (45 v. 30, F=4.26, P=0.047). CONCLUSIONS: Six-month group psychoeducation has long-lasting prophylactic effects in individuals with bipolar disorders. Group psychoeducation is the first psychological intervention showing such a long-term maintained efficacy in people with bipolar disorders.

Psychoeducation for bipolar II disorder: an exploratory, 5-year outcome subanalysis.

BACKGROUND: Bipolar II represents a significant subgroup of bipolar patients. However, there is limited evidence regarding the efficacy of pharmacological and/or psychosocial therapies. METHOD: Post-hoc analyses were undertaken using data on 20 (out of 120) patients who fulfilled DSM-IV criteria for BP II who had participated in a single-blind randomized controlled treatment trial (RCT) exploring the acute and long-term efficacy of group psychoeducation plus standard pharmacological treatment as compared with unstructured support groups plus standard pharmacological treatment. Eight BP II subjects had been randomized to a psychoeducation group and 12 to an unstructured support group. RESULTS: Psychoeducated, as compared to control group bipolar II patients, had significantly better 5-year outcomes, with lower mean number of BP episodes (p<.02), hypomanic episodes (p<.03) and depressive episodes (p<.03), fewer days spent in mood episodes (p=.004) and higher mean levels of functioning (p<.05). CONCLUSIONS: Although these findings should be treated with caution, it appears that psychoeducation plus medication can benefit bipolar II subjects. Dedicated treatment trials will need to clarify whether these therapies require modifications in duration and/or content to meet the needs of bipolar II patients.

A study on the bioequivalence of lithium and valproate salivary and blood levels in the treatment of bipolar disorder.

Lithium (Li) and valproate (VPA) are used in the treatment of bipolar disorder (BD), with narrow therapeutic window requiring periodic control of serum levels. This prevents intoxication, lack of efficacy due to low serum concentrations, and allows monitoring adherence. We aimed at evaluating the bioequivalence of salivary and blood levels of LI or VPA in a sample of adult BD patients. Secondarily, lithium bioequivalence was evaluated across different patients' lifespans. BD patients treated with either Li or VPA underwent contemporary standard serum and salivary measurements. Blood levels of both drugs were taken according to standard procedures. Li salivary levels were performed by an adapted potentiometric method on the AVL9180 electrolyte analyzer. VPA salivary levels were taken with an immune-assay method with turbidimetric inhibition. A total of 50 patients (38 on Li, 12 on VPA) were enrolled. Blood-saliva bioequivalence for VPA was not found due to a high variability in salivary measures. Li measures resulted in a high correlation (r=0.767, p<0.001), showing no partial correlation with age (r=0.147, p=0.380). Li salivary test is a reliable method of measuring Li availability and is equivalent to serum levels. Potential advantages of Li salivary testing are its non-invasive nature and the possibility of doing the test during the usual appointment with the psychiatrist.

What really matters to bipolar patients' caregivers: sources of family burden.

BACKGROUND: Identifying and modifying burdensome aspects might reduce the level of burden and their negative effects both on caregivers and patients' outcome. Most studies evaluate acutely ill patients, whereas the most relevant problems may be related to subthreshold symptoms and long-term outcome. The aims of the present study were to assess caregiver's subjective burden, to analyse which were the most burdensome aspects for caregivers and to study which variables could explain the caregiver's subjective burden. METHODS: Caregivers of 86 euthymic bipolar patients completed the subjective burden subscale from an adapted version of the Social Behaviour Assessment Schedule. RESULTS: Caregivers showed a moderate level of subjective burden. The highest levels of distress were reported regarding the patient's behaviour; the most distressing behaviours were hyperactivity, irritability, sadness and withdrawal. Regarding the patient's role performance, the most worrying aspects were those associated with the patient's work or study and social relationships. Regarding adverse effects on others, caregivers were especially distressed by the way the illness had affected their emotional health and their life in general. Poorer social and occupational functioning, an episode in the last 2 years, history of rapid cycling and the caregiver being responsible for medication intake explained a quarter of the variance of the caregiver's subjective burden. LIMITATIONS: This was a cross-sectional study focused only on primary caregivers, there was no control group of non-bipolar patients. CONCLUSIONS: This study provides relevant data concerning the burden of caregivers of stable bipolar patients, pointing at potential targets for psychosocial interventions.

Treatment guidelines for bipolar disorder: a critical review.

INTRODUCTION: The development of treatment guidelines emerged as an important element so as to standardize treatment and to provide clinicians with algorithms, which would be able to carry research findings to the everyday clinical practice. MATERIAL AND METHOD: The MEDLINE was searched with the combination of each one of the key words 'mania', 'manic', 'bipolar', 'manic-depression', 'manic-depressive' with 'treatment guidelines'. RESULTS: The search was updated until March 1st, 2004 and returned 224 articles. Twenty-seven papers concerning the publication of treatment algorithms were traced. DISCUSSION: Despite supposedly being evidence-based, guidelines for the treatment of bipolar disorder vary significantly across committees or working groups. Overall, however, at the first stage of the mania/hypomania algorithm, monotherapy with lithium, divalproex sodium or olanzapine is generally recommended. At latter stages combination therapy is strongly recommended. It is clearly stated that in bipolar depression antidepressants should be used only in combination with antimanic agents in order to avoid switching of phases. During the maintenance phase all patients should receive antimanic agents, while some may need the addition of antidepressants. The most recent guidelines emphasize the use of atypical antipsychotics for mania and lamotrigine for depression. The main problem with guidelines is that they are rapidly outdated and that the evidence base relies mainly on registration monotherapy trials that hardly reflect treatment in routine clinical conditions. CONCLUSION: Treatment guidelines may be useful to avoid non-evidence-based treatment decisions, but they are quickly out-of-date and may not fully apply to the clinical setting. The more recent guidelines point the value of atypical antipsychotics, lithium, and valproate in the treatment of mania; the role of lithium, lamotrigine, and olanzapine as options for maintenance therapy; and the scarcity of options for the treatment of bipolar depression. Psychoeducation is also supported by most guidelines as an adjunctive treatment.

Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study.

BACKGROUND: The goal of this study was to assess the efficacy and safety of risperidone in bipolar and schizoaffective disorders. METHOD: 541 patients entered this open, multicenter, 6-month study. Patients were entered provided that they fulfilled DSM-IV criteria for bipolar disorder or schizoaffective disorder, bipolar type, during a manic, hypomanic, mixed, or depressive episode. Risperidone was added to any previous mood-stabilizing medication that the patients were taking. Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions scale (CGI). Extrapyramidal symptoms (EPS) were assessed using the UKU Side Effect Rating Scale. RESULTS: 430 patients completed the study. Addition of risperidone produced highly significant improvements (p < .0001) on the YMRS and HAM-D at both 6 weeks and 6 months and on the CGI and the scales of the PANSS at both 4 weeks and 6 months. There was a significant reduction in UKU total and subscale scores at 6 months. The mean dose of risperidone was 3.9 mg/day. There was no single case of new-emergent tardive dyskinesia, and there was a very low incidence of exacerbation of mania within the first 6 weeks (2%). Adverse events were few and mostly mild. the most frequent being EPS and weight gain. CONCLUSION: This large study provides additional evidence that risperidone is effective and well tolerated when combined with mood stabilizers in the treatment of bipolar disorder and schizoaffective disorder, bipolar type. Previous concerns about exacerbation of manic symptoms were not confirmed.

Risperidone in the treatment of mania: efficacy and safety results from a large, multicentre, open study in Spain.

BACKGROUND: A number of open studies and preliminary results of unpublished double-blind trials have suggested that the novel antipsychotic risperidone may be effective and well tolerated in the treatment of acute mania in bipolar disorder. METHODS: A total of 174 patients entered this large, open, multicentre trial. Inclusion criteria were: current manic, hypomanic or mixed episode (DSM-IV), and a Young Mania Rating Scale (YMRS) score of >7. Assessments included the YMRS, Positive and Negative Syndrome Scale (PANSS), Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI), and Udvalg for Kliniske Undersøgelser (UKU) subscale for neurological side effects. RESULTS: There were significant reductions (P<0.0001) on the YMRS, PANSS and HAM-D scores and a significant improvement (P<0.0001) in CGI ratings at the endpoint. There were no statistically significant increments in the severity of extrapyramidal symptoms according to the UKU. Risperidone was generally well tolerated. The mean dose of risperidone at the endpoint was 4.9+/-2.9 mg/day. CONCLUSIONS AND CLINICAL IMPLICATIONS: This open study provides further evidence that risperidone is safe and effective in combination with mood stabilisers in the manic phase of bipolar disorder. LIMITATIONS: The open design and the use of concomitant medications make unclear to what extent the positive results were entirely related to risperidone.

Faster onset of antimanic action with haloperidol compared to second-generation antipsychotics. A meta-analysis of randomized clinical trials in acute mania.

BACKGROUND: there is a lack of scientific data regarding speed of action of antimanic treatments, a relevant issue in clinical practice. OBJECTIVE: to assess differences in the speed of onset of antimanic efficacy between haloperidol (as most studied first-generation antipsychotic) and second-generation antipsychotics. EXPERIMENTAL PROCEDURES: meta-analysis of double-blind randomized clinical trials in acute mania, comparing treatment with haloperidol and with second-generation antipsychotics. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Differences in mania scale score reduction at week 1 were assessed. RESULTS: 8 randomized clinical trials fulfilled inclusion criteria and 1 of them was excluded due to low methodological quality. 2037 Manic patients had been treated with antipsychotics in the 7 trials. Haloperidol was found to be significantly more efficacious in the reduction of the mania scale score at week 1. The effect size was small, the Standardized Mean Difference (SMD) being 0.17, with a 95% Confidence Interval ranging from 0.01 to 0.32. Haloperidol was significantly more efficacious than olanzapine (SMD: 0.40 [0.21, 0.59]) and ziprasidone (0.39 [0.18, 0.61]). A non-significant trend towards superiority of haloperidol was found over aripiprazole (SMD: 0.13 [-0.02, 0.19]). There were no significant differences between haloperidol and quetiapine (0.17 [-0.11, 0.44]), and haloperidol and risperidone (SMD: -0.10 [0.30, 0.09]). CONCLUSIONS: haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms.