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Objectives To describe the cognitive and functional impairment in individuals with the first episode of major depressive disorder (MDD) as compared to controls and individuals with recurrent MDD. Also to describe the functional and cognitive trajectory after the first episode of MDD. Methods A total of 52 studies were included in our systematic review. 32 studies compared the cognitive performance between first episode of depression (FED) and controls, 11 studies compared the cognitive performance between recurrent depression (RD) and FED, 10 compared global functioning between RD and FED, four studies assessed cognition in FED over time, and two studies assessed global functioning in FED over time. Results The majority of studies (n = 22/32, 68.8%) found that FED subjects performed significantly worse than controls on cognitive tests, with processing speed (n = 12) and executive/working memory (n = 11) being the most commonly impaired domains. Seven out of 11 studies (63.6%) found that RD performed significantly worse than FED, with verbal learning and memory being the most commonly impaired domain (n = 4). Most studies (n = 7/10, 70%) did not find a significant difference in global functioning between RD and FED. In three of four longitudinal studies assessing cognition, subgroup analyses were used instead of directly assessing cognition in FED over time while the remaining study found significant cognitive declines over time in FED when compared to controls. The two longitudinal studies assessing functional trajectory found that functioning significantly improved over time, possibly due to the improvement of depressive symptoms. Conclusion There is strong evidence that cognitive impairment is present during the first episode of depression, and individuals with multiple episodes display greater cognitive impairment than individuals with a single episode. Future studies aimed at identifying predictors of cognitive and functional impairment after the first episode of depression are needed to describe the functional and cognitive trajectory of individuals with the first episode of MDD over time.

Objectives The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address. Method Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options. Conclusion The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

OBJECTIVES To detail the biological, clinical and neurocognitive characteristics differentiating bipolar disorder (BD) from frontotemporal dementia (FTD) and to investigate whether BD is a risk factor for FTD. METHODS A total of 16 studies were included in this systematic review. Five studies described biological and/or neurocognitive characteristics between patients with BD and FTD, and 11 studies investigated whether BD was a risk factor for FTD. RESULTS Individuals with FTD presented higher levels of serum neurofilament light chain, greater grey matter reduction in frontal, parietal and temporal lobes, and increased slow wave oscillations in channels F3, F4, T3, T5, T4 and T6 within an electroencephalogram (EEG), relative to individuals with BD. Patients with FTD presented greater deficits in executive function and theory of mind compared to patients with BD in a euthymic state, and more deficits in verbal fluency compared to patients with BD in a current mood episode. Patients with BD in a current mood episode showed greater impairment in attention, working memory, verbal memory and executive function relative to individuals with FTD. In addition, retrospective studies showed that 10.2%-11.6% of patients with behavioural variant FTD (bvFTD) had a preceding history of BD. CONCLUSION Biological and neurocognitive characteristics help to distinguish between BD and FTD, and it may help to reach a more precise diagnosis. In addition, individuals with BD are at higher risk of developing FTD. More studies are needed to identify the predictors of the conversion between BD to FTD.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

Objective To assess the prospective associations of mood disorders and suicidality in a community sample of young adults from south Brazil. Method Prospective population-based cohort study. Young adults (18-24 years old) were recruited and followed up on 5 years later; people were interviewed at their homes. Suicidality, as well as mood and anxiety disorders, was assessed using the Mini-International Neuropsychiatric Interview. The impact of mood episodes on suicidality was both evaluated when they occurred in the same wave (a current episode) and when suicidality occurred prospectively, with suicidality measured at follow-up (a past episode). Results The sample included 1560 young adults at baseline, with 1244 reassessed at follow-up (80.6%). Depressive episodes, both current and past, had a significant impact on suicidality in the final multivariable model. Manic episodes, however, were less consistently associated with suicidality. Conclusion Depressive episodes have a strong, independent, and robust association with prospective suicidality. The association between manic episodes and suicidality, on the other hand, was dependent on the analysis and deserves further exploration.

Objective Frontiers between pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) are not well defined. Few studies have addressed potentially different neurobiological factors between the two disorders. Brain-derived neurotrophic factor (BDNF) has been increasingly recognized for its etiologic and prognostic role in adult bipolar disorder (BD) studies. This study aimed to examine the BDNF gene polymorphism and potential alterations in BDNF serum levels in the pediatric ADHD patients with or without comorbid BD illness. Method We assessed the non-synonymous single-nucleotide polymorphism in the BDNF gene (rs6265/Val66Met) and its serum levels in children and adolescents with BD comorbid with ADHD (BD + ADHD) and ADHD alone. Children and adolescents were assessed for psychiatric diagnoses using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). Results Using Analysis of covariance (ancova) we detected a significant group effect (patients with BD + ADHD had higher serum levels than those with ADHD – F80,3 = 8.73, P = 0.005). Conclusion Although the Val66Met polymorphism at the BDNF gene does not seem to play a significant role in children and adolescents with BD or ADHD, BDNF serum levels deserve further attention in future research on neurobiological aspects of BD and ADHD.

OBJECTIVE: We aimed to review clinical features and biological underpinnings related to neuroprogression in bipolar disorder (BD). Also, we discussed areas of controversy and future research in the field. METHOD: We systematically reviewed the extant literature pertaining to neuroprogression and BD by searching PubMed and EMBASE for articles published up to March 2016. RESULTS: A total of 114 studies were included. Neuroimaging and clinical evidence from cross-sectional and longitudinal studies show that a subset of patients with BD presents a neuroprogressive course with brain changes and unfavorable outcomes. Risk factors associated with these unfavorable outcomes are number of mood episodes, early trauma, and psychiatric and clinical comorbidity. CONCLUSION: Illness trajectories are largely variable, and illness progression is not a general rule in BD. The number of manic episodes seems to be the clinical marker more robustly associated with neuroprogression in BD. However, the majority of the evidence came from cross-sectional studies that are prone to bias. Longitudinal studies may help to identify signatures of neuroprogression and integrate findings from the field of neuroimaging, neurocognition, and biomarkers.

Objective To assess the prevalence of childhood trauma and types of trauma on mood disorders among young adults in a population-based sample. We further gathered data on family history of mood disorders to test the hypothesis that childhood trauma is a mediating factor for the association between family history of mood disorder and mood disorder in adulthood. Method This is a cross-sectional study, including young adults with bipolar disorder, major depressive disorder, and matched controls without any mood disorder. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). The Hicks and Tingley implementation was employed to assess whether trauma is a mediator of the effect of family history on diagnosis of any mood disorder. Results All types of trauma were associated with both major depression and bipolar disorder, with the exception of sexual abuse, which was only associated with bipolar disorder. Moreover, family history of psychiatric illness was also associated with mood disorder in adulthood and with childhood trauma. Using the presence of any mood disorder as the outcome, a third of the effect of having any family history of mood disorder was mediated via childhood trauma. Conclusion This investigation provides further support, in a population-based sample of young adults, of the association between childhood trauma and mood disorders, with sexual abuse being specifically linked with bipolar disorder. The hypothesis that childhood trauma would function as a partial mediator of the association between family history of mood disorder and mood disorder in adulthood was also confirmed.

Reason for withdrawal from publication This review is to be passed onto a new group of authors.

Bipolar disorder may emerge during several decades of life. Studies from many countries have reported three peaks in the distribution of the age of onset, occurring at about ages 17, 26, and over 40 (1–5). Differences in the distribution of the age of onset were also reported among countries (6), although only limited data are available from some regions of the world. Patients living in North America generally have a younger age of onset than those living in European countries (6–8). In many studies conducted in the USA, about 60% of patients experience the onset of bipolar disorder before the age of 19 (6, 9–12), as compared to a third or less for many studies in European countries (1, 5, 6, 13–16). Diverse factors may contribute to this variation in the age of onset. There is agreement among researchers that both a patient’s genetic makeup and methodological issues in defining onset contribute to the reported differences, and that the variability in the age of onset reflects the genetic heterogeneity underlying bipolar disorder (1–3, 17). A positive family history is one of the strongest predictors of early onset (18). However, in addition to the genetic component, both the broad variability in the age of onset, and the onset peaks occurring after puberty (19) suggest that non-genetic factors may have considerable influence (20). There is limited understanding of how non-genetic factors, such as socioeconomic status and the physical environment, may impact the expression of bipolar disorder (21). In a recent study, a linear association was detected between the age of onset of schizophrenia and latitude, with a much younger onset occurring in individuals living closer to the equator (22). Latitude is often used as a proxy measure of sunlight, such as in studies of seasonal and geographical variation in affective disorders and suicide (23–28). However, more direct measures of the amount of electromagnetic energy striking the surface of the earth are now available, such as solar insolation (29). Sunlight is the primary synchronizer of circadian rhythmicity in most animals, including humans (30), and disruptions in circadian function may contribute to the pathophysiology of bipolar disorder (31). The purpose of this study was to investigate if the age of onset of bipolar I (BP-I) disorder was associated with sunlight at the location of onset, as measured by solar insolation.

Background A growing body of evidence has shown an association between diabetes and depression, as well a role of brain-derived neurotrophic factor (BDNF) in diabetes and depression. The present study was designed to evaluate the behavioural and molecular effects of the anti-depressant imipramine in diabetic rats. Methods To this aim, after induction of diabetes by alloxan (150 mg/kg), Wistar rats were treated with imipramine (30 mg/kg) once a day for 14 days and then subjected to behavioural tests. BDNF was then assessed in the prefrontal cortex, hippocampus and amygdala. Results In diabetic rats treated with saline, we observed an increase in the immobility time, compared with control rats treated with saline. Treatment with imipramine decreased the immobility time in nondiabetic and diabetic rats, compared with both nondiabetic and diabetic rats treated with saline. In the open-field test, it was observed that treatment with imipramine reduced the number of crossings the diabetic rats performed, compared with nondiabetic rats treated with saline. The number of rearings did not alter in any of the groups. Diabetic rats injected with saline did not show altered BDNF levels in the prefrontal cortex, hippocampus or amygdala, but interestingly, the treatment with imipramine in diabetic animals increased BDNF levels in the prefrontal cortex. Conclusions In conclusion, this study demonstartes a link between diabetes and depression in rats and that imipramine exerted antidepressant effects in diabetic animals. Copyright © 2011 John Wiley & Sons, Ltd.

Accessible summary • The study aims to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in South Brazil. • This is a cross-sectional study. Sixty participants with BD were recruited from the outpatient Bipolar Disorder Program of the University Hospital at the Federal University, Porto Alegre, Brazil. • This is a cross-sectional study. Sixty participants with BD were recruited from the outpatient Bipolar Disorder Program of the University Hospital at the Federal University, Porto Alegre, Brazil. • The study demonstrated a correlation between stigma and poor functioning in bipolar disorder. Abstract The aim of this study was to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in South Brazil. This is a cross-sectional study. Sixty participants with bipolar disorder were recruited from an outpatient Bipolar Disorder Program. Experiences with and impact of perceived stigma were evaluated using the Inventory of Stigmatizing Experiences. Functional impairment was assessed with the Functioning Assessment Short Test (FAST). Higher scores of self-perceived stigma were correlated with higher FAST scores, indicating more disability. After linear correlation analysis, current depressive symptoms, age at onset of treatment, age at diagnosis and functioning were correlated with self-perceived stigma. The study demonstrated a correlation between stigma and poor functioning in bipolar disorder. Perceived stigma is really important to individuals with bipolar disorder, both to how they experience their illness and to its results on functioning. Potential consequences of such results for mental health care professionals are discussed. Differential clinical features, sociocultural factors and the sample size limit the generalization of the present findings.

Rosa AR, Reinares M, Amann B, Popovic D, Franco C, Comes M, Torrent C, Bonnin CM, Sole B, Valenti M, Salamero M, Kapczinski F, Vieta E. Six-month functional outcome of a bipolar disorder cohort in the context of a specialized-care program. Bipolar Disord 2011: 13: 679–686. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: A marked disparity between functional recovery and symptomatic improvement has been demonstrated in bipolar disorder. However, most of the previous studies have been conducted in the United States, and there is little prospective research from Europe on this topic. The main objective of the present six-month follow-up study was to assess functioning in a sample of Spanish bipolar disorder patients following an acute episode or subsyndromal state. Additionally, we also evaluated the sensitivity to change of the Functioning Assessment Short Test (FAST). Methods: A total of 97 bipolar disorder patients with syndromal (n = 59) or subsyndromal (n = 38) symptoms were evaluated using the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale. The FAST was the primary measure to assess multiple areas of psychosocial functioning. Functioning was evaluated at four different time periods: baseline, 21 days, three months, and six months. Results: A significant improvement in global functioning was found in the whole sample over the six-month period, as indicated by a reduction of FAST total score (mean ± standard deviation) from 39.97 ± 15.10 to 30.65 ± 16.93 (F = 36.104, p = 0.0001). This was also evident in all areas of functioning studied. However, only 26.4% of remitted patients (n = 42) achieved functional recovery, while 79.6% of the total sample (N = 97) experienced clinical remission of acute symptoms. Conclusions: Although many patients presented syndromal recovery, only a minority of them achieved favorable functioning in multiple areas, even after specialized mental health care. Furthermore, the FAST scale was sensitive to detect minimal changes in functioning in both short (21 days) and long (6 months) periods, which may be relevant to the use of this scale in clinical trials.

Objectives: Brain-derived neurotrophic factor (BDNF) is an important contributor to the pathophysiology of bipolar disorder (BD), and abnormalities in the BDNF-signaling system may be implicated in the cognitive decline observed in BD patients. We aimed to investigate serum BDNF levels in BD patients and its relation to neurocognitive function. Methods: We measured serum BDNF levels using an enzyme-linked immunosorbent assay method in 65 euthymic type I BD patients and 50 healthy controls, and administered a neuropsychological test battery to assess attention and mental control, perceptual-motor skills, executive functions, verbal fluency and abstraction, visuospatial attention, and memory. Results: We found no significant differences regarding serum BDNF levels in BD patients and healthy controls. We found significant positive associations between serum BDNF levels and illness duration, and manic and depressive episodes in female BD patients only. Serum BDNF levels were lower in patients medicated with antipsychotics and/or lithium, whereas patients on valproate and/or antidepressants showed higher serum BDNF levels. Patients performed significantly worse on 11 out of 16 neurocognitive tests as compared to controls. We found a significant positive association between serum BDNF levels and a test of verbal fluency in both BD patients and controls. Conclusions: Present results support the hypothesis that BDNF normalizes with mood stabilization and pharmacological treatment. Our findings in young and physically healthy patients with short illness duration and few mood episodes may explain the lack of association between serum BDNF levels and neurocognitive performance, even though cognitive performance in patients was overall significantly worse as compared to healthy controls.

Objective: Substance use disorders and birth-cohort have been associated with an earlier onset in bipolar disorder (BD). This study aimed at evaluating the inter-relations of these factors in age-at-onset in bipolar illness. Method: Two-hundred and thirty patients with bipolar I disorder were cross-sectionally evaluated. Patients were categorized into four age groups for analysis. Lifetime comorbidity and age-at-onset were derived from the Structured Clinical Interview for DSM-IV. Results: There was a strong linear association between age group and age-at-onset. Lifetime alcohol and drug use disorders were also associated with age-at-onset. Illicit drug and alcohol use disorders and age group remained significant in the multivariate model. No interactions appeared. Conclusion: Both age group and dual diagnoses had strong and independent impacts on age-at-onset in out-patients with BD. Substance abuse may be partly accountable for earlier symptom onset, but other features of BD in younger generations are still in need to be accounted for.

Objectives: A number of studies have now shown that subjects with bipolar disorder (BD) have significant psychosocial impairment during interepisode intervals. This study was carried out to assess the level of functioning as well as to identify potential predictors of functioning in a well-defined, euthymic bipolar sample. Methods: The study included 71 euthymic bipolar patients and 61 healthy controls. The Functioning Assessment Short Test (FAST) was used to assess multiple areas of functioning such as autonomy, occupational functioning, cognitive functioning, interpersonal relationships, financial issues, and leisure time. Multivariate analysis was used to determine the global and specific clinical predictors of outcome. Results: Sixty percent (n = 42) of the patients had overall functional impairment (defined as a FAST total score > 11) compared to 13.1% (n = 8) of the control group (p = 0.001). Bipolar patients showed a worse functioning in all the areas of the FAST. Only four variables-older age, depressive symptoms, number of previous mixed episodes, and number of previous hospitalizations-were associated with poor functioning, on a linear regression model, which accounted for 44% of the variance (F - 12.54, df = 58, p < 0.001). Conclusions: A substantial proportion of bipolar patients experience unfavorable functioning, suggesting that there is a significant degree of morbidity and dysfunction associated with BD, even during remission periods. Previous mixed episodes, current subclinical depressive symptoms, previous hospitalizations, and older age were identified as significant potential clinical predictors of functional impairment.

Background Several neurochemical abnormalities have been reported in bipolar disorder (BD), but the exact mechanisms that underlie its pathophysiology remain to be elucidated. Proton magnetic resonance spectroscopy (1HMRS) allows in vivo measurements of certain neurometabolites in the human brain. 1HMRS was used to investigate the dorsolateral prefrontal cortex (DLPFC) in bipolar subjects during a manic or mixed phase. N-acetyl-L-aspartate (NAA), choline-containing molecules (Cho), creatine plus phosphocreatine (Cr) and myoinositol (Ino) were measured. Method Ten bipolar patients (nine manic, one mixed), diagnosed by a semi-structured clinical interview (SCID), and ten age- and gender-matched healthy volunteers were studied. Absolute neurometabolites levels were measured from two 8 cm3 voxels placed in left and right DLPFC using a short TE 1HMRS method at 1.5 T. T1- and T2-weighted anatomical magnetic resonance imaging was performed to exclude any neuroanatomical abnormality. Results No significant differences were found for NAA, Cho, Cr, Ino, NAA/Cr, Cho/Cr or Ino/Cr between patients and controls. Manic/mixed patients had significantly higher left-to-right myoinositol ratios in DLPFC (p = 0.044). Conclusions Increased left-to-right myoinositol ratios in the DLPFC in bipolar patients during acute mania may represent a dysfunction in the phosphoinositide-signaling pathway. Longitudinal studies with larger samples of unmedicated patients assessing pre- and post-treatment times will be required for further clarification of the time course of these abnormalities and the relationship with treatment effects. Copyright © 2005 John Wiley & Sons, Ltd.

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.

To assess the effects of specific drugs with antioxidant properties, in comparison with placebo, as adjunctive treatment to standard mood-stabilising treatment for improving acute mood episodes and preventing relapse in people with bipolar disorder. Given the diverse range of antioxidant drugs under consideration we will only seek to draw conclusions regarding the efficacy of individual drugs as an adjunct to mood stabilisers and there will be no comment on relative efficacy between different antioxidants.

Background Azapirones are a group of drugs that work at the 5-HT1A receptor and are used to treat patients suffering from generalized anxiety disorder (GAD). However, several studies have shown conflicting results. Whether azapirones are useful as first line treatment in general anxiety disorders still needs to be answered. Objectives To assess the efficacy and the acceptability of azapirones for the treatment of GAD. Search methods Initiallyt the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Central Register of Controlled Trials (CENTRAL) were searched, incorporating results of group searches of MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), CINAHL (1982 to June 2005), PsycLIT (1974 to June 2005), PSYNDEX (1977 to June 2005), and LILACS (1982 to June 2005). Subsequently the revised Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 21-10-2005. Reference lists of relevant papers and major text books of anxiety disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning azapirones were handsearched. Selection criteria Randomized controlled trials of azapirones, including buspirone versus placebo and/or other medication and/or psychological treatment, were included. Participants were males and females of all ages with a diagnosis of generalized anxiety disorder. Data collection and analysis Data were extracted from the original reports independently by CC, MA and MT. The main outcomes studied were related to the objectives stated above. Data were analysed for generalized anxiety disorder versus placebo, versus other medication and versus psychological treatment separately. Data were analysed using Review Manager Version 4.2.7. Main results Thirty six trials were included in the review, reporting on 5908 participants randomly allocated to azapirones and/or placebo, benzodiazepines, antidepressants, psychotherapy or kava kava. Azapirones, including buspirone, were superior to placebo in treating GAD. The calculated number needed to treat for azapirones using the Clinical Global Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4). Azapirones may be less effective than benzodiazepines and we were unable to conclude if azapirones were superior to antidepressants, kava kava or psychotherapy. Azapirones appeared to be well tolerated. Fewer participants stopped taking benzodiazepines compared to azapirones. The length of studies ranged from four to nine weeks, with one study lasting 14 weeks. Authors' conclusions Azapirones appeared to be useful in the treatment of GAD, particularly for those participants who had not been on a benzodiazepine. Azapirones may not be superior to benzodiazepines and do not appear as acceptable as benzodiazepines. Side effects appeared mild and non serious in the azapirone treated group. Longer term studies are needed to show that azapirones are effective in treating GAD, which is a chronic long-term illness.