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Background The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. Method This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. Results TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. Discussion In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. Conclusions The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Objective In some individuals, recovery from episodes of mental illness may be impeded by maladaptive illness beliefs and behaviors. For individuals with chronic illness, acceptance of its presence and consequences is necessary to seek appropriate treatment, adjust their lifestyle, and adhere to recommended management strategies. Some have difficulty adjusting out of the sick role or develop a degree of illness investment. The Illness Cognitions Scale (ICS) is a 17-item validated scale that measures cognitive factors associated with the sick role. We conducted analyses to test the hypothesis that there may be an association between illness cognitions and clinical and functional measures. Methods The ICS was administered to 89 participants at the final study visit of a 24-month observational study involving patients with bipolar I disorder or schizoaffective disorder. Results Higher scores on the ICS were correlated with more severe depression ( p p =0.0002), worse functioning ( p =0.0001), and worse scores in psychosocial measures including the State Hope Scale ( p =0.0082), the Social Provisions Scale ( p =0.0054) and the Rosenberg Self-Esteem Scale ( p =0.0025). Conclusions Illness cognitions and behavior may be a neglected factor that could influence treatment outcomes in bipolar disorder. The ICS might be useful for identifying individuals whose recovery may be facilitated by targeted psychological intervention that addresses these factors.

Berk M, Brnabic A, Dodd S, Kelin K, Tohen M, Malhi GS, Berk L, Conus P, McGorry PD. Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. Bipolar Disord 2011: 13: 87–98. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objective: The staging model suggests that early stages of bipolar disorder respond better to treatments and have a more favourable prognosis. This study aims to provide empirical support for the model, and the allied construct of early intervention. Methods: Pooled data from mania, depression, and maintenance studies of olanzapine were analyzed. Individuals were categorized as having had 0, 1–5, 6–10, or >10 prior episodes of illness, and data were analyzed across these groups. Results: Response rates for the mania and maintenance studies ranged from 52–69% and 10–50%, respectively, for individuals with 1–5 previous episodes, and from 29–59% and 11–40% for individuals with >5 previous episodes. These rates were significantly higher for the 1–5 group on most measures of response with up to a twofold increase in the chance of responding for those with fewer previous episodes. For the depression studies, response rates were significantly higher for the 1–5 group for two measures only. In the maintenance studies, the chance of relapse to either mania or depression was reduced by 40–60% for those who had experienced 1–5 episodes or 6–10 episodes compared to the >10 episode group, respectively. This trend was statistically significant only for relapse into mania for the 1–5 episode group (p = 0.005). Conclusion: Those individuals at the earliest stages of illness consistently had a more favourable response to treatment. This is consistent with the staging model and underscores the need to support a policy of early intervention.

Background Tobacco smoking is more prevalent among people with mental illnesses, including bipolar disorder, than in the general community. Most data are cross-sectional, and there are no prospective trials examining the relationship of smoking to outcome in bipolar disorder. The impact of tobacco smoking on mental health outcomes was investigated in a 24-month, naturalistic, longitudinal study of 240 people with bipolar disorder or schizoaffective disorder. Method Participants were interviewed and data recorded by trained study clinicians at 9 interviews during the study period. Results Comparisons were made between participants who smoked daily (n = 122) and the remaining study participants (n = 117). During the 24-month study period, the daily smokers had poorer scores on the Clinical Global Impressions–Depression (P = .034) and Clinical Global Impressions–Overall Bipolar (P = .026) scales and had lengthier stays in hospital (P = .012), compared with nonsmokers. Limitations Smoking status was determined by self-report. Nicotine dependence was not measured. Conclusion These findings suggest that smoking is associated with poorer mental health outcomes in bipolar and schizoaffective disorder.

Background The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, observational study of participants with bipolar I or schizoaffective disorder examining clinical, functional, and economic outcomes associated with naturalistic treatment. Methods Participants prescribed mood stabilisers were assessed using various measures, including the Young Mania Rating Scale (YMRS), 21-item Hamilton Depression Rating scale (HAMD 21 ), Clinical Global Impressions-Bipolar Version Severity of Illness scale (CGI-BP), and the EuroQol instrument (EQ-5D). Results 240 participants were recruited from two sites. On average, participants were 41.8 ± 12.7 years of age (mean ± SD), 58.3% were female, and 73.3% had a diagnosis of bipolar I disorder at study entry. The majority of participants were moderately ill, with an average CGI-BP Overall score of 3.8 ± 1.3. Most participants had subthreshold mania and depression symptoms, indicated by HAMD 21 Total 13.4 ± 8.6, CGI-BP Depression 3.2 ± 1.3, YMRS Total 8.2 ± 8.5 and CGI-BP Mania 3.0 ± 1.6 average scores. For bipolar participants, 94.6% of hospitalisations for psychiatric treatment in the past 3 months were single admissions (vs. 65.2% for schizoaffective participants, p = .002). Bipolar participants rated their overall health state higher (EQ-5D scores: 68.2 ± 18.8 vs. 61.6 ± 22.7, p = .023), had a higher mean weekly wage ($500–$999, 21.3% vs. 6.3%), lower unemployment (22.2% vs. 48.4%), and higher romantic relationship status (47.1% vs. 26.6%). Limitations The observational design and small sample size may have limited the causal relationships and generalisability within the current findings. Conclusions Participants were characterised by social and occupational dysfunction at entry, but schizoaffective participants appeared to be more severely affected. Effective treatment is required to address both clinical and functional impairment.

Objectives:Recent studies have proposed the existence of three distinct subgroups of bipolar 1 disorder based on age at onset (AAO). The present study aims to investigate potential clinical and functional differences between these subgroups in an Australian sample.Methods:Participants (n= 239) were enrolled in the Bipolar Comprehensive Outcomes Study (BCOS), a 2-year longitudinal, observational, cross-sectional study. Assessment measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD21), Clinical Global Impressions Scale (CGI-BP), SF-36, SLICE/Life Scale, and the EuroQol (EQ-5D). Participants were also asked about their age at the first major affective episode.Results:Three AAO groups were compared: early (AAO < 20, mean = 15.5 ± 2.72; 44.4% of the participants); intermediate (AAO 20–39, mean = 26.1 ± 4.8; 48.14% of the participants) and late (AAO > 40, mean = 50.6 ± 9.04; 7.4% of the participants). Higher rates of depression, suicidal ideation and binge drinking were reported by the early AAO group. This group also reported poorer quality of life in a number of areas. The early AAO group had a predominant depressive initial polarity and the intermediate group had a manic predominance.Conclusion:Early AAO is associated with an adverse outcome.

Background Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes. Methods GBM was applied to pooled data from 12 randomised clinical trials of 4987 participants experiencing an acute depressive episode who were treated with duloxetine, an SSRI or placebo to predict treatment remission. Additional analyses were conducted on the same dataset using the logistic regression model for comparison between these two methods. Results With GBM, there were noticeable differences between treatments when identifying which and to what extent variables were associated with remission. A single logistic regression only revealed a decreasing or increasing relationship between predictors and remission while GBM was able to reveal a complex relationship between predictors and remission. Limitations These analyses were conducted post-hoc utilising clinical trials databases. The criteria for constructing the analyses data were based on the characteristics of the clinical trials. Conclusions GBM can be used to identify and quantify patient variables that predict remission with specific treatments and has greater flexibility than the logistic regression model. GBM may provide new insights into inter-individual differences in treatment response that may be useful for selecting individualised treatments. Trial registration IMPACT clinical trial number 3327; IMPACT clinical trial number 4091; IMPACT clinical trial number 4689; IMPACT clinical trial number 4298; NCT00071695; NCT00062673; NCT00036335; NCT00067912; NCT00073411; NCT00489775; NCT00536471; NCT00666757 (note that trials with IMPACT numbers predate mandatory clinical trial registration requirements)

In view of the controversial relationship between certain aspects of panic disorder with agoraphobia (PDA), suicidal ideation and comorbidity, the purposes of this study were to compare severity of PDA and Axis I and Axis II comorbidity in PDA patients with and without suicidal ideation, and to examine predictors of suicidal ideation in these patients. Eighty-eight consecutive outpatients with PDA were administered structured diagnostic interviews for the DSM-IV Axis I and Axis II disorders (SCID-I and SCID-II), while the severity of PDA was assessed by means of the Panic Disorder Severity Scale. Of the patients, 25 (28.4%) reported suicidal ideation in past years ('ideators'). The severity of PDA was greater among ideators, and they were significantly more likely to have a personality disorder and more than one comorbid Axis I and Axis II disorder. There were no ideators without either Axis I or Axis II comorbidity. Univariate logistic regression identified several predictors of suicidal ideation: any DSM-IV Cluster C personality disorder, any DSM-IV Cluster B personality disorder, any comorbid mood disorder, and severity of PDA. With multivariate logistic regression, a combination of any Cluster C personality disorder and severity of PDA emerged as the most significant predictor of suicidal ideation. These findings have implications for clinical practice in that PDA patients should be carefully assessed for the severity of their illness and presence of certain personality disorders and comorbid mood disorders, because they may all increase the risk for suicidal ideation.

The SCID-II Personality Questionnaire, modified for DSM-IV and ICD-10 Diagnostic Criteria for Research (ICD-10-DCR), was administered to 58 consecutive patients with agoraphobia with panic disorder in order to screen for personality disorders (PDs) and assess diagnostic agreement between DSM-IV and ICD-10-DCR. The diagnostic agreement, as expressed by kappa values, was 0.78 for the presence of any personality disorder (PD), but it ranged from 0.51 for schizoid PD to 0.83 for dependent PD. There was a tendency for ICD-10-DCR to overdiagnose PDs, except for borderline and dependent PDs. The sources of disagreement can be traced to differences in the conceptualization of some PDs and differences in diagnostic criteria and diagnostic thresholds; these are further examined in an effort to improve diagnostic criteria and attain greater compatibility between the two diagnostic systems.

We examined whether identification of patients with placebo-remitter characteristics and placebo-nonremitter characteristics enhances the ability to identify drug-placebo treatment differences and, perhaps, differences between agents in major depressive disorder (MDD). We hypothesized: 1) that drug-placebo differences in remission rates would be greater for both duloxetine and selective serotonin reuptake inhibitors (SSRIs) among placebo nonremitters than placebo remitters and: 2) that the difference between active treatments would also be greater in placebo nonremitters than placebo remitters.Data were obtained from seven randomized, parallel, double-blind MDD studies which compared the effects of duloxetine (N = 795), placebo (N = 510), and SSRIs (N = 551). The 17-item Hamilton depression rating scale (HAMD) was used to assess depression severity. The classification of participants as having placebo-remitter or placebo-nonremitter characteristics was based on age, duration of current MDD episode, HAMD anxiety score, and HAMD core score. Odds ratios (ORs) for remission comparing active treatment and placebo were obtained from logistic regression models. Tests of homogeneity were used for between-group comparisons.For placebo nonremitters, both duloxetine (OR = 3.52 [95% CI: 2.21, 5.62; P 0.0001]) and SSRIs (OR = 2.38 [95% CI: 1.45, 3.89; P = 0.0006]) showed significantly higher remission rates compared to placebo. Drug-placebo differences in remission were significantly greater for placebo nonremitters than for placebo remitters for both duloxetine (P = 0.02) and SSRIs (P = 0.049). For placebo remitters, remission with duloxetine (OR = 1.83 [95% CI: 1.35, 2.47; P = 0.0001]), but not the SSRIs selected for this study (OR = 1.31 [95% CI: 0.93, 1.84; P = 0.12]), was significantly greater than placebo. Contrary to expectation, the advantage of duloxetine over the SSRIs was not greater in placebo nonremitters. However, the fact that our analysis required patient-level data limited the number of agents studied, compromising generalization.Our study suggests that drug-placebo differences in remission rates will be greater in subjects with placebo-nonremitter than with placebo-remitter characteristics.

Mental illness has been observed to follow a neuroprogressive course, commencing with prodrome, then onset, recurrence and finally chronic illness. In bipolar disorder and schizophrenia responsiveness to treatment mirrors these stages of illness progression, with greater response to treatment in the earlier stages of illness and greater treatment resistance in chronic late stage illness. Using data from 5627 participants in 15 controlled trials of duloxetine, comparator arm (paroxetine, venlafaxine, escitalopram) or placebo for the treatment of an acute depressive episode, the relationship between treatment response and number of previous depressive episodes was determined. Data was dichotomised for comparisons between participants who had >3 previous episodes (n=1697) or ≤3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled. There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness.

Haya Ascher-Svanum, Alan JM Brnabic, Anthony H Lawson, Bruce J Kinon, Virginia L Stauffer, Peter D Feldman, Katarina KelinLilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USAAbstract: It is often difficult to determine whether a patient may best benefit by augmenting their current medication or switching them to another. This post-hoc analysis compares patients’ clinical and functional profiles at the time their antipsychotic medications were either switched or augmented. Adult outpatients receiving oral antipsychotic treatment for schizophrenia were assessed during a 12-month international observational study. Clinical and functional measures were assessed at the time of first treatment switch/augmentation (0–14 days prior) and compared between Switched and Augmented patient groups. Due to low numbers of patients providing such data, interpretations are based on effect sizes. Data at the time of change were available for 87 patients: 53 Switched and 34 Augmented. Inadequate response was the primary reason for treatment change in both groups, whereas lack of adherence was more prevalent in the Switched group (26.4% vs 8.8%). Changes in clinical severity from study initiation to medication change were similar, as indicated by Clinical Global Impressions–Severity scores. However, physical and mental component scores of the 12-item Short-Form Health Survey improved in the Augmented group, but worsened in the Switched group. These findings suggest that the patient’s worsening or lack of meaningful improvement prompts clinicians to switch antipsychotic medications, whereas when patients show some improvement, clinicians may be more likely to try bolstering the improvements through augmentation. Current findings are consistent with physicians’ stated reasons for switching versus augmenting antipsychotics in the treatment of schizophrenia. Confirmation of these findings requires further research.Keywords: augmentation, drug substitution, polypharmacy, schizophrenia, switching

Background The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with ‘real-world’ treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication. Methods Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale – Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data. Results On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts. Conclusions Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.

Katarina Kelin1, Timothy JR Lambert2, Alan JM Brnabic3, Richard Newton4, Wendy Ye3, Raúl I Escamilla5, Kuang-Peng Chen6, Liana Don7, William Montgomery1, Jamie Karagianis8, Haya Ascher-Svanum91Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 2Discipline of Psychiatry, Brain and Mind Research Institute, The University of Sydney, Camperdown, NSW, Australia; 3Intercontinental Information Sciences, Eli Lilly Australia Pty Ltd, Macquarie Park, NSW, Australia; 4Peninsula Health Psychiatric Services, Frankston Hospital, Frankston, VIC, Australia (current affiliation: Department of Psychiatry, Austin Hospital, Heidelberg, VIC, Australia); 5Schizophrenia Clinic, National Institute of Psychiatry, Mexico City, Mexico; 6Department of Psychiatry, National Taiwan University Hospital, Yun-Lin, Taiwan; 7Department of Psychiatry, University of Medicine Iuliu Hatieganu Cluj Napoca, Romania; 8Lilly USA, Eli Lilly and Company, Indianapolis, IN, USA; 9Global Health Outcomes, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USABackground: This study aimed to improve physicians' understanding of the treatment circumstances and needs of outpatients with schizophrenia at risk of nonadherence, by naturalistically assessing antipsychotic treatment patterns, clinical outcomes, and health care service use in this little-studied patient population.Methods: In this one-year, prospective, multicenter, noninterventional, observational study, patients considered at risk of nonadherence by their physicians were switched from their primary oral antipsychotic to another oral or a depot antipsychotic at study entry. All cause treatment discontinuation (antipsychotic switch, augmentation, or discontinuation) during the study was assessed using Kaplan–Meier survival analyses and descriptive statistics. Patients’ illness severity, quality of life, attitude towards medication, patient-reported adherence, and health care resource utilization were assessed during the study.Results: Of the 406 enrolled patients, 43 (10.6%) were switched to depot and 363 (89.4%) were switched to oral antipsychotics at study entry. During the study, 99 (24.4%) patients switched, augmented, or discontinued their antipsychotic (all cause treatment discontinuation). Of the 99 patients who switched, augmented, or discontinued their antipsychotic, 8 (18.6%) were taking depot and 91 (25.0%) were taking oral antipsychotics. These patients were switched to either depot (n = 15) or oral (n = 78) antipsychotics, or discontinued their antipsychotic medication (n = 6). Inadequate response was the most frequently reported reason for medication discontinuation. During the study, patients’ clinical and functional status improved significantly and service use was low. Most patients considered themselves to be adherent at study entry, and this favorable self-perception increased during the study (from 68.5% to 88.1%).Conclusion: Although identified as at risk of nonadherence, few patients in this naturalistic study discontinued their prescribed antipsychotic medication during the study. The discrepancy between the physicians’ perception of their patient’s medication adherence and the patients’ self-perceived adherence highlights the need to better understand the underlying reasons for this phenomenon.Keywords: antipsychotic drugs, medication persistence, outpatients, schizophrenia, depot antipsychotic, nonadherence

Katarina Kelin1, Alan JM Brnabic2, Richard Newton3, Raúl I Escamilla4, Liang-Jen Chuo5, Malina Simu6, Wenyu Ye2, William Montgomery1, Jamie Karagianis7, Haya Ascher-Svanum81Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 2Intercontinental Information Sciences, Eli Lilly Australia Pty Ltd, Macquarie Park, NSW, Australia; 3Peninsula Health Psychiatric Services, Frankston Hospital, Frankston, VIC, Australia (current affiliation: Department of Psychiatry, Austin Hospital, Heidelberg, VIC, Australia); 4Schizophrenia Clinic, National Institute of Psychiatry, Mexico City, México D.F; 5Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan; 6St Stelian Hospital, Bucharest, Romania; 7Eli Lilly Canada Inc., Toronto, ON, Canada; 8US Outcomes Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USAAbstract: In this year-long, prospective observational study, sociodemographic, clinical, and functional characteristics were assessed in outpatients with schizophrenia from Australia, ­Mexico, Romania, and Taiwan who were switched from their primary oral antipsychotic to another oral or depot antipsychotic at study entry because of physician-perceived ­nonadherence risks. Patients (N = 406) rated their quality of life and functioning level as low. Few patients (10.6%, 43/406) were switched to depot antipsychotics, with country-specific differences (P < 0.001). Although illness severity was similar between subgroups, the depot switch ­subgroup had: a documented history of nonadherence (32.6% versus oral: 4.7%); recent alcohol (48.8% versus 23.2%; P < 0.001) or illicit drug use (16.3% versus 5.0%; P = 0.010); recent depot antipsychotic (20.7% versus 7.5%; P = 0.030) and mood stabilizer use (51.7% versus 26.3%; P = 0.008); poorer attitudes towards medication (P = 0.004); and poorer illness ­awareness (P = 0.041). Findings indicate that even when a risk of nonadherence has been identified, few patients with schizophrenia receive depot antipsychotics, despite being prime candidates for depot therapy. Findings suggest physicians may select depot therapy based on previous ­nonadherence, substance use, recent depot antipsychotic and mood stabilizer use, poor attitudes towards medications, and poor illness awareness.Keywords: antipsychotic drugs, schizophrenia, depot antipsychotic, nonadherence

Objectives The clinical significance of subthreshold mixed states is unclear. This study investigated the clinical outcomes in participants with bipolar I disorder or schizoaffective disorder, using the Cassidy and Benazzi criteria for manic and depressive mixed states, respectively. Methods Participants (N = 239) in a prospective observational study of treatment and outcomes in bipolar I or schizoaffective disorder, bipolar type, were grouped based on study entry clinical presentation as having pure depression (n = 63) if they satisfied DSM-IV-TR criteria for a Major Depressive Episode (MDE), depressive mixed state if they also had at least three concurrent hypomanic symptoms (n = 33), or not depressed (n = 143) if they did not satisfy the criteria for MDE. Participants were similarly grouped as having pure mania (n = 3) if they satisfied DSM-IV criteria for a Manic Episode, manic mixed state if they also had at least two concurrent depressive symptoms (n = 33), or not manic (n = 203). Clinical data were collected by interview every 3 months over a 24-month period. Results Measures of quality of life, mental and physical health over the 24-month period were significantly worse for participants who were classified as having mixed states at study entry on most outcome measures compared to participants who were not in an illness episode at study entry. A depressive mixed state was predictive of greater manic symptomatology over the 24 months compared to participants with pure depression. Conclusion In participants with a current episode of mood disorder, the presence of subthreshold symptoms of opposite polarity was associated with poorer clinical outcomes over a 24-month period.

We assessed the impact of real danger on several aspects of the panic disorder (PD) patients' psychopathology and level of disability. At the time of the NATO air strikes on Belgrade, 84 PD patients who were in partial or complete remission were administered the Panic and Agoraphobia Scale (PAS). All had been treated previously, and the majority (58.3%) were taking antipanic medications. The PAS, which was used as part of the regular follow-up assessment battery for PD patients, measures the overall severity of PD and the severity of key aspects and components of PD. Compared to the PAS assessments made before the onset of air strikes, the PAS assessments made at the time of air strikes showed significant differences in terms of decreased overall severity of PD, fewer health concerns, decrease in the level of disability, and greater intensity and frequency of anticipatory anxiety. Differences on the measures of panic attacks and agoraphobic avoidance were negligible. These results suggest that there is no relationship between panic attacks and real danger and lend support to the notion that panic attacks and fear induced by real danger are different phenomena. Contrary to the expectations of many PD patients, the presence of real danger does not seem to be associated with deterioration in their functioning, and PD patients can be reassured that they are not likely to cope worse under conditions of danger.

Several aspects of the quality of life after sex reassignment surgery in 32 transsexuals of both sexes (22 men, 10 women) were examined. The Belgrade Team for Gender Identity Disorders designed a standardized questionnaire for this purpose. The follow-up period after operation was from 6 months to 4 years, and four aspects of the quality of life were examined: attitude towards the patients' own body, relationships with other people, sexual activity, and occupational functioning. In most transsexuals, the quality of life was improved after surgery inasmuch as these four aspects are concerned. Only a few transsexuals were not satisfied with their life after surgery.

Background There are obstacles to early identification of bipolar disorder. Identifying and treating illness early in its time course may be associated with a better prognosis. Methods A questionnaire was administered at interview, when the participant was euthymic, to participants (n = 240) enrolled in the Bipolar Comprehensive Outcomes Study (BCOS). Information was collected about the sequential timeline of specific symptoms of mental illness up to when they first received a diagnosis of Bipolar Disorder or Schizoaffective Disorder. Results Any symptoms of mental illness were first experienced at 17.5 years (median; Inter Quartile Range (IQR) 13.8–24.3; n = 216) and mood swings at 18.0 years (IQR 14–25; n = 197). Symptoms of depression were experienced at 18.0 years (IQR 14–25; n = 197), a full episode of depression at 21.2 years (IQR 17–28.5; n = 200), symptoms of mania at 21.0 years (IQR 16.8–29.5; n = 212) and a full episode of mania at 24.1 years (IQR 19–30.5; n = 205). Medical treatment was sought at 24.0 years (IQR 19–31.5; n = 217). Participants received a diagnosis of Bipolar Disorder or Schizoaffective Disorder at 30.0 years (IQR 23–37.3; n = 215). Having had a previous diagnosis other than Bipolar Disorder or Schizoaffective Disorder was reported by 120 of 216 participants who answered this question, most commonly unipolar depression (26.6%). Diagnostic delay was greater in individuals with early onset disorder. Conclusions Participants typically experience a long sequential course of symptoms, episodes, treatments and diagnosis. The polarity of onset is most commonly depressive, and subthreshold symptoms tend to precede threshold symptoms of both polarities. Limitations Data were collected retrospectively.