Differentiating mania/hypomania from happiness using a machine learning analytic approach.

Background: This study aimed to improve the accuracy of bipolar disorder diagnoses by identifying symptoms that help to distinguish mania/hypomania in bipolar disorders from general ‘happiness’ in those with unipolar depression. Methods: An international sample of 165 bipolar and 29 unipolar depression patients (as diagnosed by their clinician) were recruited. All participants were required to rate a set of 96 symptoms with regards to whether they typified their experiences of manic/hypomanic states (for bipolar patients) or when they were ‘happy’ (unipolar patients). A machine learning paradigm (prediction rule ensembles; PREs) was used to derive rule ensembles that identified which of the 94 non-psychotic symptoms and their combinations best predicted clinically-allocated diagnoses. Results: The PREs were highly accurate at predicting clinician bipolar and unipolar diagnoses (92% and 91% respectively). A total of 20 items were identified from the analyses, which were all highly discriminating across the two conditions. When compared to a classificatory approach insensitive to the weightings of the items, the ensembles were of comparable accuracy in their discriminatory capacity despite the unbalanced sample. This illustrates the potential for PREs to supersede traditional classificatory approaches. Limitations: There were considerably less unipolar than bipolar patients in the sample, which limited the overall accuracy of the PREs. Conclusions: The consideration of symptoms outlined in this study should assist clinicians in distinguishing between bipolar and unipolar disorders. Future research will seek to further refine and validate these symptoms in a larger and more balanced sample

Categorical differentiation of the unipolar and bipolar disorders

There has been a longstanding debate as to whether the bipolar disorders differ categorically or dimensionally, with some dimensional or spectrum models including unipolar depressive disorders within a bipolar spectrum model. We analysed manic/hypomanic symptom data in samples of clinically diagnosed bipolar I, bipolar II and unipolar patients, employing latent class analyses to determine if separate classes could be identified. Mixture analyses were also undertaken to determine if a unimodal, bimodal or a trimodal pattern was present. For both a refined 15-item set and an extended 30-item set of manic/hypomanic symptoms, our latent class analyses favoured three-class solutions, while mixture analyses identified trimodal distributions of scores. Findings argue for a categorical distinction between unipolar and bipolar disorders, as well as between bipolar I and bipolar II disorders. Future research should aim to consolidate these results in larger samples, particularly given that the size of the unipolar group in this study was a salient limitation

The bipolar disorders: A case for their categorically distinct status based on symptom profiles

Background: It is unclear whether the bipolar disorders (i.e. BP-I/BP-II) differ dimensionally or categorically. This study sought to clarify this issue. Methods: We recruited 165 patients, of which 69 and 96 had clinician-assigned diagnoses of BP-I and BP-II respectively. Their psychiatrists completed a data sheet seeking information on clinical variables about each patient, while the patients completed a different data sheet and scored a questionnaire assessing the prevalence and severity of 96 candidate manic/hypomanic symptoms. Results: We conducted a series of analyses examining a set (and two sub-sets) of fifteen symptoms that were significantly more likely to be reported by the clinically diagnosed BP-I patients. Latent class analyses favoured two-class solutions, while mixture analyses demonstrated bimodality, thus arguing for a BP-I/BP-II categorical distinction. Statistically defined BP-I class members were more likely when manic to have experienced psychotic features and over-valued ideas. They were also more likely to have been hospitalised, and to have been younger when they received their bipolar diagnosis and first experienced a depressive or manic episode. Limitations: The lack of agreement between some patients and managing clinicians in judging the presence of psychotic features could have compromised some analyses. It is also unclear whether some symptoms (e.g. grandiosity, noting mystical events) were capturing formal psychotic features or not. Conclusions: Findings replicate our earlier study in providing evidence to support the modelling of BP-I and BP-II as categorically discrete conditions. This should advance research into aetiological factors and determining optimal (presumably differing) treatments for the two conditions

Effect of increasing intraperitoneal infusion rates on bupropion hydrochloride-induced seizures in mice

<p>Abstract</p> <p>Background</p> <p>It is not known if there is a relationship between input rate and incidence of bupropion-induced seizures. This is important, since different controlled release formulations of bupropion release the active drug at different rates.</p> <p>Methods</p> <p>We investigated the effect of varying the intraperitoneal infusion rates of bupropion HCl 120 mg/kg, a known convulsive dose₅₀(CD₅₀), on the incidence and severity of bupropion-induced convulsions in the Swiss albino mice. A total of 69 mice, approximately 7 weeks of age, and weighing 21.0 to 29.1 g were randomly assigned to bupropion HCl 120 mg/kg treatment by intraperitoneal (IP) administration in 7 groups (9 to 10 animals per group). Bupropion HCl was infused through a surgically implanted IP dosing catheter with infusions in each group of 0 min, 15 min, 30 min, 60 min, 90 min, 120 min, and 240 min. The number, time of onset, duration and the intensity of the convulsions or absence of convulsions were recorded.</p> <p>Results</p> <p>The results showed that IP administration of bupropion HCl 120 mg/kg by bolus injection induced convulsions in 6 out of 10 mice (60% of convulsing mice) in group 1. Logistic regression analysis revealed that infusion time was significant (p = 0.0004; odds ratio = 0.974) and increasing the IP infusion time of bupropion HCl 120 mg/kg was associated with a 91% reduced odds of convulsions at infusion times of 15 to 90 min compared to bolus injection. Further increase in infusion time resulted in further reduction in the odds of convulsions to 99.8% reduction at 240 min.</p> <p>Conclusion</p> <p>In conclusion, the demonstration of an inverse relationship between infusion time of a fixed and convulsive dose of bupropion and the risk of convulsions in a prospective study is novel.</p

Convulsive liability of bupropion hydrochloride metabolites in Swiss albino mice

<p>Abstract</p> <p>Background</p> <p>It is known that following chronic dosing with bupropion HCl active metabolites are present in plasma at levels that are several times higher than that of the parent drug, but the possible convulsive effects of the major metabolites are not known.</p> <p>Methods</p> <p>We investigated the convulsive liability and dose-response of the three major bupropion metabolites following intraperitoneal administration of single doses in female Swiss albino mice, namely erythrohydrobupropion HCl, threohydrobupropion HCl, and hydroxybupropion HCl. We compared these to bupropion HCl. The actual doses of the metabolites administered to mice (n = 120; 10 per dose group) were equimolar equivalents of bupropion HCl 25, 50 and 75 mg/kg. Post treatment, all animals were observed continuously for 2 h during which the number, time of onset, duration and intensity of convulsions were recorded. The primary outcome variable was the percentage of mice in each group who had a convulsion at each dose. Other outcome measures were the time to onset of convulsions, mean convulsions per mouse, and the duration and intensity of convulsions.</p> <p>Results</p> <p>All metabolites were associated with a greater percentage of seizures compared to bupropion, but the percentage of convulsions differed between metabolites. Hydroxybupropion HCl treatment induced the largest percentage of convulsing mice (100% at both 50 and 75 mg/kg) followed by threohydrobupropion HCl (50% and 100%), and then erythrohydrobupropion HCl (10% and 90%), compared to bupropion HCl (0% and 10%). Probit analysis also revealed the dose-response curves were significantly different (p < 0.0001) with CD₅₀values of 35, 50, 61 and 82 mg/kg, respectively for the four different treatments. Cox proportional hazards model results showed that bupropion HCl, erythrohydrobupropion HCl, and threohydrobupropion HCl were significantly less likely to induce convulsions within the 2-h post treatment observation period compared to hydroxybupropion HCl. The mean convulsions per mouse also showed the same dose-dependent and metabolite-dependent trends.</p> <p>Conclusion</p> <p>The demonstration of the dose-dependent and metabolite-dependent convulsive effects of bupropion metabolites is a novelty.</p

Oxcarbazepine as monotherapy of acute mania in insufficiently controlled type-1 diabetes mellitus: a case-report

<p>Abstract</p> <p>Background</p> <p>Type-1 diabetes mellitus (DM) is a lifelong serious condition which often renders the application of standard treatment options for patients' comorbid conditions, such as bipolar disorder I, risky – especially for acute manic episodes. We present such a case whereby the application of standard anti-manic treatments would have jeopardized a patient whose physical condition was already compromised by DM.</p> <p>Methods</p> <p>We report the case of a 55-year-old female with a history of type-1 DM since the age of 11, and severe ocular and renal vascular complications thereof. While on the waiting list for pancreatic islet cell transplantation, she developed a manic episode that proved recalcitrant to a treatment with gabapentin, lorazepam and quetiapine. Moreover, her mental state affected adversely her already compromised glycemic control, requiring her psychiatric hospitalization. Her psychotropic medication was almost discontinued and replaced by oxcarbazepine (OXC) up to 1800 mg/day for 10 days.</p> <p>Results</p> <p>The patient's mental state improved steadily and on discharge, 3 weeks later, she showed an impressive improvement rate of over 70% on the YMRS. Moreover, she remains normothymic 6 months after discharge, with OXC at 1200 mg/day.</p> <p>Conclusion</p> <p>Standard prescribing guidelines for acute mania recommend a combination of an antipsychotic with lithium or, alternatively, a combination of an antipsychotic with valproate or carbamazepine. However, in our case, administration of lithium was at least relatively contra-indicated because of patient's already compromised renal function. Furthermore, antipsychotics increase glucose levels and thus were also relatively contra-indicated. Moreover, the imminent post-transpantation immunosupressant treatment with immuno-modulating medicines also contra-indicated both valproate and carbamazepine. Despite the severe methodological limitations of case reports in general, the present one suggests that OXC as monotherapy might be both safe and efficacious in the treatment of acute mania in patients with early-onset type-1 DM, whose already compromised physical condition constitutes an absolute or relative contra-indication for the administration of standard treatments, though there are no, as yet, randomized clinical trials attesting to its efficacy unambiguously.</p

Combination of psychotherapy and benzodiazepines versus either therapy alone for panic disorder: a systematic review

<p>Abstract</p> <p>Background:</p> <p>The efficacy of combined psychotherapy and benzodiazepine treatment for panic disorder is still unclear despite its widespread use. The present systematic review aims to examine its efficacy compared with either monotherapy alone.</p> <p>Methods:</p> <p>All randomised trials comparing combined psychotherapy and benzodiazepine for panic disorder with either therapy alone were identified by comprehensive electronic search on the Cochrane Registers, by checking references of relevant studies and of other reviews, and by contacting experts in the field. Two reviewers independently checked eligibility of trials, assessed quality of trials and extracted data from eligible trials using a standardized data extraction form. Our primary outcome was "response" defined by global judgement. Authors of the original trials were contacted for further unpublished data. Meta-analyses were undertaken synthesizing data from all relevant trials.</p> <p>Results:</p> <p>Only two studies, which compared the combination with behaviour (exposure) therapy, met our eligibility criteria. Both studies had a 16-week intervention. Unpublished data were retrieved for one study. The relative risk for response for the combination was 1.25 (95%CI: 0.78 to 2.03) during acute phase treatment, 0.78 (0.45 to 1.35) at the end of treatment, and 0.62 (0.36 to 1.07) at 6–12 months follow-up. Some secondary outcomes hinted at superiority of the combination during acute phase treatment.</p> <p>One study was identified comparing the combination to benzodiazepine. The relative risk for response was 1.57 (0.83 to 2.98), 3.39 (1.03 to 11.21, statistically significant) and 2.31 (0.79 to 6.74) respectively. The superiority of the combination was observed on secondary outcomes at all the time points. No sub-group analyses were conducted due to the limited number of included trials.</p> <p>Conclusion:</p> <p>Unlike some narrative reviews in the literature, our systematic search established the paucity of high quality evidence for or against the combined psychotherapy plus benzodiazepine therapy for panic disorder. Based on limited available published and unpublished data, however, the combined therapy is probably to be recommended over benzodiazepine alone for panic disorder with agoraphobia. The combination might be superior to behaviour therapy alone during the acute phase, but afterwards this trend may be reversed. We know little from these trials about their adverse effects.</p

Effectiveness of psychotherapeutic, pharmacological, and combined treatments for chronic depression: a systematic review (METACHRON)

<p>Abstract</p> <p>Background</p> <p>Chronic depressions represent a substantial part of depressive disorders and are associated with severe consequences. Several studies were performed addressing the effectiveness of psychotherapeutic, pharmacological, and combined treatments for chronic depressions. Yet, a systematic review comparing the effectiveness of multiple treatment options and considering all subtypes of chronic depressions is still missing.</p> <p>Methods/Design</p> <p>Aim of this project is to summarize empirical evidence on efficacy and effectiveness of treatments for chronic depression by means of a systematic review. The primary objectives of the study are to examine, which interventions are effective; to examine, if any differences in effectiveness between active treatment options exist; and to find possible treatment effect modifiers. Psychotherapeutic, pharmacological, and combined treatments will be considered as experimental interventions and no treatment, wait-list, psychological/pharmacological placebo, treatment as usual, and other active treatments will be seen as comparators. The population of patients will include adults with chronic major depression, dysthymia, double depression, or recurrent depression without complete remission between episodes. Outcomes of the analyses are depressive symptoms, associated consequences, adverse events, and study discontinuation. Only randomized controlled trials will be considered.</p> <p>Discussion</p> <p>Given the high prevalence and serious consequences of chronic depression and a considerable amount of existing primary studies addressing the effectiveness of different treatments the present systematic review may be of high relevance. Special attention will be given to the use of current methodological standards. Findings are likely to provide crucial information that may help clinicians to choose the appropriate treatment for chronically depressed patients.</p

Dimensions and Latent Classes of Episodic Mania-Like Symptoms in Youth: An Empirical Enquiry

The dramatic increase in diagnostic rates of bipolar disorder in children and adolescents in the USA has led to an intense interest in the phenomenology of the disorder. Here we present data from a newly-developed instrument to assess episodic mania-like symptoms in youth in a large population-based sample (N = 5326) using parent- and self-report. We found that a substantial proportion of children screened positive for having episodes of “going high” and were at an increased risk for morbidity and impairment. Using factor analysis, we identified that episodic mania-like symptoms comprised two dimensions: An under-controlled dimension that was associated with significant impairment, and a low-risk exuberant dimension. Using latent class analysis, we identified a small group of children scoring high on a range of manic symptoms and suffering from severe psychosocial impairment and morbidity. Our results carry implications for the nosology and psychosocial impairment associated with episodic mood changes in young people

Evidence For Genetic Heterogeneity Between Clinical Subtypes of Bipolar Disorder

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P = 3.28 × 10 − 8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia (SCZ) and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I h2 = 0.35; BD II h2 = 0.25; P = 0.02) with a genetic correlation between BD I and BD II of 0.78,compared with a genetic correlation of 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for SCZ and BD in patients with BD I compared with patients with BD II, and a greater load of SCZ risk alleles in the bipolar type of schizoaffective disorder (SAB) compared with both other BD subtypes. These results point to a partial difference in genetic architecture of BD subtypes, and are suggestive of a molecular correlate for the clinical division of BD into subtypes