Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Psychosocial functioning in relation to symptomatic remission: A longitudinal study of first episode schizophrenia.

OBJECTIVES: The aims of the study were: (1) to evaluate longitudinally symptomatic remission in first-episode (FE) schizophrenia, (2) to describe symptoms, social functioning and quality of life (Qol) in relation to remission status, and (3) to determine the long-term outcome of schizophrenia and its early predictors. METHODS: Sixty-four patients were assessed 1 month after a first hospitalization (T1), 12 months (T2), 4-6 years (T3), and 7-11 years (T4) after T1. The patients were allocated to three remission groups according to their remission status over the whole observation period, e.g. stable remission (SR), unstable remission (UR) and non-remission (NR). The PANSS, Social Functioning Scale and WHOQoL were used to evaluate the patients' psychosocial functioning levels, symptomatic and functional remissions and satisfying QoL. A good outcome was defined as meeting, simultaneously, the criteria of symptomatic and functional remissions and satisfying QoL at T4, while failure to meet all of these criteria was defined as a poor outcome. RESULTS: Among them, 17.2% patients were in stable remission, 57.8% in unstable remission and 25.0% were unremitted at all time points. The SR group had lower levels of psychopathological symptoms and reported better social functioning and QoL than the NR group. During the follow-up, the symptoms increased, social functioning slightly improved and QoL did not change. At T4, 53% of the sample had a poor outcome, which was independently predicted by the longer duration of untreated psychosis and a lack of satisfying QoL at T1. CONCLUSIONS: Our results demonstrate that: (1) the long-term course in schizophrenia is heterogeneous and that three illness trajectories exist, (2) social functioning and QoL are only partially connected with symptomatic remission (3), the risk of a poor outcome may potentially be reduced by appropriate interventions at an early stage of the illness.

Relationships between obesity, bipolar spectrum features, and personality traits: a case-control study.

OBJECTIVE: Recently there has been widening stream of research on the relationships between obesity and mental disorders. Patients with obesity seem to be prone to developing bipolar spectrum disorders and they present with specific personality traits. The aim of this study was to analyze the associations between obesity, bipolarity features, and personality traits. PATIENTS AND METHODS: A nested case-control study was performed. Patients with obesity constituted the sample of cases (N = 90), and healthy individuals were ascribed to the control group (N = 70). The lifetime presence of bipolarity features was analyzed with the Mood Disorder Questionnaire (MDQ), while personality traits were assessed with the NEO-Five Factor Inventory (NEO-FFI). RESULTS: Bipolarity features were more prevalent in the patients with obesity, as compared to healthy individuals. Patients with obesity had both higher mean value of MDQ score (p = 0.01) and a higher proportion of subjects with MDQ score ≥ 7 points (p = 0.012) as well as lower score on the NEO-FFI openness to experience (p > 0.001), compared to control subjects. Using multivariate model, in patients with obesity, a significant positive correlation between bipolarity and neuroticism, and negative with agreeableness and conscientiousness was established. Such relationship was not observed in control subjects. CONCLUSIONS: In the population of patients with obesity, there is a specific combination between bipolarity and personality traits (high-trait neuroticism, low-trait conscientiousness, and low-trait agreeableness). This may have some consequences for both pharmacological and psychological management of such patients.

Low Risk for Switch to Mania during Treatment with Sleep Promoting Antidepressants.

INTRODUCTION: Sleep-promoting antidepressants are of interest because they are used not only as antidepressants, but also to promote sleep. METHODS: We reviewed case reports describing the switch to mania during treatment with trazodone, mirtazapine, or agomelatine. RESULTS: Trazodone, mirtazapine, and agomelatine may induce manic symptoms. However, the risk of switching is related, first of all, to doses recommended for antidepressant treatment, administered without mood-stabilizer co-therapy. Low doses of these antidepressants, used for their hypnotic or sedative effects, were observed to cause mania only in patients with other risk factors for switching. There is no evidence for trazodone or mirtazapine and only sparse evidence for agomelatine, claiming that treatment with these antidepressants is related to an increased risk of switching to mania when administered in combination with a mood stabilizer. DISCUSSION: These findings suggest that low doses of trazodone and mirtazapine are safe in bipolar disorder, and should still be considered important alternatives to hypnotics when long-term pharmacological treatment of insomnia is necessary. It seems that these antidepressants and agomelatine can also be used safely in antidepressant doses when combined with a mood stabilizer.

Single ketamine infusion and neurocognitive performance in bipolar depression.

We estimated neurocognitive performance using the trail making test (TMT) and the Stroop color-word interference test before, and on the 3(rd) day after a single infusion of ketamine, in 18 bipolar depressed patients receiving mood-stabilizing drugs. The performance on all tests significantly improved on the 3(rd) day after ketamine infusion which correlated positively with baseline intensity of neuropsychological impairment and was not associated either with baseline intensity of depression or reduction of depressive symptoms after 3 or 7 days. The results suggest that in such population of patients, single ketamine infusion may improve neuropsychological performance independently of antidepressant effect.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

OBJECTIVE: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. METHOD: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. RESULTS: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. CONCLUSION: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.

BACKGROUND: Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). METHOD: To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. RESULTS: The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). CONCLUSIONS: Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

Vitamin B12 level may be related to the efficacy of single ketamine infusion in bipolar depression.

The single infusion of ketamine, an N-methyl-d-aspartic acid (NMDA) glutamate receptor antagonist, exerts a therapeutic effect in both unipolar and bipolar depression. Homocysteine (HCY) acts agonistically on the NMDA receptor, hyperhomocysteinemia is related to depression, and folic acid and vitamin B12 are associated with HCY system. We estimated the serum levels of these substances in 20 bipolar depressed patients before ketamine infusion. 10 patients responded favorably to this procedure, as their score on the Hamilton depression rating scale, compared to baseline, was reduced by more than 50%, after 7 days. The vitamin B12 level was significantly higher in "responders" compared to the remaining patients. No differences between the 2 groups were found with regard to HCY, folic acid levels and such clinical factors as age, duration of illness and duration of current episode. These preliminary data suggest that the vitamin B12 level may be connected with the efficacy of ketamine infusion in bipolar depression.

Hyperprolactinemia in antipsychotic-naive patients with first-episode psychosis.

BACKGROUND: Hyperprolactinemia is frequent in patients with schizophrenic psychoses. It is usually regarded as an adverse effect of antipsychotics but has recently also been shown in patients without antipsychotic medication. Our objective was to test whether hyperprolactinemia occurs in antipsychotic-naive first-episode patients (FEPs). METHOD: In the framework of the European First Episode Schizophrenia Trial (EUFEST), 249 out of 498 FEPs were eligible for this study, of whom 74 were antipsychotic naive. All patients were investigated regarding their serum prolactin levels with immunoassays standardized against the 3rd International Reference Standard 84/500. RESULTS: Twenty-nine (39%) of the 74 antipsychotic-naive patients showed hyperprolactinemia not explained by any other reason, 11 (50%) of 22 women and 18 (35%) of 52 men. CONCLUSIONS: Hyperprolactinemia may be present in patients with schizophrenic psychoses independent of antipsychotic medication. It might be stress induced. As enhanced prolactin can increase dopamine release through a feedback mechanism, this could contribute to explaining how stress can trigger the outbreak of psychosis.

Comorbid substance abuse in first-episode schizophrenia: effects on cognition and psychopathology in the EUFEST study.

UNLABELLED: Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients. METHOD: In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patients with (FE-SUD, N=119, consisting of N=88 patients with persisting SUD at baseline and N=31 patients with previous SUD) and without SUD (FE-non-SUD, N=204) were compared at baseline and 6 months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding. RESULTS: In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p=0.033, Cohen's d=0.26) in patients with SUD at 6 months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p=0.008, Cohen's d=0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16 years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption. CONCLUSIONS: FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6 months of antipsychotic treatment.

Lithium treatment of a bipolar patient with Wilson's disease: a case report.

We present the case of a male patient with a family history of both bipolar disorder (BD) and Wilson's disease (WD). Wilson's disease was diagnosed for this patient in 2008, at the age of 28 years, and shortly thereafter his bipolar illness began with depressive episodes. The patient has been treated with zinc sulphate for WD and with antidepressants for depression. In 2009, lithium was added, and in 2010 antidepressants were discontinued. During treatment with zinc sulphate, a gradual improvement of hepatic indices and a decrease of mandibulofacial dystonia was noted. In 2011, a hypomanic state occurred which subsided with an increase of the lithium dose. Since then, the patient has been mostly in a euthymic mood with subclinical hypomanic periods. We suggest that lithium may be a viable option for treating bipolar illness in patients with Wilson's disease.

Familial sinistrality and handedness in patients with first episode schizophrenia: the EUFEST study.

The population with schizophrenia is characterised by a leftward shift in handedness-sinistrality. However, findings are inconsistent in chronic patients, and familial sinistrality (FS), defined as the presence of left-handed close relatives, might contribute to the discrepancies. Therefore the aim of this study was to investigate the strength of manual lateralisation in patients with first episode schizophrenia, taking into account familial sinistrality. The Edinburgh Inventory (EI) allowed us to categorise 179 patients from the EUFEST study and 189 controls presenting "strong handedness" (SH: EI absolute value between ∣81∣ and ∣100∣) or "weak-handedness" (WH: EI value between -80 and +80). The nominal logistic regression did not show an FS effect, but a nearly significant interaction between illness and FS (p =.07). There were fewer participants without FS presenting SH among patients (99/151: 65.6%) than among controls (134/164: 81.7%, p =.001). In contrast, the number of participants with FS presenting SH was similar between controls (68%) and patients (75%, p =.57). The presence of left-handed relatives (FS + ) tended to reduce manual lateralisation, but only in controls. This supports the notion that reduced manual lateralisation in schizophrenia is related to the illness rather than to familial left-handedness.

Use of the Hypomania Checklist-32 and the Mood Disorder Questionnaire for detecting bipolarity in 1051 patients with major depressive disorder.

PURPOSE: To use the hypomania checklist (HCL-32) and the mood disorder questionnaire (MDQ), for detecting bipolarity in depressed patients. PATIENTS: One thousand and fifty-one patients fulfilling ICD-10 criteria for unipolar major depressive episode, single or recurrent, were studied. Patients were assessed using a structured demographic and clinical data interview, and by the Polish versions of the HCL-32 and MDQ questionnaires. RESULTS: Hypomanic symptoms exceeding cut-off criteria for bipolarity by HCL-32 were found in 37.5% of patients and, by MDQ, in 20% of patients. Patients with HCL-32 (+) or MDQ (+) differed significantly from patients with HCl-32 (-) and MDQ (-) respectively, by being less frequently married, having more family history of depression, bipolar disorder, alcoholism and suicide, earlier onset of illness, and more depressive episodes and psychiatric hospitalizations. The percentage of patients resistant to treatment with antidepressant drugs was significantly higher in HCL-32 (+) vs. HCL-32 (-) and in MDQ (+) vs. MDQ (-): 43.9% vs. 30.0%, and 26.4% vs. 12.4%, respectively. CONCLUSIONS: The results confirm a substantial percentage of bipolarity in major depressive disorder. Such patients have a number of clinical characteristics pointing on a more severe form of the illness and their depression is more resistant to treatment with antidepressants.

Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy.

AIM: The aim of the study was to evaluate serum brain-derived neurotrophic factor (BDNF) levels in a group of euthymic bipolar patients on long-term prophylactic lithium treatment and to delineate putative relationships between lithium efficacy and BDNF concentrations. METHODS: 141 euthymic bipolar patients (51 male, 90 female) on long-term lithium treatment were studied. Three categories of prophylactic lithium response were delineated: excellent lithium responders (ER; 30 patients), partial lithium responders (PR; 61 patients) and lithium nonresponders (NR; 50 patients). The control group consisted of 75 age- and gender-matched healthy subjects. RESULTS: The lithium-treated patients as a whole group had lower BDNF levels compared to the healthy controls. However, after breaking down the patients into ER, PR and NR, it appeared that only NR had significantly lower BDNF levels compared with the healthy control subjects. No association between the age of the patients, duration of bipolar illness, and serum lithium and BDNF levels was found. CONCLUSION: The results point to a relationship between lithium prophylactic efficacy and plasma BDNF levels in euthymic bipolar patients where lithium NR had reduced BDNF levels. These findings suggest that serum BDNF is associated with lithium efficacy in bipolar disorder.

Dopamine D1 receptor gene polymorphism is associated with prophylactic lithium response in bipolar disorder.

BACKGROUND: Previously, we have found an association between the -48 A/G polymorphism of the dopamine receptor D1 (DRD1) gene and bipolar disorder. The aim of the present study was to investigate a possible association of this polymorphism with the quality of the prophylactic lithium response in bipolar patients. METHODS: Ninety-two patients (39 male, 53 female), aged 30-77 (mean: 54 years) were studied. They have received lithium for prophylactic purposes for 5-27 years (mean: 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 48 patients as partial responders (PR), and 20 patients were non-responders (NR). They all were genotyped for -48 A/G polymorphism of the DRD1 gene. RESULTS: The frequency of G/G genotype in ER, PR, and NR patients was 21%, 48%, and 60%, respectively, and the frequency of G allele was 58%, 76%, and 80%, respectively. DISCUSSION: The results obtained suggest that the higher frequency of G allele, and G/G genotype, which has been associated with a predisposition to bipolar illness, is also connected with a poorer prophylactic effect of lithium.

Chronic paranoid psychosis and dementia following interferon-alpha treatment of hepatitis C: a case report.

Low-dose interferon-alpha is a standard therapy for hepatitis C. Psychotic disorders have been described as a rare complication of such treatments that resolve with its termination. Here, we present a patient without significant risk factors for interferon-alpha-induced serious mental disorders who developed a psychotic disorder with a cognitive impairment achieving the level of dementia after seven months of interferon-alpha therapy. The disturbances have persisted for three years despite cessation of interferon and introduction of antipsychotic treatment. The possibility of severe neuropsychiatric adverse effects of interferon-alpha therapy in a susceptible individual may necessitate regular psychiatric consultations during the treatment.

Psychiatry in selected countries of Central and Eastern Europe: an overview of the current situation.

OBJECTIVE: To review the current status of psychiatry in selected countries of Central and Eastern Europe: Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, and Slovenia. METHOD: A group of psychiatrists from the region evaluated the status of psychiatry at the end of 2004 based on data from their countries and information available on WHO homepages. RESULTS: There is a shift from traditional in-patient facilities towards out-patient and community services as evidenced by a decreasing number of hospital beds. Economic pressures affect the financing of psychiatric services, and reimbursement for novel psychotropics. Political changes were followed by updated legislation. Psychiatric training, pre-, postgraduate and continuous medical education, are gradually being transformed. Scientific output as measured by publications in peer-reviewed journals has been significantly lower than in the West. CONCLUSION: The major changes in the period of transition documented in the review pose new challenges for psychiatry.