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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Abnormalities of lithium transport across the erythrocyte membrane in depression and schizophrenia.

Three mechanisms of lithium transport across erythrocyte membrane [lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC), and passive lithium diffusion (PLD)] were estimated in 27 acutely schizophrenic patients, 27 acutely depressed affective patients and in 18 control subjects. The activities of all mechanisms studied were significantly lower in both schizophrenic and depressed patients compared with controls. Analysis by gender showed that in control subjects, mean values of erythrocyte LSC and LPC were significantly higher in males compared with females. The decrease of LSC and LPC in depression and LSC in schizophrenia compared with control subjects was observed only in male patients but not in female ones. The results obtained suggest that lithium transport abnormalities during acute psychotic episodes are not specific to affective patients where lithium exerts its therapeutic action, but are also observed in schizophrenia. These abnormalities are more evident in male patients.

The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness.

The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was performed in forty patients with depression (12 male, 28 female), aged 20-68 years, in the course of affective illness (16 bipolar, 24 unipolar) both during acute depressive episode and in remission. The results were compared with those of 20 healthy control subjects (10 male, 10 female), aged 22-52 years. During acute depressive episode, cortisol concentration at 16 h after dexamethasone, 1.5 mg, and cortisol release after subsequent infusion of CRH, 100 microg, were significantly elevated in bipolar patients compared with unipolar ones and with control subjects. Patients with multiple episodes of unipolar depression exhibited greater cortisol levels after CRH than control subjects. In remission, significantly higher cortisol concentrations measured at 30 min(-1) h after CRH infusion were found in bipolar than in unipolar patients. Male bipolar patients had significantly higher cortisol level than bipolar females before and at 1.5 h after CRH. First episode unipolar patients during remission had lower levels of cortisol than control subjects before and at 1.5 h after CRH. Correlation between the magnitude of cortisol response and age was found within unipolar depressed patients but not in bipolar ones. On the other hand, correlation of test results with intensity of depression measured by Hamilton scale as well as with insomnia and anxiety subscales was more robust in bipolar subjects than in unipolar ones. It is concluded that the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity, detected by DEX/CRH test is significantly more marked in patients with depression in the course of bipolar affective illness than in unipolar depression. Within unipolar depression, this dysregulation may increase with the time course of the illness.

Beyond the Winokur concept of depression spectrum disease: which types of alcoholism are related to primary affective illness?

BACKGROUND: This study explored the familial relationship between alcoholism and depression. The familial prevalence of major depression and alcoholism among alcoholic probands and controls was examined. METHOD: Alcoholic patients were classified on the basis of absence or presence of major depression preceding or following alcohol dependence. Research Diagnosis Criteria (RDC) family history method was performed on 62 males and 49 females with alcohol dependence, on 50 healthy controls and on first degree relatives from all subjects. RESULTS: Female alcoholics had most commonly primary depression (74%) and alcoholic men had predominantly pure alcoholism (55%) and alcoholism with secondary depression (29%). Subjects with comorbid alcoholism and depression had earlier onset of alcohol dependence. The first degree relatives of probands with primary depression and secondary alcoholism had greater risk of alcoholism compared with the relatives of probands with alcoholism and secondary depression and with the relatives of pure alcoholics. In families of probands with primary depression and secondary alcoholism, increased prevalence of depression was observed. LIMITATION: The study has a relatively small population and only family history method to collect familial data of alcoholism and depression was used. CONCLUSION: Our results support Winokur's depressive spectrum hypothesis from another perspective. In our sample, male and female probands with primary depression and secondary alcoholism had the highest familial prevalence of both alcoholism and depression.

Depression and T lymphocytes in patients with irritable bowel syndrome.

In 74 patients (23 male, 51 female) with irritable bowel syndrome (IBS) and in 15 matched control persons, an assessment of depression by means of the Zung Depression Self-Rating Scale (ZDS) and a determination of the number of total lymphocytes and T lymphocytes were carried out. In patients with IBS, the depression score was significantly higher than in controls. Among patients with IBS, the intensity of depressive symptoms did not relate to age, gender or to the type of the illness. IBS patients with a depression score on ZDS of 50 or more (31% of subjects) had a significantly lower number of total lymphocytes and T lymphocytes than the rest of IBS patients. The results may suggest a possible association between depression and indices of cellular immunity in IBS patients.

Concentration and microheterogeneity glycophorms of alpha-1-acid glycoprotein in major depressive disorder.

Serum alpha-1-acid glycoprotein (AGP) concentration and its microheterogeneity were measured in 46 patients with major depressive disorder and in 20 age- and sex-matched controls. The changes in major microheterogeneity of AGP were expressed as reactivity coefficient (AGP-RC). Also measured were the levels of C-reactive protein as well as leukocyte, neutrophil and monocyte counts. The results obtained showed that two thirds of the depressed patients studied, exhibited some immune disturbances during acute episode: first with a high AGP and high AGP-RC, and secondly with a low AGP-RC. The patients with the highest AGP-RC and higher AGP values had a longer duration of the illness and of the last depressive episode, a higher resistance to previous treatments, and a higher monocyte count. The character of the changes in the microheterogeneity of AGP bears some similarity to those observed in other diseases with immunological disturbances.

Hoigné's syndrome: a procaine-induced limbic kindling.

Procaine-induced limbic kindling may be a principal pathogenetic factor for the psychiatric symptoms of the acute non-allergic reaction to procaine penicillin (Hoigné's syndrome). The syndrome develops with repeated injections of the drug and runs a rapidly spasmodic course. Its acute symptoms (anxiety, perceptual disturbances, sympathetic hyperactivity) are similar to those in temporal lobe and limbic system seizures and are also reminiscent of psychiatric complications following the repeated use of other local anesthetics (lidocaine, cocaine). Compatible with the mechanisms of kindling are also possible predispositions to the occurrence of this reaction as well as the recurrent after-effects during follow-up. Penicillin, a second component of the injection may contribute to the development of kindling by its properties of antagonizing GABA neurotransmission.

Dexamethasone suppression test and suicide attempts in schizophrenic patients.

The suicide attempts were assessed in 32 schizophrenic patients on whom the dexamethasone suppression test (DST) was done twice in the course of illness: in the years 1985-91 and 1996-97. In the 1985-91 period, both baseline and post-dexamethasone cortisol levels were significantly higher in the patients with previous suicide attempts and baseline cortisol was higher in the patients who were to make a future attempt. In 1996-97, DST non-suppression was shown in more than half of the patients with a history of suicide attempt and in none of those without such history: all cortisol levels were significantly higher in the patients with a history of suicide attempt. Although the mean intensity of depression was higher in the patients with a history of suicide attempt, no association between the intensity of depression and present or previous DST non-suppression status was found. It is suggested that the hyperactivity of the hypothalamic-pituitary-adrenal axis may constitute an element of diathesis for suicidal behavior in schizophrenic patients.

[Detection of anti-Borna disease virus antibodies in patients hospitalized in psychiatric hospitals located in the mid-Western region of Poland]. / Przeciwciala prezeciwko wirusowi choroby Borna u pacjentów hospitalizowanych w szpitalach psychiatrycznych na terenach województw lubuskiego i wielkopolskiego.

Borna Disease Virus (BDV) is single stranded RNA virus, which may infect a wide range of animal species. Manifestations of the experimental BDV infection show some resemblance to psychopathological symptoms of mental disorders in humans. Several reports suggest the higher prevalence of anti-BDV antibodies in psychiatric patients than in healthy controls. However, the seroprevalence of anti-BDV antibodies varied due to the different serological methods used in the previous studies. Electrochemiluminescence Immunoassay (ECLIA) is a recently developed, highly specific method of detecting antibodies directed toward two BDV proteins: p24 and p40. We used the ECLIA method for the assessment of seropositivity in 946 psychiatric patients hospitalized in the psychiatric hospitals in the western part of Poland. All patients were clinically diagnosed with ICD-10 criteria. Anti-p40 antibodies have not been found in the studied sample. We found anti p-24 antibodies in 23 cases, which give the seroprevalence rate of 2.4%. This result is consistent with the outcome of Japanese population assessment, done with the same methodology. The seropositive cases did not show diagnostic specificity. We did not find statistically significant gender differences in rate of seropositivity. The seroprevalence of anti-BDV antibodies was not significantly different in patients of urban and rural residence, and in patients of different age groups. This is the first demonstration of anti-BDV antibodies in the Polish population of patients hospitalized in psychiatric hospitals.

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.