Jens M. Langosch

Cognitive functioning in euthymic bipolar I and bipolar II patients

OBJECTIVE There is growing evidence of cognitive impairment as a trait factor in bipolar disorder. The generalizability of this finding is limited because previous studies have either focussed exclusively on bipolar I disorder or have analysed mixed patient groups. Thus, it is still largely unknown whether bipolar II patients perform differently from bipolar I patients on measures of cognitive functioning. METHODOLOGY A total of 65 patients with bipolar I disorder, 38 with bipolar II disorder, and 62 healthy controls participated in the study. Patients had to be euthymic for at least one month. Clinical and demographic variables were collected in a clinical interview and with the Structured Clinical Interview for DSM-IV. Cognitive functioning was assessed using a neuropsychological battery. Univariate and multivariate analyses of variance were conducted for analyzing possible differences between the groups. RESULTS The multivariate analysis of covariance (MANCOVA) indicated overall differences in neuropsychological performance between the three groups (Pillai Spur: F 1.96, p = 0.003). Post hoc comparisons revealed that patients with bipolar I disorder showed significantly lower scores in psychomotor speed, working memory, verbal learning, delayed memory, and executive functions than healthy controls. Patients with bipolar II disorder showed significant deficits in psychomotor speed, working memory, visual/constructional abilities, and executive functions compared to controls, but not on verbal learning and delayed memory. The two patient groups did not differ significantly from each other on any domain tested. CONCLUSION These results support a similar pattern of cognitive deficits in both subtypes of bipolar disorder.

Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients.

The objective of this study was to compare the effects of carbamazepine (CBZ) and valproate (VPA) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders. In this controlled clinical trial, 27 patients with an ICD-10 diagnosis of schizophrenia (N = 24) or schizoaffective disorder (N = 3) were randomly assigned to receive 4 weeks of treatment with either haloperidol alone, haloperidol with CBZ, or haloperidol with VPA. Whereas the haloperidol dose remained stable, the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels. Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale. The use of CBZ was associated with significantly lower haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy. VPA had no significant effect on either plasma levels or on psychopathology. Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure. This might be a result of a pharmacokinetic interaction on the hepatic level. The concomitant use of VPA with neuroleptic therapy is not impaired by clinically significant drug interactions, but it is not associated with a better outcome under our conditions.

Clinical management and burden of bipolar disorder: results from a multinational longitudinal study (WAVE-bd).

Bipolar disorder is a mood disorder which requires complex treatment. Current treatment guidelines are based on the results of published randomized clinical trials and meta-analyses which may not accurately reflect everyday clinical practice. This multi-national, multi-centre, observational cohort study describes clinical management and clinical outcomes related to bipolar disorder in real-life settings, assesses between-country variability and identifies factors associated with clinical outcomes. Adults from 10 countries in Europe and South America who experienced at least one mood episode in the preceding 12 months were included. Overall, 2896 patients were included in the analyses and followed for at least 9 months across a retrospective and prospective study phase. Main outcome measures were the number and incidence rate of mood episodes (relapses and recurrences) and healthcare resource use including pharmacological treatments. Relapses and recurrences were reported in 18.2 and 40.5% of patients, respectively; however, the reported incidence rate of relapses was higher than that of recurrences [1.562 per person-year (95% CI 1.465-1.664) vs. 0.691 per person-year (95% CI 0.657-0.726)]. Medication use was high during all episode types and euthymia; the percentage of patients receiving no medication ranged from 11.0% in mania to 6.1% in euthymia. Antipsychotics were the most commonly prescribed drug class in all disease phases except for patients with depression, where antidepressants were more frequently prescribed. Visits to the psychiatrist were the most frequently used healthcare resource. These results provide a description of treatment patterns for bipolar disorder across different countries and indicate factors related to relapse and recurrence.

Aripiprazole as adjunct to a mood stabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study

The use of atypical antipsychotics (AAPs) for the treatment of unipolar and bipolar depression has been more and more frequently evaluated, and aripiprazole showed positive effects in the treatment of unipolar depression. However, no placebo‐controlled studies of adjunctive aripiprazole for the treatment of bipolar depression have been performed yet.

Differential treatment of bipolar disorder with old and new antiepileptic drugs

Although lithium remains the preferred medication for bipolar disorders, new investigations suggest that only 60 to 80% of patients have a good response with a classical presentation. The antiepileptics carbamazepine and valproate are important alternatives. Several studies have shown that lithium, carbamazepine and valproate are effective in pure mania. Mixed mania and rapid cycling respond, however, well to valproate. One disadvantage of carbamazepine is its enzyme inducing property with the consequence of a decrease of plasma levels of other psychotropic medications and a worsening of psychopathology. First data indicate a good antimanic and antidepressive efficacy of the new antiepileptic drug lamotrigine.

Assessing cerebral dysfunction with probe-evoked potentials in a CNV task -- a study in alcoholics.

OBJECTIVES Contrary to event-related potential (ERP) components N1, N2 and P3, slow ERPs have rarely been used in assessing cerebral dysfunction in mental disorders. Focussing on slow waves (SWs) and on patients with mild cerebral dysfunction, we recorded ERPs in alcoholics using a dual task design. METHODS ERPs to auditory probes presented either 1s before the warning or 1s before the imperative stimulus of a visual contingent negative variation (CNV) paradigm were recorded from 33 scalp electrodes in 27 alcoholics following detoxification and 12 healthy controls. Independent component analysis (ICA) was used to separate potentially overlapping spatial components. RESULTS In alcoholics compared to controls, probe ERPs showed increased N2, decreased P3 and increased negative SWs of two types appearing pre- and post-P3, respectively. Both negative SWs significantly correlated with neuropsychological indices reflecting verbal intelligence and memory functions. The increase in probe-evoked N1 and P3 potentials during CNV, putatively associated with enhanced cortical excitability, significantly correlated with clinical features of protracted alcohol withdrawal syndrome in alcoholics. CONCLUSIONS Our experimental approach revealed two types of negative SWs which strongly correlated with neuropsychological deficits of mildly impaired patients. It is suggested that our methods might enhance diagnostic efficiency of ERPs. An electrophysiological measure of protracted alcohol withdrawal might be useful for managing central nervous system dysfunction in alcoholics.

Effects of (+/-)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats.

Kava pyrones extracted from pepper Piper methysticum are pharmacologically active compounds. Since kava pyrones exhibit anticonvulsive, analgesic and centrally muscle relaxing properties, the influence of a synthetic kava pyrone, (+/-)-kavain, on voltage-dependent ion channel currents was studied. Effects of (+/-)-kavain on voltage-activated inward currents were analysed in cultured dorsal root ganglion cells derived from neonatal rats. Voltage-activated Ca2+ and Na+ currents were elicited in the whole-cell configuration of the patch clamp technique. Extracellularly applied (+/-)-kavain dissolved in hydrous salt solutions reduced voltage-activated Ca2+ and Na+ channel currents within 3-5 min. As the solubility of (+/-)-kavain in hydrous solutions is low, dimethyl sulfoxide (DMSO) was added to the saline as a solvent for the drug in most experiments. When (+/-)-kavain was dissolved in DMSO, the drug induced a fast and pronounced reduction of both Ca2+ and Na+ currents, which partly recovered within 2-5 min even in the presence of the drug. The present study indicates that (+/-)-kavain reduces currents through voltage-activated Na+ and Ca2+ channels.

The Hypomania Checklist-32 and the Mood Disorder Questionnaire as screening tools — going beyond samples of purely mood-disordered patients

BACKGROUND Bipolar disorders are often not recognized. Several screening tools have been developed, e.g., the Hypomania Checklist-32 (HCL-32) and the Mood Disorder Questionnaire (MDQ) to improve this situation. Whereas the German HCL-32 has been used in non-clinical samples, neither the HCL-32 nor the MDQ has been validated in German samples of mood-disordered patients. Additionally, hardly any prior study has included patients with non-mood disorders or has considered potential effects of comorbid conditions. Therefore the goal of this study was to test the validity of both scales in a diverse patient sample while also taking into account psychiatric comorbidity. METHOD A multi-site study was conducted involving seven centers. Patients (n=488) completed the HCL-32 and MDQ and were independently interviewed with the Structured Clinical Interview for DSM (SCID). RESULTS Sensitivity for bipolar I was similar for HCL-32 and MDQ (.88 and .84) but slightly different for bipolar II (.90 and .83), specificity, however, was higher for MDQ. In general, a comorbid condition led to increased scores in both tools regardless of whether the primary diagnosis was bipolar or not. LIMITATIONS AND DISCUSSION: Although we included not just mood-disordered patients, detailed subgroup analyses for all diagnostic categories were not possible due to sample sizes. In summary, HCL-32 and MDQ seem fairly comparable in detecting bipolar disorders although their effectiveness depends on the goal of the screening, psychiatric comorbidity, and potentially the setting.

Efficacy of Quetiapine Monotherapy in Rapid-Cycling Bipolar Disorder in Comparison With Sodium Valproate

Background: Rapid-cycling bipolar disorder is often characterized by a lack of response to psychopharmacological treatment, and a standard therapy has not been developed yet. The aim of this study was to examine the long-term efficacy and safety of a monotherapy with quetiapine or sodium valproate (VPA) in patients with rapid-cycling bipolar disorder. Methods: This open-label, randomized, parallel group monotherapy pilot study was conducted at 3 German centers. A sample of 38 remitted or partly remitted patients with bipolar disorder and rapid cycling (quetiapine n = 22; VPA n = 16) were treated with quetiapine or VPA (flexible dose design) for 12 months. Results: Forty-one percent of the patients with quetiapine and 50% with VPA completed the trial. On the basis of ITT-LOCF, Life Chart Method data showed that patients being treated with quetiapine had significantly less moderate to severe depressive days than patients on VPA (mean ± SD, 11.7 ± 16.9 days vs 27.7 ± 24.9 days; P = 0.04) while they did not differ in the number of days with manic or hypomanic symptoms. Furthermore, according to the Clinical Global Impression Scale, bipolar version, the responder rates tended to be higher for quetiapine than for VPA. There were no differences found evaluating the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Scale, and the Young Mania Rating Scale. The incidence of adverse events, especially of orthostatic dysregulation, sedation, and weight gain, was significantly higher in the quetiapine group. Conclusions: In this study, quetiapine was more effective than VPA on the number of depressive days and similar to VPA in the treatment of manic symptoms. Quetiapine was associated with a greater incidence of side effects, particularly orthostatic dysregulation, sedation, and weight gain.

Effects of substance P and its antagonist L-733060 on long term potentiation in guinea pig hippocampal slices

The neuropeptide substance P (SP) has been suggested to be involved in several physiological and pathological conditions including learning and memory and the processing of pain. This study investigated for the first time acute effects of SP and the neurokinin-1 (NK-1) receptor antagonist L-733060 on long term potentiation (LTP) in the hippocampus. Electrically evoked fEPSP was tested under the influence of SP in the CA1 region of the guinea pig hippocampus. Concentrations of 1 and 10 microM SP increased fEPSP slopes to 114.3+/-4.5% and 115.8+/-2.7%, respectively. A threshold concentration was found at 0.1 microM SP. The SP-specific NK-1 receptor antagonist L-733060 did not influence fEPSP in a concentration of 1 microM. In experiments with LTP, a significant increase of potentiations after 60 min was seen with 1 microM SP. Even if the initial baseline increase due to SP (1 microM) was subtracted, potentiations were bigger compared to controls. L-733060 (1 microM) suppressed the excitatory effects of 1 microM SP nearly complete and subsequent induced LTP was not increased. In conclusion, SP has excitatory effects in the hippocampus and is able to facilitate LTP via activation of the NK-1 receptor.