[Therapeutic management of bipolar disorder in France and Europe: a multinational longitudinal study (WAVE-bd)]. / Prise en charge thérapeutique des patients présentant un trouble bipolaire en France et en Europe : étude multinationale longitudinale WAVE-bd.

BACKGROUND: Bipolar disorder is a complex disease which requires multiple healthcare resources and complex medical care programs including pharmacological and non pharmacological treatment. If mood stabilizers remain the corner stone for bipolar disorder treatment, the development of atypical antipsychotics and their use as mood stabilizers has significantly modified therapeutic care. At the present time, psychiatrists have a large variety of psychotropic drugs for bipolar disorder: mood stabilizers, atypical antipsychotics, antidepressants, anxiolytics… However, despite the publication of guidelines on pharmacological treatment, with a high degree of consensus, everyday clinical practices remain heterogeneous. Moreover, there are few longitudinal studies to describe therapeutic management of bipolar disorder, whatever the phase of the disease is. Indeed, most of the studies are carried out on a specific phase of the disease or treatment. And there is no study comparing French and European practices. OBJECTIVES: In this paper, we aim to present the comparison of the management of pharmacological treatments of bipolar disorder between France and Europe, using the data of the observational Wide AmbispectiVE study of the clinical management and burden of bipolar disorder (WAVE-bd study). METHODS: The WAVE-bd study is a multinational, multicentre and non-interventional cohort study of patients diagnosed with BD type I or type II, according to DSM IV-TR criteria, in any phase of the disorder, who have experienced at least one mood event during the 12 months before enrolment. In total, 2507 patients have been included across 8 countries of Europe (480 in France). Data collection was retrospective (from 3 to 12 months), but also prospective (from 9 to 15 months) for a total study length of 12 to 27 months. Main outcome measures were the healthcare resource use and pharmacological treatments. RESULTS: Our results show differences in the therapeutic management of bipolar disorder between France and other European countries. Regarding healthcare resource use, our results show that French patients consult more frequently a psychiatrist or a psychologist and less frequently a general practitioner or the emergency ward in comparison with patients from other European countries. In the whole European population, including France, atypical antipsychotics are widely used. Only 25% of the patients receive lithium and more than 50% of the patients receive antidepressants, while their use in bipolar disorder remains controversial. Most of the patients receive polymedication. Considering all phases of the disease pooled, less lithium and less atypical antipsychotics are prescribed to French patients, whereas they receive more antidepressants and more benzodiazepines than patients from other European countries. On the over hand, prescription of anticonvulsants and electroconvulsive therapy are equal. Moreover, data analyses by polarity of the episodes globally confirm these trends. There are a few exceptions: mixed states, in which lithium is twice more prescribed in France in comparison to other countries; depressive states, in which antidepressants are even more prescribed in other countries than in France; and less prescription of anticonvulsants in manic, mixed and euthymic phases in France. CONCLUSION: The WAVE-bd study is the first observational study conducted on a large sample of bipolar I and II patients that compares therapeutic management between France and other European countries. The differences observed in therapeutic care across the different phases of the disease show that treatments differ depending on the countries studied, but also according to the preventive or curative phases, polarity of the bipolar disorder, comorbidities, impact of guidelines, and care organization. Although French patients have been treated by less lithium and less atypical antipsychotics than other European patients, they receive more antidepressants and more benzodiazepines. Finally, patients generally receive polymedication and the diversity in prescriptions shows how bipolar disorder is a complex disorder.

Short-term prospective comparison of prepulse inhibition between schizophrenic patients and healthy controls.

INTRODUCTION: The prepulse inhibition (PPI) of acoustic startle reflex is impaired in schizophrenic individuals compared to normal controls, and has been suggested to be a biomarker for sensorimotor gating. In fact, some cross-sectional studies suggest a different type of effect on PPI changes depending on the kind of antipsychotic treatment but few prospective studies have been conducted to investigate the short-term course of PPI alterations during the first few weeks of treatment. This study aimed to investigate schizophrenic subjects and controls over 4 weeks to analyze the course of PPI changes between groups at baseline and during follow-up, to determine whether potential PPI alterations are influenced by type of antipsychotic medication and whether these alterations are accompanied by changes in psychopathology. METHODS: 39 schizophrenic patients and 39 controls were enrolled into this open prospective trial. Acoustic startle response (PPI) measurements and clinical (PANSS) performance were obtained shortly after admission and every 14 days for a 4-week follow-up period (T1 to T3). RESULTS: Patients were treated with first and/or second generation antipsychotics in an open-label design. At baseline (T1) significant deficits were detected between schizophrenic subjects and controls for several PPI conditions. Neither was a relationship between type of antipsychotic treatment and PPI measures detected at baseline and during follow-up, nor was any association with PANSS psychopathology found. DISCUSSION: The results of our study confirm previous research on PPI deficits in schizophrenic subjects. As with previous prospective PPI studies in schizophrenic subjects, initial PPI deficits were not observed during the follow-up period, independent of the kind of antipsychotic treatment and severity of psychopathology. These findings may indicate that PPI serves as a biological marker of schizophrenic psychosis and sensorimotor gating independent of type of antipsychotic administered or severity of psychotic symptoms.

[Recovery and remission in schizophrenia. Results from a naturalistic 2-year follow-up inpatient study]. / Recovery und Remission bei Schizophrenie. Ergebnisse einer naturalistischen 2-Jahres-Katamnesestudie ehemals stationärer Patienten.

INTRODUCTION: Remission in schizophrenia is defined as a period of at least 6 months in which symptom reduction occurs. In comparison, the term recovery is defined to include not only long-term symptomatic improvement but also good psychosocial functioning and improved quality of life. The aim of this naturalistic study is to prospectively investigate all these variables and their interrelationship in a sample of subjects with schizophrenia over a period of two years. METHODS: Seventy-seven subjects were included into the analysis. Criteria of remission for each domain were assessed using the BPRS (brief psychiatric rating scale, symptomatic remission), GAF (global assessment of functioning, functional remission) and the SWN-K (subjective well-being under neuroleptics, remission of subjective well-being). Subjects were considered to have "recovered" if they remitted in all three domains at discharge (t0), one (t1) and two-year (t2) follow-up assessments. RESULTS: Symptomatic and functional remissions were rare and occurred only in 10 % of the subjects at t0, t1 and t2. Approximately one-third of the individuals had remission with a stable quality of life. Correlations between quality of life and functional and symptomatic remissions were weak. None of the subjects met the criteria for recovery. CONCLUSION: Compared to previous studies, the rates of remission and recovery in the current sample were quite low. The contrasting results may be due to the naturalistic characteristics of this sample of initially inpatient subjects while previous studies investigated selected samples of schizophrenic individuals. However, despite their functional and symptomatic impairments, the results also indicate that the schizophrenic subjects have a largely satisfying quality of life.

[Psychotropic drug-induced change of weight: a review]. / Gewichtsveränderungen unter Therapie mit Psychopharmaka.

OBJECTIVE: The purpose of this study is to give a systematic review of change of weight associated with commonly used psychotropic drugs. METHODS: Mainly based on a MEDLINE-supported review until April 2005, data from clinical studies with antidepressants, anticonvulsants, mood stabilizers and neuroleptics were scanned for change of weight during treatment. RESULTS: Among antidepressants amitryptiline and nortriptyline have the highest incidence of weight gain followed by imipramine. Maprotiline and mirtazapine have an intermediate weight increasing potential. SSRI (except paroxetine) and MAOI had no or only slight weight inducing effects. In contrary, bupropion was associated with weight reduction. Regarding mood stabilizers and anticonvulsants, a marked gain in weight with lithium and sodium valproate was reported frequently. With gabapentin and vigabatrin a slight to moderate gain in weight was found. Minor changes of weight were found with carbamazepine and lamotrigine. Treatment with topiramate and felbamate reportedly lead to weight loss. The atypical neuroleptics clozapine and olanzapine were frequently related to a strong gain in weight followed by risperidone. Quetiapine has intermediate effects. Stable weight was found with aripiprazole and ziprasidone. A gain in weight is less frequent with older/typical neuroleptics. CONCLUSION: Beside some methodological restrictions like inconsistent information of weight changes (e. g. percent vs. mass) and the small sample of available long term studies, this review specifies the incidence of weight changes for commonly used psychotropic drugs and might be helpful to look for alternatives.

The Inventory of Depressive Symptomatology: German translation and psychometric validation.

The Inventory of Depressive Symptomatology (IDS) is a rating scale for depression, widely used in international multicentre studies. There are two corresponding versions: a self-rated (IDS-SR) and a clinician-rated (IDS-C) scale. The aim of this study was to evaluate the reliability and validity of the German versions of the IDS-SR and IDS-C in comparison to the Hamilton Rating Scale for Depression (HRSD) and to the Beck Depression Inventory (BDI). The sample consisted of 59 inpatients and outpatients treated for unipolar or bipolar disorders. Internal consistency of the IDS-SR and IDS-C was found highly acceptable (alpha = 0.94 and alpha = 0.93). Item-total-correlations of the IDS-SR revealed that 68% of the items were strongly correlated with the sum score (> or =0.50). This was in the same range with the IDS-C (54%), the HRSD (53%) and the BDI (76%). Furthermore, there is a high concurrent validity (r > or = 0.88) of the IDS-SR with the IDS-C, the BDI and the HRSD. Substantial score-differences between inpatients and outpatients indicate a good discriminant validity. It is concluded that the German version of the IDS is a useful instrument for the assessment of depressive symptoms and that it has the same highly acceptable psychometric properties as the original English version.

Mirtazapine increases cortical excitability in healthy controls and epilepsy patients with major depression.

BACKGROUND: Epilepsy is often complicated by depression requiring antidepressant treatment. Such treatment might be proconvulsive. OBJECTIVE: To examine the effects of the noradrenergic and specific serotonergic antidepressant mirtazapine on motor cortex excitability in epilepsy patients with depression and in healthy controls, using transcranial magnetic stimulation (TMS). METHODS: Seven clinically depressed epilepsy patients treated with anticonvulsant drugs and six healthy volunteers were studied. Before intake of mirtazapine and 24 hours afterwards (and also three weeks afterwards in the patients), the active and resting motor threshold (AMT, RMT), the size of the motor evoked potential (MEP), the cortical silent period (SP), and intracortical inhibition/facilitation and intracortical facilitatory I wave interactions were determined using single and paired pulse TMS. RESULTS: At baseline, AMT and RMT were higher (p = 0.049 and p = 0.04, respectively) and the ratio SP duration/MEP area greater in patients (p = 0.041). In patients but not in healthy subjects AMT was lower 24 hours after intake of mirtazapine (p = 0.028). Mirtazapine had no significant effect on the MEP size, duration of the SP, or the ratio of SP duration to MEP size in patients. The duration of the SP was longer (p = 0.037) but the ratio of SP duration to MEP size remained similar in healthy subjects after mirtazapine. There were no significant differences in paired pulse measures between the two groups either at baseline or after mirtazapine. CONCLUSIONS: Mirtazapine increased neuronal excitability of pyramidal tract axons in an activated state in both healthy controls and epilepsy patients with major depression.

Event-related potential correlates selectively reflect cognitive dysfunction in schizophrenics.

UNLABELLED: Schizophrenics show event-related potential (ERP) and particularly P3 abnormalities. To study the more detailed relationships between these ERP alterations and cognitive dysfunction we recorded and analyzed ERPs using a particular experimental approach. In 34 schizophrenics and 25 controls ERPs were obtained by a visual Go/Nogo task requiring response inhibition and were decomposed into temporally independent topographical components using Independent Component Analysis (ICA). ICA disentangled different subcomponents of P3. Subcomponent P3b with a parietal maximum amplitude was significantly reduced in the schizophrenics, probably reflecting their attentional deficits. Subcomponent P3ng with a frontal maximum amplitude and enhanced during Nogo condition appeared as an electrophysiological index of response inhibition. A significantly reduced P3ng enhancement, found in schizophrenics, probably reflects their impaired response control. CONCLUSIONS: ICA can successfully identify ERP subcomponents with distinct scalp topographies representing significant differential indices of normal and abnormal cognitive processing. Involvement of frontal brain areas in disturbed executive control in schizophrenics is supported by our ICA findings.

Epilepsy, psychosis and clozapine.

Six patients with epilepsy and severe psychosis were treated with the atypical antipsychotic clozapine. The use of clozapine might be complicated in epileptic patients because of an increased risk of seizures. However, none of the reported patients had an increase of their seizure frequency, in contrast, three patients had a substantial reduction of seizures. One patient had a reduction of non-epileptic seizures as well. In the second part of this paper, combinations of clozapine with newer and older anticonvulsants as well as their interactions and associated risks are discussed.

Kava pyrones exert effects on neuronal transmission and transmembraneous cation currents similar to established mood stabilizers--a review.

1. Antiepileptic drugs that are successful as mood stabilizers, e.g. carbamazepine, valproate and lamotrigine, exhibit a characteristic pattern of action on ion fluxes. As a common target, they all affect Na+- and Ca2+ inward and K+ outward currents. 2. Furthermore, they have a variety of interactions with the metabolism and receptor occupation of biogenic amines and excitatory and inhibitory amino acids, and, by this, also influence long- term potentiation (LTP) to different degrees. 3. The kava pyrones (+/-)-kavain and dihydromethysticin are constituents of Piper methysticum. Anticonvulsant, analgesic and anxiolytic properties have been described in small open trials. 4. In the studies summarized in this article the effects mainly of (+/-)-kavain were tested on neurotransmission and especially on voltage gated ion channels. It is assumed that effects on ion channels may significantly contribute to clinical efficacy. 5. Experimental paradigms included current and voltage clamp recordings from rat hippocampal CA 1 pyramidal cells and dorsal root ganglia as well as field potential recordings in guinea pig hippocampal slices. 6. The findings suggest that (i) kava pyrones have a weak Na+ antagonistic effect that may contribute to their antiepileptic properties (ii) that they have pronounced L- type Ca2+ channel antagonistic properties and act as an positive modulator of the early K+ outward current. These two actions may be of importance for mood stabilization. (iii) Furthermore, kava pyrones have additive effects with the serotonin-1A agonist ipsapirone probably contributing to their anxiolytic and sleep- inducing effects. (iv) Finally, they show a distinct pattern of action on glutamatergic and GABAergic transmission without affecting LTP. The latter, however, seems not to be true for the spissum extract of Kava where suppression of LTP was observed. 7. In summary, kava pyrones exhibit a profile of cellular actions that shows a large overlap with several mood stabilizers, especially lamotrigine.

Effects of Hypericum perforatum L. on evoked potentials in guinea pig hippocampal slices.

Therapeutic uses of Hypericum extracts have been demonstrated as safe and effective in treating mild to moderate depression in numerous clinical trials. To date, however, no definitive statements on their mode of action can be made, and little information on their electrophysiological effects is available. The present communication summarises the results of our efforts directed towards clarifying the effects of an ethanolic Hypericum extract (HYP) and its hydrosoluble fraction (HYPWS), and two of its constituents hypericin and hyperforin on electrically evoked population spikes in guinea pig hippocampal slices. In higher concentrations (>10 microM), the two extract constituents tested revealed inhibitory effects only, whereas concentration-dependent (between 10(-6) to 10(-4) g/l) excitatory effects were observed for HYP and HYPWS. The excitatory effects were strongly amplified by the GABA(B) antagonist phaclofen, whereas the effects of bicucullin, a GABA(A) antagonist, were marginal. The excitations were completely blocked by the AMPA antagonist CNQX, but not by the NMDA antagonists APV and MK801 or the L-type calcium-channel blocker verapamil. This kind of excitatory effect on the hippocampus is unknown in other antidepressants and; indeed, many of the latter reduce neuronal excitability. We conclude, therefore, that the mechanisms involved in the antidepressant activity of Hypericum extracts are different from those of conventional antidepressants, and that identifying their excitatory components may facilitate their more rational standardisation.

Antimanic efficacy of topiramate in 11 patients in an open trial with an on-off-on design.

BACKGROUND: A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients. METHOD: Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression. RESULTS: Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient. CONCLUSION: The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.

New insights into the mechanisms and sites of action of lamotrigine.

This study was aimed at investigating the effects of lamotrigine (LTG) on electrically evoked field excitatory postsynaptic potentials (fEPSP) and population spikes in the CA1 hippocampal region of guinea pigs. The concentration response curves showed different actions of LTG on fEPSP and on population spikes. The data are in contrast to previous findings that suggest the drug acts primarily on presynaptic sites via a blockade of the release of excitatory amino acids. In the range of therapeutic plasma levels, synaptic transmission was not affected.

Modulation of neural cell membrane conductance by the herbal anxiolytic and antiepileptic drug aswal.

To evaluate the effects of aswal on ionic fluxes and neuronal excitation, we performed extracellular and whole cell patch clamp recordings on CA1 pyramidal neurons of guinea pigs and Long-Evans rats. Aswal (100- 250 mg/l) was administered systemically, and its effects on the rate of synchronized extracellular field potentials (EFP), membrane parameters, action potentials and postsynaptic potentials were recorded. The extracellular results obtained are consistent with calcium antagonistic properties. Intracellular recordings suggest that a direct sodium antagonistic effect as seen in many antiepileptic drugs plays no significant role. Further effects on ligand gated ion channels are discussed controversially. In summary, the cellular action of aswal appears heterogeneous with calcium antagonism playing a prominent role in counteracting excitation which may be a common feature in epilepsy and different psychiatric conditions as mood and anxiety disorder.

Effects of lamotrigine on field potentials and long-term potentiation in guinea pig hippocampal slices.

PURPOSE: To investigate the effects of lamotrigine (LTG), a new anticonvulsant, on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) in guinea pig hippocampal slices. METHODS: Electrically evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) were investigated in the CA1 region of the hippocampus. RESULTS: The concentration-response curves showed different actions of LTG in concentrations near therapeutic plasma levels (10 microM) on fEPSPs and PSs. The initial slopes of fEPSPs were not affected, whereas the amplitudes of PSs were significantly decreased. Higher concentrations of LTG decreased both fEPSP slopes and PS amplitudes; however, the effects on PSs were much stronger. Also, there were no differences in fEPSP slopes or PS amplitudes compared with controls when LTP was induced in the presence of LTG (10 microM). CONCLUSIONS: Our data are in contrast to previous findings that suggest LTG acts primarily on presynaptic sites by blocking the release of excitatory amino acids. Further, LTP was not affected by LTG.

Dysregulation of ion fluxes in bipolar affective disorder.

Bipolar disorder has attracted numerous research from different neurobiological angles. This review will summarize selected findings focusing on the role of disturbed transmem-braneous ion fluxes. Several mood stabilizers exhibit a distinct profile including effects on sodium, calcium and potassium conductance. In summary, some decisive mechanisms of action as calcium antagonism and modulation of potassium currents may play a crucial role in the success of any given mood stabilizer in 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.