Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) over the left temporo-parietal region has been proposed as a treatment for resistant auditory verbal hallucinations (AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology. METHOD: Twenty-seven patients with schizophrenia and medication-resistant AVH participated to a randomized, double-blind, placebo-controlled, add-on rTMS study. The stimulation targeted a language-perception area individually determined using functional magnetic resonance imaging and a language recognition task. AVH were assessed using the hallucination subscale of the Scale for the Assessment of Positive Symptoms (SAPS). The spatial location of AVH was assessed using the Psychotic Symptom Rating Scales. RESULTS: A significant improvement in SAPS hallucination subscale score was observed in both actively treated and placebo-treated groups with no difference between both modalities. Patients with external AVH were significantly more improved than patients with internal AVH, with both modalities. CONCLUSIONS: A marked placebo effect of rTMS was observed in patients with resistant AVH. Patients with prominent external AVH may be more likely to benefit from both active and placebo interventions. Cortical effects related to non-magnetic stimulation of the auditory cortex are suggested.

Balneotherapy Together with a Psychoeducation Program for Benzodiazepine Withdrawal: A Feasibility Study.

Benzodiazepines should be prescribed on a short-term basis, but a significant proportion of patients (%) use them for more than 6 months, constituting a serious public health issue. Indeed, few strategies are effective in helping patients to discontinue long-term benzodiazepine treatments. The aim of this study was to assess the feasibility and the impact of a program including cognitive behavioural therapy, psychoeducation, and balneotherapy in a spa resort to facilitate long-term discontinuation of benzodiazepines. We conducted a prospective multicentre cohort study. Patients with long-term benzodiazepine use were recruited with the aim of anxiolytic withdrawal by means of a psychoeducational program and daily balneotherapy during 3 weeks. The primary efficacy outcome measure was benzodiazepine use 6 months after the program, compared to use at baseline. A total of 70 subjects were enrolled. At 6 months, overall benzodiazepine intake had decreased by 75.3%, with 41.4% of patients completely stopping benzodiazepine use. The results also suggest a significantly greater improvement in anxiety and depression symptoms among patients who discontinued benzodiazepines compared to patients who only reduced their use. Our findings suggest that balneotherapy in association with a psychoeducative program is efficient in subjects with benzodiazepine addiction.

Resilience and corpus callosum microstructure in adolescence.

BACKGROUND: Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. METHOD: Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. RESULTS: Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. CONCLUSION: High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

[Switch antidepressants: when? How? Why?]. / Changer d'antidépresseur: quand, comment, pourquoi?

BACKGROUND: The switch is generally admitted as one of the available options in the event of non-response to an antidepressant treatment, despite uncertainties about its implementation in current practice: what time window before switching? Is it necessary to proceed with a direct or with a gradual switch? Is it necessary to change for a different pharmacotherapeutic class? How to minimize interaction risks? If a treatment fails because of poor compliance due to intolerance, it is possible to remain within the same therapeutic class and select another treatment with a more favourable safety profile for the patient. In the remaining non-response cases, changing therapeutic class is the more logical course and may be slightly more efficacious than the switch within the same class. LITERATURE FINDINGS: A review of the literature shows that it is recommended to wait 4 to 8 weeks before changing treatment if the response is insufficient. However, an early switch is possible in case of non-response at 2-4 weeks. Direct switch is possible and well tolerated in most instances, except for situations implicating a monoamine oxidase inhibitor (MAOI) or a tricyclic antidepressant. Direct switch is easy and, therefore, compliance issues associated with the complexity of treatment tapering can be avoided. DISCUSSION: From the pharmacologic standpoint, the lack of effect on the cytochrome P450 isoenzymes, the absence of active metabolites, and the poor binding to plasmatic proteins are all important elements to be identified in order to minimize the risk of interaction. Current research on physiopathology of depression and mechanisms of action of drugs both support expectations for new perspectives for patients' care. The switch increases the chances for a treatment to be successful with response rates of 20 to 70% in the open-labelled clinical studies. It also has the advantage of minimizing adverse effects compared to polytherapy. CONCLUSION: A great number of depressed patients require more than one treatment protocol to obtain or maintain a response. Switching is part of the therapeutic pattern of depression and is recommended by the French authorities. The available data allow the specification of switch modalities as function of the evolution of the initial treatment.

Effects of lithium on saccadic eye movements in healthy subjects in a ten-day double-blind placebo-controlled cross-over pilot study.

INTRODUCTION: Although previous studies have shown that lithium modifies eye movements or psychomotor speed, no studies have ever explored the predictive saccades or memory guided saccades during lithium administration. We took the objective to determine the influence of lithium in pseudo-random, predictive or memory-guided saccades in healthy subjects with a view to detect reduced psychomotor speed, inability to anticipate incoming events, or working memory deficits. METHODS: A ten day lithium-placebo randomized double-blind cross-over pilot study was carried out with 12 healthy male volunteers. The cognitive assessment included pseudo-random, predictive and memory guided saccades before and after lithium and placebo periods. A biological assay substantiated the lithium effect on TSH and thyroid hormones. RESULTS: There was no change in pseudo-random or memory guided saccades when comparing lithium or placebo administration. However the ratio of anticipated saccades decreased under the lithium sequence while it remained stable under placebo. Also, subjects having lithium serum levels of > 0.5 meq/l had longer latencies in anticipated saccades. CONCLUSION: The findings do not support a major effect of lithium on alertness or on working memory, although the dosage and duration of lithium was sufficient to modify TSH blood level. Nevertheless, lithium treatment was associated with decreased anticipation in predictive saccades, suggesting this could reflect a reduced ability to anticipate quick motor movements and could be related to the well-known effect of lithium as an anti-impulsive medication.

Antidepressant efficacy and cognitive effects of repetitive transcranial magnetic stimulation in vascular depression: an open trial.

BACKGROUND: Beneficial effects of repetitive transcranial magnetic stimulation (rTMS) were demonstrated by many controlled studies in major depression. Moreover, this promising and non invasive therapeutic tool seems to be better tolerated than electroconvulsive therapy.Vascular depression is a subtype of late-life depression, associated with cerebrovascular disease and means a poorer response to antidepressant treatment. We employed rTMS over the left prefrontal cortex in 11 patients with late-onset resistant vascular depression. The primary purpose of this two-week open study was to examine antidepressant efficacy of rTMS in vascular depression. The secondary aim was to evaluate cognitive effects of rTMS in our sample. METHODS: Clinical status, as measured with the Hamilton Depression Rating Scale (HDRS), and cognitive effects, as evaluated by neuropsychological tests, were assessed at baseline and after two weeks of rTMS. Brain measurements to obtain an index of prefrontal atrophy were performed at both the motor cortex and prefrontal cortex. RESULTS: Five out of 11 resistant patients with late-onset vascular depression were responders. They showed a clinically meaningful improvement in HDRS scores, with a decrease of 11, 4 points (p<0.01). Antidepressant response is correlated to the relative degree of prefrontal atrophy (p = 0.05). After two weeks, verbal fluency and visuospatial memory improved. No cognitive performance deteriorated except for verbal memory, as the delayed recall decreased significantly in the responders' group. CONCLUSIONS: Our preliminary observations prompt to perform a subsequent controlled study to examine if rTMS may constitute an alternative to electroconvulsive therapy.

Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers.

OBJECTIVE: The principal objective was to compare the effects of milnacipran, an antidepressant characterized by a dual-action on serotonin and noradrenaline reuptake, with placebo on memory, attention and psychomotor performance in healthy volunteers. The secondary objective was to evaluate the effects of milnacipran on mood, anxiety and vigilance in these subjects. METHODS: In a double-blind crossover randomized trial, milnacipran (50 mg b.d.) or placebo was administered during two periods of 7 days separated by a washout period of 7 days. Memory tests (recall of words, images and coloured bars), tests to evaluate attention and vigilance (squares test, critical flicker fusion test and choice reaction time test) and visual analogue scales for affect and sleep were used. RESULTS: There were no significant differences between milnacipran and placebo groups with respect to the psychomotor functions tested. No differences were observed in the Norris scales for vigilance, anxiety or satisfaction or in the sleep questionnaire (sleep latency, sleep quality and waking). CONCLUSION: Milnacipran, administered at 100 mg per day for 7 days to healthy volunteers, had no effects on cognitive functions.

Evolution of plasma homovanillic acid (HVA) levels during treatment in schizo-affective disorder.

1. Plasma Homovanillic Acid (p HVA) levels were measured by HPLC (high performance liquid chromatography) in 5 schizo-affective depressed patients receiving a standardized treatment. (lithium, chlorpromazine and clomipramine) during 4 weeks. 2. Four patients were pretreated, without a washout period. 3. No significant difference was observed between patients and normal controls at baseline. Under treatment, pHVA levels increased (p<0.02) with clinical improvement (MADRS and PANSS scores). 4. Although effects of medications prior to the study period were not controlled, these findings suggest that depressed schizo-affective patients may have normal pHVA levels that increase with clinical improvement, unlike schizophrenic patients whose increased pHVA concentrations decline with neuroleptic treatment.

Evolution of plasma homovanillic acid (HVA) in chronic schizophrenic patients treated with haloperidol.

In a 4-week study of 14 drug-free schizophrenic patients (according to DSM-III-R), free and conjugated fractions of plasma homovanillic acid (pHVA) were repeatedly measured. Free HVA levels decreased during the first 2 h of haloperidol intake (P < 0.03). Conjugated HVA levels slowly decreased during the following weeks (P < 0.05), while free HVA levels remained stable. After 4 weeks, free HVA levels remained unchanged 2 h after morning haloperidol intake, but conjugated HVA levels tended to increase. In haloperidol responders, at baseline the free/total HVA ratio was significantly higher than that in non-responders (P < 0.01). Tolerant patients, i.e. those whose post-treatment free HVA levels decreased below pre-treatment levels, were not found to respond better to haloperidol than non-tolerant patients. The balance between free and conjugated pHVA may be a better reflection of the action of haloperidol than free pHVA levels and it may be of prognostic value in terms of drug response.

New statistical proposals to evaluate the benefit/risk ratio of long-term treatment of depression: application to a one-year double-blind study comparing medifoxamine with fluoxetine.

The aim of this study was to determine the benefit/risk ratio of long-term treatment with medifoxamine, a non-tricyclic, non-monoamine oxidase inhibitor agent, and fluoxetine in patients with acute depressive episode and at high risk of relapse and/or recurrence. The study involved a 12-month double-blind, randomised, parallel-group design with a multicentric trial setting conducted by 64 participating physicians. 155 and 158 patients of either gender, aged between 18 and 70 years, were allocated to fluoxetine and medifoxamine, respectively. All patients had an acute depressive episode defined by the presence of at least five of the DSM III-R criteria with a minimal score of 25 on the Montgomery and Asberg Depression Rating Scale (MADRS). All subjects had at least one previous documented depressive episode in their medical history. The main outcome criterion consisted of good therapeutic response defined by a sustained 50% reduction of the Clinical Global Impression (CGI) score combined with the absence of any serious or troublesome (i.e. intensity motivating study discontinuation) events. In the fluoxetine and medifoxamine groups, respectively, 45.2% and 43% of the randomised patients completed the 12-month follow-up period with no major differences between groups regarding the reasons for treatment withdrawal. With each treatment 58% of the patients reached at least a 50% decrease in their CGI score, with no differences on the evolution of the MADRS, Hamilton Anxiety Rating Scale (HARS), the Self Rating Depression Scale of Zung (Zung scale) and Scott depression visual analogue scale (VAS) scores on average. According to the main efficacy criterion, 26% of the patients in the fluoxetine group were considered as responders compared with 36% in the medifoxamine group (p = 0.047). When only serious adverse effects were considered in combination with CGI scores to define response rates, the respective percentages were in favour of medifoxamine but the difference (45 vs 53%) was not significant. Results with medifoxamine were better in the elderly whereas, with fluoxetine, best responses were observed in younger patients. In conclusion, medifoxamine was an active and well tolerated drug in the continuation and maintenance treatment of depression. Its benefit/risk ratio appeared to be superior to fluoxetine, but this difference was mainly based on the occurrence of less minor adverse effects, a potential advantage not sufficient to favour better compliance with long-term therapy. Nevertheless, efficacy and tolerance of medifoxamine merits further evaluation in specific elderly populations.

[Meta-process paraphrenia in manic-depressive disorder]. / Une paraphrénie méta-processus d'une maladie maniaco-dépressive.

A typical case report exemplifies existing links between paraphrenia and affective disorders. Kraepelin noted similarities between paraphrenia and manic-depressive illness, particularly between mania and paraphrenia confabulans. Thereafter, the German school has insisted on similarities of symptoms and course of the two entities. The French school, on the contrary, has insisted on the instrumental role of affective disorder in the development of paraphrenia: paraphrenia is considered as a potential evolution of primary psychotic disorders. If cases of post-schizophrenic paraphrenia have been reported, the development of paraphrenia on a background of bipolar disorder seems rarer. Such a case is presented and discussed, supporting the concept and its mechanisms as illustrated by French psychiatrists.

Differences in the natural autoantibody patterns of patients with schizophrenia and normal individuals.

The expression of IgG and IgM autoantibodies directed against various autoantigens, either part of the central nervous system or not, was investigated in the sera of inpatients with schizophrenia (n = 10). An enzyme immunoassay was used to measure the levels of these autoantibodies in whole sera, IgG-depleted sera, and isolated IgG fractions. IgG and IgM antibodies, reacting with all the antigens tested, were present in the sera of patients with schizophrenia as well as in the sera of normal individuals. Among patients suffering from schizophrenia, IgM natural autoantibody reactivities could be higher (myoglobin, serotonin, tubulin), lower (dopamine), or even identical to those of normal individuals, depending on whether whole or fractionated sera were assayed and on the group of patients with schizophrenia (responders and nonresponders) considered. The isolated IgG fractions of patients suffering from schizophrenia had higher anti-DNA and antiserotonin reactivities than those detected in normal individuals.