Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects.

BACKGROUND: Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism. METHOD: Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed. RESULTS: A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum. CONCLUSIONS: Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

Bilateral bispectral index monitoring during and after electroconvulsive therapy compared with magnetic seizure therapy for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective and established treatment for depression. Magnetic seizure therapy (MST) has recently been developed and seems equally effective while associated with fewer side-effects. Both require general anaesthesia, which could be quantified using the bispectral index (BIS). We compared ECT and MST with respect to recovery times, left-sided BIS, and left-right differences in BIS. METHODS: In this prospective, observational study, we enrolled 10 successive patients receiving ECT and 10 patients undergoing MST. Anaesthesia was performed with propofol and monitored with a bilateral BIS sensor. The seizure was elicited when the BIS was within a range from 50 to 60. The time to eye opening was measured and bilateral BIS were recorded for 10 min after seizure induction. RESULTS: A comparable anaesthetic depth was observed in the ECT and MST groups at baseline [mean (standard deviation, sd) BIS values of 94.1 (4.1) and 95.5 (3.0), respectively] and before seizure induction [mean (sd) BIS values of 52.3 (9.6) and 55.2 (10.3), respectively]. Post-ictally, MST patients opened their eyes significantly earlier than ECT patients [3.0 (1.0) vs 6.7 (1.3) min, P<0.001]. They showed a significantly higher BIS at 2 min after seizure induction [69.2 (10.1) vs 50.9 (15.9), P=0.003], and this difference was still present at 10 min after seizure induction [BIS 81.5 (6.5) vs 68.0 (16.4), P<0.001]. Significant differences between the left and right BIS were observed in neither the ECT nor the MST group. CONCLUSIONS: At a comparable anaesthetic depth, MST is superior to ECT in terms of post-ictal recovery, which is correctly reflected by higher post-ictal BIS values. Unilateral BIS monitoring is sufficient to monitor anaesthetic depth in ECT and MST patients. TRIAL REGISTRY NUMBER: NCT 01318018.

Deep brain stimulation for major depression.

A third of patients suffering from major depression cannot be helped by conventional treatment methods. These patients face reduced quality of life, high risk of suicide, and little hope of recovery. Deep brain stimulation (DBS) is under scientific evaluation as a new treatment option for these treatment-resistant patients. First clinical studies with small samples have been stimulated at the subgenual cingulate gyrus (Cg25/24), the anterior limb of the capsula interna (ALIC), and the nucleus accumbens (NAcc). Long-term antidepressant effects, augmentation of social functioning, and normalization of brain metabolism have been shown in about 50% of patients. Cognitive safety regarding attention, learning, and memory has been reported. Adverse events were wound infection, suicide, and hypomania, amongst others. Larger studies are under way to confirm these preliminary encouraging results. New hypothesis-guided targets (e.g., medial forebrain bundle, habenula) are about to be assessed in clinical trials. The application of DBS for other psychiatric diseases (e.g., bipolar disorder, alcohol dependency, opioid addiction, schizophrenia) is debated and single case studies are under way. Standards are needed for study registration, target selection, patient inclusion and monitoring, and publication of results to guarantee safety for the patients and scientific exchange.

Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response.

BACKGROUND: Selective serotonin reuptake inhibitors take several weeks to achieve their full antidepressant effects. Post-synaptic 5-HT2A receptor activation is thought to be involved in this delayed therapeutic effect. Pipamperone acts as a highly selective 5-HT2A/D4 antagonist when administered in low doses. The purpose of this study was to compare citalopram 40 mg once daily plus pipamperone 5 mg twice daily (PipCit) versus citalopram plus placebo twice daily for magnitude and onset of therapeutic effect. METHOD: An 8-week, randomized, double-blind study in patients with major depressive disorder was carried out. RESULTS: The study population comprised 165 patients (citalopram and placebo, n=82; PipCit, n=83) with a mean baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 32.6 (s.d.=5.5). In the first 4 weeks, more citalopram and placebo than PipCit patients discontinued treatment (18% v. 4%, respectively, p=0.003). PipCit patients had significantly greater improvement in MADRS score at week 1 [observed cases (OC), p=0.021; last observation carried forward (LOCF), p=0.007] and week 4 (LOCF, p=0.025) but not at week 8 compared with citalopram and placebo patients. Significant differences in MADRS scores favoured PipCit in reduced sleep, reduced appetite, concentration difficulties and pessimistic thoughts. Mean Clinical Global Impression-Improvement scores were significantly improved after 1 week of PipCit compared with citalopram and placebo (OC and LOCF, p=0.002). CONCLUSIONS: Although the MADRS score from baseline to 8 weeks did not differ between groups, PipCit provided superior antidepressant effects and fewer discontinuations compared with citalopram and placebo during the first 4 weeks of treatment, especially in the first week.

Clinical milestones predict symptom remission over 6-month and choice of treatment of patients with major depressive disorder (MDD).

BACKGROUND: It is uncertain as to what short-term outcomes predict long-term treatment compliance and outcomes in patients with MDD. AIMS: To determine what treatment milestones predict symptom remission with long-term treatment with antidepressant medication. METHOD: Pooled analysis of four randomised, double-blind, active comparator, 6-month trials in MDD. RESULTS: Patients received double-blind treatment with escitalopram (N=699) or a comparator (citalopram, duloxetine, or paroxetine) (N=699). Onset of effect at week 2 was correlated with response at week 8, and response at week 8 with completion of 6-month treatment. Week 8 response was associated with a greater probability of achieving later remission. Week 24 remission (MADRS>or=10) was significantly (p<0.01) higher for patients treated with escitalopram (70.7%) than for the pooled comparators (64.7%). Week 24 complete remission (MADRS

Vagus nerve stimulation for depression: efficacy and safety in a European study.

BACKGROUND: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS: VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

Pattern of regional cerebral blood-flow changes induced by acute heroin administration--a perfusion MRI study.

PURPOSE: Although both the subjective and physiological effects of abused psychotropic substances have been characterized, less is known about their effects on brain function. We examined the actions of intravenous diacetylmorphine (heroin), the most widely abused opioid, on regional cerebral blood flow (rCBF), as assessed by perfusion-weighted MR imaging (PWI) in a double-blind and placebo-controlled setting. MATERIAL AND METHODS: Eight male subjects dependent of diacetylmorphine (mean age 36 years, range: 26 to 44 years), who had participated in a clinical diacetylmorphine maintenance program, underwent PWI with gadolinium injection. At two sessions separated by 2-7 days, the participants were examined 80 s after intravenous administration of either diacetylmorphine or saline. rCBF in four regions of interest (amygdala, vermis of the cerebellum, anterior cingulated cortex and thalamus) was compared with heroin versus placebo. RESULTS: In the cerebellum, thalamus and cingulated cortex, there were no significant differences in perfusion values between diacetylmorphine and placebo. In the amygdala, perfusion values were 0.8+/-0.4 and 0.5+/-0.2 on the left, and 0.9+/-0.4 and 0.6+/-0.3 on the right, with diacetylmorphine and with placebo, respectively (t-test results were P=0.044 and P=0.033 on the left and right sides, respectively). Other differences in perfusion values between the drug and placebo did not reach statistical significance. CONCLUSION: Perfusion MRI demonstrated differences in brain hemodynamics induced by drug intake.

Transcranial magnetic stimulation for treating depression.

BACKGROUND: Transcranial magnetic stimulation can either excite or inhibit cortical areas of the brain, depending on whether the speed of the repetitive stimulation is applied at high or low frequencies. It has been used for physiological studies and it has also been proposed as a treatment for depression. OBJECTIVES: To assess the clinical efficacy and safety of transcranial magnetic stimulation for treating depression. SEARCH STRATEGY: An electronic search was performed including the Cochrane Collaboration Depression, Neurosis and Anxiety Review Group trials register (last searched June, 2001), the Cochrane Controlled Trials Register (Issue 2, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), PsycLIT (1980-2001), and bibliographies from reviewed articles. Unpublished data and grey literature were searched through personal communications with researchers. SELECTION CRITERIA: Randomised controlled trials assessing the therapeutic efficacy and safety of transcranial magnetic stimulation for depression. DATA COLLECTION AND ANALYSIS: All reviewers independently extracted the information and verified it by cross-checking. Disagreements were resolved through discussion. Continuous data: When similar studies were grouped, the overall standardised mean difference was calculated under a fixed effect model weighted by the inverse variance method with 95% confidence intervals. (In the presence of statistical heterogeneity, a random effects model was to be used.) MAIN RESULTS: Sixteen trials were included in the review and fourteen contained data in a suitable form for quantitative analysis. Most comparisons did not show differences between rTMS and other interventions. No difference was seen between rTMS and sham TMS using the Beck Depression Inventory or the Hamilton Depression Rating Scale, except for one time period (after two weeks of treatment) for left dorsolateral prefrontal cortex and high frequency; and also for right dorsolateral prefrontal cortex and low frequency, both in favour of rTMS and both using the Hamilton scale. Comparison of rTMS (left dorsolateral prefrontal cortex and high frequency) with electroconvulsive therapy showed no difference except for psychotic patients after two weeks treatment, using the Hamilton scale, which indicated that electroconvulsive therapy was more effective than rTMS. REVIEWER'S CONCLUSIONS: The information in this review suggests that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit.

Hemispheric asymmetry in visuospatial attention assessed with transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) was used to study visuospatial attention processing in ten healthy volunteers. In a forced choice recognition task the subjects were confronted with two symbols simultaneously presented during 120 ms at random positions, one in the left and the other in the right visual field. The subject had to identify the presented pattern out of four possible combinations and to press the corresponding response key within 2 s. Double-pulse TMS (dTMS) with a 100-ms interstimulus interval (ISI) and an intensity of 80% of the stimulator output (corresponding to 110-120% of the motor threshold) was applied by a non-focal coil over the right or left posterior parietal cortex (PPC, corresponding to P3/P4 of the international 10-20 system) at different time intervals after onset of the visual stimulus (starting at 120 ms, 270 ms and 520 ms). Double-pulse TMS over the right PPC starting at 270 ms led to a significant increase in percentage of errors in the contralateral, left visual field (median: 23% with TMS vs 13% without TMS, P=0.0025). TMS applied earlier or later showed no effect. Furthermore, no significant increase in contra- or ipsilateral percentage of errors was found when the left parietal cortex was stimulated with the same timing. These data indicate that: (1) parietal influence on visuospatial attention is mainly controlled by the right lobe since the same stimulation over the left parietal cortex had no significant effect, and (2) there is a vulnerable time window to disturb this cortical process, since dTMS had a significant effect on the percentage of errors in the contralateral visual hemifield only when applied 270 ms after visual stimulus presentation.

Cerebral blood flow in obsessive-compulsive patients with major depression: effect of treatment with sertraline or desipramine on treatment responders and non-responders.

We examined the effects of sertraline and of desipramine on patients with OCD and comorbid major depressive episodes at study entry. Sixteen patients, 9 receiving sertraline and 7 desipramine, received HMPAO SPECT scans while free of medication and after 12 weeks of treatment. Patients on sertraline showed significantly reduced regional cerebral blood flow (rCBF) in the right prefrontal and temporal regions. Patients on desipramine showed more diffuse rCBF reductions in frontal and temporal regions, more so in the left side. In a second analysis, patients who had a symptom reduction on the Yale-Brown Obsessive Compulsive Scale (YBOCS), irrespective of the type of medication, were retrospectively classified as 'responders' to treatment. Eleven patients were 'responders' and 5 'non-responders'. Before being medicated, responders differed from non-responders through higher rCBF in prefrontal regions, mostly on the left, and higher rCBF in the cingulate and basal ganglia bilaterally. After 12 weeks of treatment, responders showed a diffuse reduction of rCBF in prefrontal regions while non-responders showed only a few scattered low-frequency responses. Thus, higher prefrontal and subcortical activity was associated with better response to drug treatment. In addition, clinical change, but not the administration of medication as such, was associated with a decrease of prefrontal rCBF.

Double-pulse transcranial magnetic stimulation over the frontal eye field facilitates triggering of memory-guided saccades.

The study investigated the influence of double-pulse transcranial magnetic stimulation (dTMS) on memory-guided saccade triggering. Double pulses with interstimulus intervals (ISIs) of 35, 50, 65 or 80 ms were applied over the right frontal eye field (FEF) and as control over the occipital cortex. A significant dTMS effect was found exclusively for contralateral saccades; latency of memory-guided saccades was reduced after FEF stimulation with an ISI of 50 ms compared to latency without stimulation. This effect proved to be specific for the ISI of 50 ms over the FEF because control stimulation with the same ISI over the occipital cortex had no significant effect on latency of memory-guided saccades. The results of our study showed that, by using an appropriate ISI, dTMS is able to facilitate contralateral saccade triggering by stimulating the FEF. This suggests that TMS interferes specifically with saccade triggering mechanisms, probably by acting on presaccadic neurons of the FEF.

High frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral cortex: EEG topography during waking and subsequent sleep.

Repetitive transcranial magnetic stimulation (rTMS) is a novel research tool in neurology and psychiatry. It is currently being evaluated as a conceivable alternative to electroconvulsive therapy for the treatment of mood disorders. Eight healthy young (age range 21-25 years) right-handed men without sleep complaints participated in the study. Two sessions at a 1-week interval, each consisting of an adaptation night (sham stimulation) and an experimental night (rTMS in the left dorsolateral prefrontal cortex or sham stimulation; crossover design), were scheduled. In each subject, 40 trains of 2-s duration of rTMS (inter-train interval 28 s) were applied at a frequency of 20 Hz (i.e. 1600 pulses per session) and at an intensity of 90% of the motor threshold. Stimulations were scheduled 80 min before lights off. The waking EEG was recorded for 10-min intervals approximately 30 min prior to and after the 20-min stimulations, and polysomnographic recordings were obtained during the subsequent sleep episode (23.00-07.00 h). The power spectra of two referential derivations, as well as of bipolar derivations along the antero-posterior axis over the left and right hemispheres, were analyzed. rTMS induced a small reduction of sleep stage 1 (in min and percentage of total sleep time) over the whole night and a small enhancement of sleep stage 4 during the first non-REM sleep episode. Other sleep variables were not affected. rTMS of the left dorsolateral cortex did not alter the topography of EEG power spectra in waking following stimulation, in the all-night sleep EEG, or during the first non-REM sleep episode. Our results indicate that a single session of rTMS using parameters like those used in depression treatment protocols has no detectable side effects with respect to sleep in young healthy males.

Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers.

This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.

Repetitive transcranial magnetic stimulation activates specific regions in rat brain.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique to induce electric currents in the brain. Although rTMS is being evaluated as a possible alternative to electroconvulsive therapy for the treatment of refractory depression, little is known about the pattern of activation induced in the brain by rTMS. We have compared immediate early gene expression in rat brain after rTMS and electroconvulsive stimulation, a well-established animal model for electroconvulsive therapy. Our result shows that rTMS applied in conditions effective in animal models of depression induces different patterns of immediate-early gene expression than does electroconvulsive stimulation. In particular, rTMS evokes strong neural responses in the paraventricular nucleus of the thalamus (PVT) and in other regions involved in the regulation of circadian rhythms. The response in PVT is independent of the orientation of the stimulation probe relative to the head. Part of this response is likely because of direct activation, as repetitive magnetic stimulation also activates PVT neurons in brain slices.

SPECT brain blood flow changes with continuous ligand infusion during previously learned WCST performance.

Performance of the Wisconsin Card Sorting Test (WCST) and related brain-activation patterns reflect both task learning and execution. Normal subjects learned the WCST prior to performance during slow SPECT ligand infusion. Blood flow increased in bilateral inferior frontal, right middle and inferior parietal cortices. Activity decreased in hippocampi, temporal cortex, anterior cingulate and caudate.

Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects.

OBJECTIVE: Humans experience the subjective effects of mu and kappa opioid agonists differently: mu agonists produce mainly euphoria, while kappa agonists are more likely to produce dysphoria. This study tested the hypothesis that these subjective effects would be associated with anatomically distinct changes in regional cerebral blood flow (CBF) relative to baseline as assessed with single photon emission computed tomography (SPECT). METHOD: Nine nondependent opioid abusers participated in the study. In the first phase of the study, the participants were acclimated to effects of the study drugs. In the second phase they underwent repeat challenges with the study drugs followed by an assessment of CBF with use of the SPECT tracer [99mTc]HMPAO. Medications tested were the prototypic mu agonist hydromorphone, the mixed agonist/antagonist butorphanol (which has a kappa agonist component of activity), and saline placebo. RESULTS: Subjective effects of the drugs were distinctly different. Hydromorphone produced increased ratings of "good effects," while butorphanol led to more "bad effects." Hydromorphone significantly increased regional CBF in the anterior cingulate cortex, both amygdalae, and the thalamus--all structures belonging to the limbic system. Butorphanol caused a less distinct picture of regional CBF increases, mainly in the area of both temporal lobes. CONCLUSIONS: This study demonstrates that opioids with different subjective effects also produce statistically significant patterns of change in regional CBF from baseline, and the regions of statistical significance appear in different brain regions. In addition, these results demonstrate the applicability of SPECT functional neuroimaging in the study of medications with potential abuse liability.

Self-reported somatization symptoms associated with risk for extreme alcohol use.

BACKGROUND: The high rates of alcohol use in the population, the increased general health care utilization associated with untreated alcohol problems, and the often diffuse nature of somatization symptoms led us to hypothesize that somatization symptoms might be associated with alcohol use. OBJECTIVE: To determine whether a relationship exists between somatization symptoms and alcohol use. DESIGN: Multivariable logistic regression models were used to analyze existing cross-sectional and 1-year longitudinal survey data from the National Institute of Mental Health Epidemiologic Catchment Area Program. SETTING: Community households. SUBJECTS: Probability sample. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalent and incident heavy or binge drinking ("extreme alcohol use"). These measures are part of the National Institute of Mental Health Epidemiologic Catchment Area Program public core data set that was collected without regard for specific hypotheses. RESULTS: After control for sex, age, and education, 13 self-reported somatization symptoms showed independent cross-sectional associations to prevalent extreme alcohol use. The greater the number of somatization symptoms, the greater the risk, up to a maximum increased odds ratio of 138 to 1, of having comorbid extreme alcohol use when reporting all 13 somatization symptoms in the model. A smaller set of items was associated with the risk for subsequent new onset of extreme alcohol use. CONCLUSIONS: Self-reported somatization symptoms could add to the detection of extreme alcohol use. In addition, primary care and other physicians should consider somatic complaints as possible indicators of concurrent and future risk for extreme alcohol use. Potential benefits of better detection of extreme alcohol use include supporting primary and secondary prevention efforts and reduced expenditures for the diagnostic workup of somatic complaints.

Onset and recovery from panic disorder in the Baltimore Epidemiologic Catchment Area follow-up.

BACKGROUND: The objective is to estimate parameters of the natural history of panic disorder, including its prodrome, incidence, recovery and recurrence. METHOD: In 1981 the Baltimore Epidemiologic Catchment Area Study interviewed 3481 individuals probabilistically selected from the household population. During 1993-1996, 1920 of these individuals (73% of survivors) were interviewed again. Baseline and follow-up interviews included the National Institute of Mental Health Diagnostic Interview Schedule. During the follow-up, a subsample was assessed by psychiatrists using the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry (SCAN). RESULTS: There were 35 new cases of panic disorder in 24,475 person years of exposure, yielding an annual incidence of 1.43 per 1000 per year. Data from the SCAN assessments suggest the incidence estimate is conservative. Incidence is greater in females and declines with age. About one-third of the new cases arise without agoraphobia, but about half have anxiety of some sort present for many years prior to meeting criteria for diagnosis. People with agoraphobia have less intense onsets but slower recoveries than those without agoraphobia. CONCLUSIONS: Panic is heterogeneous in its pattern of onset and recovery. Some of the heterogeneity is associated with the presence of other anxiety over a long period of the life.