Quetiapine as combination treatment with citalopram in unipolar depression with prominent somatic symptoms: a randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Patients with major depressive disorder (MDD) accompanied by physical symptoms may be less responsive to antidepressant treatment. Quetiapine has been evaluated in the treatment of bipolar depression and has been recently approved as an add-on therapy for unipolar depression. Less is known about the efficacy of combination therapies in patients suffering from MDD with somatic symptoms. The aim of the present study was to evaluate the efficacy of quetiapine as adjunctive therapy to the SSRI citalopram in patients with MDD and somatic complaints. SUBJECTS AND METHODS: 41 inpatients with nonpsychotic DSM-IV MDD experiencing significant symptoms of somatic distress as defined by a baseline score on the SCL-90-R somatization subscale greater one standard deviation above adult nonpatient norms were randomly assigned to receive either citalopram 40 mg/day plus placebo (n=20) or citalopram 40 mg/day plus quetiapine, 300 to 600 mg/day (n=21) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. RESULTS: Mean changes in HDRS scores from baseline to week 6 using last-observation-carried-forward methods were -12.3±6.2 and -10.7±5.1 in the citalopram-quetiapine and citalopram-placebo group, respectively. Remission rates were significant higher in the citalopram-quetiapine-group (41.1%) than in the citalopram-placebo-group (26.3%), respectively. CONCLUSIONS: Although quetiapine as add-on to citalopram did not separate statistically from placebo on the HDRS score in improving depressive symptoms and somatic symptoms in patients with MDD and prominent somatic complaints, higher remission rates and other second outcome parameters showed advantages for quetiapine. Larger, double-blind, placebo-controlled trials of quetiapine as augmentation therapy in MDD with somatic symptoms are warranted.

Stimulus pulse-frequency-dependent efficacy and cognitive adverse effects of ultrabrief-pulse electroconvulsive therapy in patients with major depression.

BACKGROUND: : Electroconvulsive therapy (ECT) is a highly effective treatment for major depression. New ECT devices with shorter pulse widths seem to induce seizures more effectively at a lower seizure threshold and with fewer cognitive adverse effects. Suprathreshold right unilateral (RUL) ultrabrief-pulse ECT with pulse widths between 0.25 and 0.30 millisecond seem to be especially effective with regard to efficacy and cognitive adverse effects. A lower pulse frequency (50 pulses per second) in RUL ECT was found to be more efficient than a higher pulse frequency (200 pulses per second) in inducing seizures. However, effective stimulus dose can often be achieved only with high stimulus frequency, whereas the impact of increased stimulus frequency on antidepressant efficacy and cognitive adverse effects is not known. METHODS: : Forty patients with major depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were randomly assigned to 2 groups of 20 patients each and stimulated with either 40 or 100 Hz with equal initial stimulus doses in 9 sessions of suprathreshold RUL ultrabrief-pulse ECT. Depressive symptoms and measures of verbal and working memory were assessed for both groups. RESULTS: : Patients in the 40-Hz condition showed significantly more improvement in Hamilton Rating Scale for Depression scores compared with patients in the 100-Hz condition after 9 ECT sessions. Frequency group had no significant impact on measures of verbal and working memory. CONCLUSIONS: : Within the discussed limitations, our preliminary data suggest an advantage for administering stimulus dose in suprathreshold RUL ultrabrief-pulse ECT with a lower stimulus frequency (40 Hz) as compared with a higher frequency (100 Hz). Further studies are needed to assess whether increasing pulse widths or frequency is the better option for augmenting stimulus dose once other stimulus parameters are at a maximum.

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

OBJECTIVE: 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. METHODS: In this prospective, double-blind, placebo-controlled, randomized trial, 23 inpatients with bipolar depression according to DSM-IV criteria were included. Before randomization, patients had to be on a constant mood stabilizer treatment with lithium or valproate for at least 1 week. After inclusion, all patients were openly treated with additional citalopram and with additional aripiprazole or placebo for 6 weeks. The primary outcome parameter was the reduction in depressive symptoms according to the Hamilton Depression Rating Scale (HDRS) within 6 weeks. RESULTS: After 6 weeks of treatment, the HDRS score decreased in both groups. There was no significant difference between both the groups at any point of time with respect to the HDRS. CONCLUSIONS: Derived from this small pilot study, adjunctive aripiprazole does not seem to be a promising strategy for the acute treatment of bipolar depression. However, this lack of additional benefit seems to stem from the already good effectiveness of the control group, namely the treatment with citalopram.

Endogenous tetrahydroisoquinolines associated with Parkinson's disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines.

N-methyl-norsalsolinol and related tetrahydroisoquinolines accumulate in the nigrostriatal system of the human brain and are increased in the cerebrospinal fluid of patients with Parkinson's disease. We show here that 6,7-dihydroxylated tetrahydroisoquinolines such as N-methyl-norsalsolinol inhibit tyrosine hydroxylase, the key enzyme in dopamine synthesis, by imitating the mechanisms of catecholamine feedback regulation. Docked into a model of the enzyme's active site, 6,7-dihydroxylated tetrahydroisoquinolines were ligated directly to the iron in the catalytic center, occupying the same position as the catecholamine inhibitor dopamine. In this position, the ligands competed with the essential tetrahydropterin cofactor for access to the active site. Electron paramagnetic resonance spectroscopy revealed that, like dopamine, 6,7-dihydroxylated tetrahydroisoquinolines rapidly convert the catalytic iron to a ferric (inactive) state. Catecholamine binding increases the thermal stability of tyrosine hydroxylase and improves its resistance to proteolysis. We observed a similar effect after incubation with N-methyl-norsalsolinol or norsalsolinol. Following an initial rapid decline in tyrosine hydroxylation, the residual activity remained stable for 5 h at 37 degrees C. Phosphorylation by protein kinase A facilitates the release of bound catecholamines and is the most prominent mechanism of tyrosine hydroxylase reactivation. Protein kinase A also fully restored enzyme activity after incubation with N-methyl-norsalsolinol, demonstrating that tyrosine hydroxylase inhibition by 6,7-dihydroxylated tetrahydroisoquinolines mimics all essential aspects of catecholamine end-product regulation. Increased levels of N-methyl-norsalsolinol and related tetrahydroisoquinolines are therefore likely to accelerate dopamine depletion in Parkinson's disease.

Positive predictors for antidepressive response to prefrontal repetitive transcranial magnetic stimulation (rTMS).

Repetitive transcranial magnetic stimulation (rTMS) is a brain stimulation technique which had recently been investigated as a putative antidepressant intervention. However, there is little agreement about clinically useful predictors of rTMS outcome. Therefore, the objective of the present study was to determine whether specific biographical, clinical, and psychopathological parameters are associated with the antidepressant response to rTMS in a large sample of 70 depressive patients. We performed a logistic regression analysis in 70 patients with major depressive disorder treated with rTMS of the left dorsolateral prefrontal cortex testing the predictive value of various domains of the depression syndrome as well as the variables episode duration, degree of treatment resistance, and CORE criteria. Response was defined as a 50% reduction of the initial Hamilton score (HAMD). After two weeks of treatment, 21% of the patients showed a response to rTMS. The binary logistic regression model correctly assigned 86.7% of the responders and 96.4% of the non-responders to their final response group. In the model, a high level of sleep disturbances was a significant predictor for treatment response to rTMS. Also, a low score of treatment resistance and a short duration of episode were positive predictors. These findings provide new evidence that especially pronounced sleep disturbances may be a significant clinical predictor of a response to rTMS. Prospective rTMS studies are necessary to validate the predictive value of the derived model.

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression.

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.

Region-specific glutamate changes in patients with unipolar depression.

The present study aimed to investigate glutamate concentrations in patients with unipolar depression in the midcingulate cortex (MCC) as compared to the left dorsolateral prefrontal cortex (DLPFC). We hypothesized a dissociation of glutamate levels with unchanged levels in DLPFC and abnormally changed levels in MCC as well as differential effects of antidepressant pharmacotherapy. Glutamate was determined using magnetic resonance spectroscopy at 3 T in DLPFC and MCC in fourteen depressed patients and matched healthy volunteers. A follow-up measurement was performed after 4 weeks of antidepressant treatment. The main finding is a region-specific pattern of glutamate concentrations with increased MCC glutamate concentrations and no significant differences in DLPFC glutamate concentrations in unipolar depressive patients compared to healthy controls. Response and non-response to antidepressant pharmacotherapy were predicted by high glutamate at baseline in DLPFC and MCC, respectively. In addition, treatment responders showed a further increase in DLPFC glutamate levels after successful antidepressant treatment. Findings indicate altered region-specific glutamate concentrations in DLPFC and MCC that are predictive of response and non-response, respectively, to antidepressant pharmacotherapy. These findings might serve as a starting point for future studies in which the value of this metabolite pattern for treatment response prediction should be investigated.

Abnormal cingulate and prefrontal cortical neurochemistry in major depression after electroconvulsive therapy.

BACKGROUND: Metabolic changes after electroconvulsive therapy (ECT) have been described in depressed patients, but results are heterogeneous. To determine the concentrations of N-acetyl-aspartate (NAA), choline-containing compounds, creatine + phosphocreatine (tCr), and glutamate in the left dorsolateral prefrontal cortex (DLPFC) and left anterior cingulum of depressed patients before and after ECT, we used proton magnetic resonance spectroscopy. METHODS: Metabolite concentrations in the DLPFC and anterior cingulum were determined in 25 patients with major depressive disorder (MDD) and 27 healthy control subjects using the point resolved spectroscopy sequence. Neuropsychological and clinical parameters were determined before and after nine sessions of right unilateral ultrabrief pulse ECT. RESULTS: In the cingulum, baseline glutamate and NAA levels were decreased in depressed patients. High glutamate at baseline predicted a greater treatment response. After ECT, increased NAA levels were observed in responders to treatment and tCr levels were significantly decreased across all depressive patients. In the left DLPFC, NAA levels were significantly decreased in responders to ECT compared with nonresponders. Autobiographic memory was deteriorated in all patients after ECT. CONCLUSIONS: Low glutamatergic state in depressive patients emphasizes the role of dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD. The low NAA level at baseline in the patients supports neurodegenerative changes in MDD. N-acetyl-aspartate levels might serve as early surrogate marker for dynamic metabolic changes due to ECT, reflecting both neuroprotection and lowered neuronal viability. The tCr decrease in the cingulum suggests altered mitochondrial energy metabolism.

Effects of 3 different stimulus intensities of ultrabrief stimuli in right unilateral electroconvulsive therapy in major depression: a randomized, double-blind pilot study.

OBJECTIVE: Efficacy and cognitive outcome of ECT is depending on electrode placement, pulse width and electrical dosage. Several studies showed that high-dosage right unilateral ECT (RULECT) had a better antidepressant effects than low-dosage RULECT and less cognitive side effect than bilateral stimulation. In this prospective, randomized, double-blind trial, we examined the efficacy and cognitive side effects of RULECT with three different (high dose) stimulus intensities (4×, 7× and 10× above the seizure threshold (ST)). METHODS: 41 patients with treatment resistant unipolar or bipolar depression were randomized to one of the three stimulation intensities. For stimulation, we used an ultrabrief pulse (0.3 ms). Primary outcome measures were reduction of the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI) and the response rate (50% reduction of the HDRS) in the three groups. For cognitive side effects, a neuropsychological test battery was assessed. RESULTS: All three groups responded significantly to 9 ECTs (p < 0.005), but there were no statistical significant differences in the response rates between the three intensity groups. Besides of the Verbal Learning Memory Recognition Test (VLMT), which showed significant impairments in the high dose intensity groups, no differences could be shown between the three study groups in all neuropsychological tests. CONCLUSION: A RULECT with ultrabrief pulse stimulation and 4× ST intensity is effective and from good tolerability. Higher intensity dosages seem to be associated with more cognitive side effects during a course of acute ECT treatment.

Evidence of specificity of a visual P3 amplitude modulation deficit in schizophrenia.

BACKGROUND: In a previous study, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients compared with healthy controls during inhibition in the Attention Network Test (ANT). The objective of the present study was to replicate this finding and to explore whether this cortical processing deficit is specific to schizophrenia. METHODS: Sixteen schizophrenic patients, sixteen depressive patients, and sixteen healthy controls matched for age, sex, and education were included. Participants were tested with the ANT, a test of selective attention that provides behavioral estimates for alerting, orienting, and inhibition. 32-Channel electroencephalogram was recorded and visual P3 amplitudes were topographically analyzed and compared between groups. RESULTS: There were no significant behavioral between-group differences in terms of mean reaction time, accuracy, and ANT effects alerting, orienting, and inhibition. Absolute visual P3 amplitude was not reduced in schizophrenia or depression. P3 amplitude modulation was defined as P3 amplitude at Pz as a function of ANT flanker conditions. We found a parietal P3 amplitude modulation deficit in schizophrenic patients (-.015) that was absent in both healthy controls (-.705; p = .002) and depressive patients (-1.022; p = .001). CONCLUSION: The results provide evidence that a deficit of visual P3 amplitude modulation distinguishes schizophrenia from healthy and disease controls and provides greater discriminative power than absolute visual P3 amplitude.

Motor cortical excitability in depressive patients after electroconvulsive therapy and repetitive transcranial magnetic stimulation.

Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques that are used as therapeutic interventions in major depression. However, the exact therapeutic mode of action needs further clarification. In this case report, we describe the impact of these stimulation techniques on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 2 patients who received consecutively both rTMS and ECT. Both patients showed a decrease in motor cortical excitability after response to antidepressant brain stimulation, whereas parameters of motor cortical excitability remained unchanged after the first non-successful intervention. These results suggest that both ECT and rTMS may have an impact on parameters of motor cortical neuronal excitability. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of different antidepressant stimulation techniques.

Modification of tyrosine hydroxylase activity by chloral derived beta-carbolines in vitro.

Beta-carbolines have been suggested to be involved in the pathogenesis of Parkinson's disease as a result of their structural similarity to the neurotoxin N -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The chloral-derived beta-carboline derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) causes cell loss in neuronal and glial cell cultures and induces a slowly developing neurodegenerative process in rats. In our experiments, effects of TaClo and its derivatives 2-methyl-TaClo (2-Me-TaClo), and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2) -THbetaC) on tyrosine hydroxylase (TH) activity were investigated in TH assays using homogenate preparations of the rat nucleus accumbens and recombinant human TH (hTH1). TH activity was determined in vitro by measuring l-DOPA production with HPLC-ECD. Using homogenate preparations, TaClo, 2-Me-TaClo, and 1-CCl(2) -THbetaC inhibited TH in concentrations of 0.1 mm, while 1-CCl(2) -THbetaC in low concentrations enhanced TH activity. When TH was activated by PACAP-27, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC also inhibited activated enzyme activity in high concentrations. However, in the case of 2-Me-TaClo and 1-CCl(2) -THbetaC a biphasic effect was observed with a marked increase of TH activity in the nanomolar range. In our experiments using recombinant hTH1, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC did not modify enzyme activity. After activation of hTH1 by PKA all the tetrahydro-beta-carbolines investigated in this study decreased l-DOPA formation. We suggest that these beta-carbolines modulate dopamine synthesis by interacting with a protein kinase TH-activating system.