Saccadic eye velocity after selective GABAergic treatment with tiagabine in healthy volunteers.

BACKGROUND: Saccadic eye velocity (SEV) has been shown to be a reliable neurophysiological tool for the assessment of gamma-aminobutyric acid GABA(A) receptor sensitivity. Administration of benzodiazepines targeting the GABA(A) receptor decreases SEV in healthy volunteers. Tiagabine is a new antiepileptic drug which acts via selective blockade of GABA reuptake. Therefore, we examined the effects of tiagabine on saccade parameters. METHODS: SEV was analyzed in 8 healthy volunteers before and after 7 days of tiagabine treatment. Subjects received tiagabine in a daily dose of 15 mg. Saccades were measured using a noninvasive infrared oculographic device. Amplitude, latency, and SEV were analyzed as a function of treatment and target eccentricity. RESULTS: SEV and saccade latency increased with target amplitude. Treatment with tiagabine had no significant effect on SEV and saccade amplitude. A trend was found for increased latencies after tiagabine. CONCLUSION: In contrast to findings with benzodiazepines, tiagabine treatment had no impact on SEV in healthy volunteers. The subchronic tolerance effects or the different site of action on the GABA(A)/BZD receptor complex may account for this deviating profile.

Genetic variants in the angiotensin I-converting-enzyme (ACE) and angiotensin II receptor (AT1) gene and clinical outcome in depression.

The insertion/(I)/deletion (D) polymorphism of the angiotensin-converting enzyme gene (ACE) is of increasing interest in etiology and treatment of various neuropsychiatric disorders. The present study aimed to replicate own earlier findings that depressive patients with the ACE D-allele are responding better to treatment with antidepressants than those with the II genotype. We further investigated a common polymorphism (A1166C) in the angiotensin II receptor gene (AT1) to examine a possibly combined influence. A sample of 273 patients with major depression, being treated with different classes of antidepressants, was enrolled in the study. Genotyping was carried out using a polymerase chain reaction and snapshot method, respectively, and the severity of depression was monitored using the HAMD-17 scale before and after 4 weeks of treatment. The ACE II genotypes showed poorer improvement in HAMD-17 scale after 4 weeks of treatment (ANOVA: F=4.49, p=0.01) than carriers with one or two D-alleles. Similarly, more than 70% of the AT1 CC homozygotes had a 50% reduction in the HAMD-17 scale within 4 weeks of treatment. Our data might further suggest that patients with a haplotype combining the CC and DD/ID genotypes respond better to treatment than those with either single allele. These results should however be replicated in future research.

The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men.

Angiotensin converting enzyme (ACE) is expressed in the central nervous system (CNS), where its primary function comprises degradation of neuropeptides including substance P (SP). Because of the possible antidepressant effects of SP antagonists, the influence of SP on both pathophysiology and mitigation of depression has been hypothesized. It was shown that ACE plasma concentration is determined by an insertion/deletion (I/D) polymorphism represented by the presence or absence of a 287 bp DNA fragment within the ACE gene. Because the D allele was associated with higher ACE levels this may have a positive impact on the therapeutic efficacy of antidepressant treatment. Thus, variations in CNS expression of ACE might influence the response to various antidepressant therapies. We could show a divergent clinical outcome in relation to different genotypes in 313 depressed patients who were treated with various antidepressants. A lower HAM-D17 score after 4 weeks of treatment in D/D and I/D in comparison to I/I genotypes was detected; the duration of hospitalization was shorter in D allele carriers. The D allele seems to be a predictor for a faster onset of different antidepressant therapies. The patients' gender influences these outcome effects significantly. After subdivision of the patients according to their gender only female patients contributed significantly to the genotype dependent therapeutic outcome. Our investigation gives the first hint that the speed of onset of antidepressant therapies may be dependent on both variants of the ACE genes and the gender of the patients.

Effects of tiagabine on cholecystokinin-tetrapeptide (CCK-4)-induced anxiety in healthy volunteers.

There is increasing evidence that a dysregulation of the gamma-aminobutyric acid (GABA) system plays a role in the pathophysiology of panic disorder. Selective enhancement of GABAergic neurotransmission has been shown to improve anxiety in experimental animals and in patients with panic disorder. Tiagabine is an antiepileptic drug, which increases GABA via selective blockade of GABA reuptake. Apart from its anticonvulsant activity anxiolytic properties could therefore be suggested. To investigate the putative anxiolytic properties of the GABA reuptake blocker tiagabine, we studied the impact of tiagabine treatment on cholecystokinin tetrapeptide (CCK-4)-induced panic. Fifteen healthy volunteers received 15 mg tiagabine daily for 1 week. A CCK-4 challenge was performed before and after treatment. Panic was assessed using the API- and PSS-score. There was a marked improvement of CCK-4-induced panic after 1 week of treatment. Both API- and PSS-scores showed a significant reduction. Our results suggest anxiolytic properties of tiagabine in humans, which provide sufficient rationale to assess its putative anxiolytic effects in patients with panic disorder under controlled conditions.

No Influence of a functional polymorphism within the serotonin transporter gene on partial sleep deprivation in major depression.

Sleep deprivation exerts transient antidepressant efficacy. As a potential mechanism of action an enhancement of serotonergic and dopaminergic neurotransmission within the CNS is discussed. Because genetic variations influencing neurotransmission could have an impact on therapeutic outcome and stability of improvement, we investigated the functional polymorphism of the serotonin transporter (5-HTT) gene, the 5-HTT-linked polymorphic region (5-HTTLPR), to examine the serotonergic pathway. We included 56 patients with major depression (DSM-IV). Psychiatric ratings including the HAM-D21 and HAM-D6 scale were assessed on the day prior to partial sleep deprivation (PSD) and on day 1 and 2 after PSD and related to the different genotypes. The 5-HTTLPR variants were determined following PCR amplification using genomic DNA. 58.1% of the patients were responders to PSD. A significant overall reduction in depression scores could be observed on day 1. Subdivision according 5-HTTLPR gene variants showed no differences in clinical outcome on day 1. As expected the therapeutical effect of PSD was only transient and most patients experienced an exacerbation of depressive symptoms on day 2. 5-HTTLPR variants had no influence on reduction of depressive symptoms on day 2 or relapse on day 3. Thus, the previously reported influence of the serotonin transporter gene on PSD outcome in bipolar depression could not be confirmed in unipolar depressed patients.

Influence of a functional polymorphism within the angiotensin I-converting enzyme gene on partial sleep deprivation in patients with major depression.

Partial sleep deprivation (PSD) exerts transient antidepressant efficacy. As a potential mechanism of action an enhancement of dopaminergic neurotransmission within the CNS is discussed. Because genetic variations influencing neurotransmission could have an impact on therapeutic outcome and stability of improvement, we investigated the functional insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to examine a possible influence on the dopaminergic pathway. We included 56 patients with major depression (DSM-IV). Psychiatric ratings including the HAM-D6 scale were assessed prior to and after PSD and related to the different genotypes. The ACE I/D polymorphism was determined following PCR amplification using genomic DNA. A total of 58.1% of the patients were PSD responders. As expected, the therapeutical effect of PSD was transient and most patients experienced an exacerbation of depressive symptoms on day 2. Subdivision according ACE gene variants showed a significantly less pronounced relapse of symptoms in ACE gene D-allele carriers (P=0.02). Our results give first hints that the ACE I/I genotype, probably influencing dopaminergic neurotransmission, could be an indicator for relapse after PSD. This should result in earlier and more intense additional therapeutic interventions in this group of patients.

Attenuation of hypothalamic-pituitary-adrenocortical hyperactivity in depressed patients by mirtazapine.

RATIONALE: It has been suggested that hypothalamic-pituitary-adrenocortical (HPA) system dysregulation plays an important role in the pathophysiology of depression and that normalization of HPA axis hyperactivity precedes successful treatment with antidepressants. Mirtazapine acts as an antagonist at presynaptic alpha(2)-receptors and at postsynaptic 5-hydroxytryptamine (5-HT)(2), 5-HT(3) and histamine H(1) receptors. It has been shown acutely to inhibit cortisol secretion in healthy subjects. OBJECTIVE: In this study, we investigated whether mirtazapine may downtune HPA axis hyperactivity in depressed patients and whether this is related to treatment outcome. METHODS: Forty patients suffering from a major depressive episode (DSM-IV criteria) were treated with mirtazapine for 5 weeks. The combined dexamethasone suppression/CRH stimulation test (DEX/CRH test) was performed before and after 1 week of mirtazapine treatment (45 mg daily). RESULTS: Mirtazapine effectively reduced the overshoot of cortisol and ACTH during the DEX/CRH test both in treatment responders and non-responders within 1 week. CONCLUSIONS: Apparently, mirtazapine rapidly attenuates HPA axis hyperactivity in depressed patients via direct pharmacoendocrinological effects. However, this amelioration of HPA system dysregulation is not necessarily related to clinical improvement.

Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.

There is evidence for altered levels of neuroactive steroids in major depression that normalize after successful antidepressant pharmacotherapy. Currently it is not known whether this is a general principle of clinically effective antidepressant therapy or a pharmacological effect of antidepressants. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) may affect plasma concentrations of neuroactive steroids in a similar way as antidepressant pharmacotherapy. Progesterone, 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta- tetrahydroprogesterone (3alpha,5beta-THP), 3beta,5alpha-tetrahydroprogesterone (3beta, 5alpha-THP) and dehydroepiandrosterone (DHEA) were quantified in 37 medication-free patients suffering from a major depressive episode before and after 10 sessions of left prefrontal rTMS. Plasma samples were analyzed by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was a significant reduction of depressive symptoms after rTMS. However, plasma concentrations of neuroactive steroids were not affected by rTMS and not related to clinical response. Clinical improvement after extended daily treatment with rTMS is not accompanied by changes in neuroactive steroid levels. Changes in neuroactive steroid levels after antidepressant pharmacotherapy more likely reflect specific pharmacological effects of antidepressant drugs and are not necessary for the amelioration of depressive symptoms.

Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity.

Repetitive transcranial magnetic stimulation (rTMS) has been found to exert modest to substantial antidepressant effects in the majority of prior clinical studies. As effect sizes and stimulation conditions have varied greatly, controversy persists regarding effective stimulation parameters (e.g. intensity, frequency, localization). In the present controlled study, we investigated whether the antidepressant efficacy of rTMS may be related to the stimulation intensity applied. Thirty-one patients suffering from a pharmacotherapy-resistant major depressive episode were randomly assigned to three treatment groups receiving rTMS at different stimulation intensities: (1) intensity at the individual motor threshold (MT); (2) 90% subthreshold intensity; and (3) low intensity of standard sham rTMS. Each patient underwent 10 sessions of 10 Hz rTMS with 1500 stimuli/day over the left dorsolateral prefrontal cortex. Improvement of depressive symptoms after rTMS significantly increased with stimulation intensity across the three groups. A 30% to 33% reduction of baseline depression scores was observed after rTMS at MT intensity. Similarly, groups differed significantly regarding the clinical course after rTMS with the lowest number of antidepressant interventions and the shortest hospital stay in the MT intensity group. These findings support the hypothesis of a relationship between stimulation intensity of rTMS and its antidepressant efficacy.

Hypothalamic-pituitary-adrenocortical axis dysregulation in patients with major depression is influenced by the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene.

The Dex/CRH test is one of the most reliable neuroendocrine function tests for hypothalamic-pituitary-adrenocortical (HPA) system dysregulation in depression. Persistent overdrive of HPA system activity after successful antidepressant treatment predicts an enhanced risk for relapse of a depressive episode. As the renin-angiotensin system has been shown to play a role in HPA system activity, we investigated the impact of the angiotensin converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism, which determines ACE plasma concentrations, on HPA system dysregulation. We performed repeated combined Dex/CRH tests in 115 patients suffering from major depression. Dex/CRH test results were related to the I/D polymorphism within the ACE gene, which was assessed by PCR. Genotype frequencies were comparable to those in the general population (I/I 16.8%, I/D 59.3%, D/D 23.9%). D/D genotypes showed a higher cortisol stimulation during the first Dex/CRH test after admission than homozygous I-allele carriers (repeated measurement ANOVA: P=0.034). Cortisol area under the curve values were highest in those with the D/D genotype (mean+/-SEM [nmol/l*75 min]: 12700+/-2220), intermediate in those with the I/D genotype (9570+/-1000), and lowest in those with the I/I genotype (5160+/-1000; ANOVA: P=0.04). After successful antidepressive treatment and attenuation of HPA system overdrive these differences were no more detectable. The HPA axis stimulating properties of higher ACE and consecutively higher AT-II and/or lower substance P concentrations may be crucial factors for the HPA system hyperactivity during major depressive episodes.