Escitalopram dose-response revisited: an alternative psychometric approach to evaluate clinical effects of escitalopram compared to citalopram and placebo in patients with major depression

In continuation of a previous psychometric analysis of dose-response data for citalopram in depression, the corresponding study data for escitalopram is of interest, since escitalopram is the active enantiomer of citalopram and because citalopram was used as the active control. Revisiting those corresponding data, the psychometric properties of the Montgomery-Asberg Depression Scale (MADRS) and the Hamilton Depression Scale (HAMD) were investigated by focusing on the unidimensional HAMD6 and MADRS6. Effect sizes were calculated and compared for two dosages of escitalopram (10 mg and 20 mg daily) and between each of these two dosages and 40 mg citalopram daily. The results showed that the three depression scales MADRS6, MADRS10 and HAMD6 were psychometrically acceptable (coefficient of homogeneity of 0.40 or higher). In the severely depressed patients (MADRS10> or =30) a rather clear dose-response relationship for escitalopram was seen on all three scales after 6 and 8 wk of therapy. Thus, the effect size for 10 mg escitalopram ranged from 0.28 to 0.38 while the effect sizes for 20 mg escitalopram ranged from 0.57 to 0.77. This difference was statistically significant (p<0.01). The effect size for 40 mg citalopram ranged from 0.36 to 0.47, which is within the range found for 40 mg citalopram in our previous dose-response analysis of citalopram after 6 wk of therapy. The numerically largest difference between 20 mg escitalopram and 40 mg citalopram was seen after 8 wk of therapy for MADRS10 (effect size 0.71 vs. 0.37). An item analysis identified 'suicidal thoughts' to be the most discriminating item in this respect. These results for the severely depressed patients were confirmed by the patients self-reported quality of life evaluation. When all included patients were analysed, however, no clear dose-response relationship was seen. In conclusion, a dose-response relationship for escitalopram was seen in the severely depressed patients on all outcome scales after 6 and 8 wk of treatment. After 8 wk of treatment 20 mg escitalopram was superior to 40 mg citalopram, but not after 2 wk of treatment.     

Efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of affective disorders.

Transcranial magnetic stimulation (TMS) is a relatively noninvasive technique to interfere with the function of small cortical areas through currents induced by alternating magnetic fields emanating from a handheld coil placed directly above the targeted area. This technique has clear effects on a whole range of measures of brain function and has become an important research tool in neuropsychiatry. More recently, TMS has been studied in psychiatry mainly to assess its putative therapeutic effects in treatment refractory major depression. Most studies indicate that both low-frequency TMS and higher (20 Hz) frequency repetitive TMS may have some antidepressant properties. However, definite therapeutic effects of clinical significance still remain to be demonstrated.     

Priming stimulation enhances the effectiveness of low-frequency right prefrontal cortex transcranial magnetic stimulation in major depression

OBJECTIVES: Low-frequency, right-sided repetitive transcranial magnetic stimulation (rTMS) to the prefrontal cortex has been shown to have antidepressant effects. Recent research has suggested that preceding low-frequency rTMS with a period of low-intensity, 6-Hz stimulation ("priming") enhances the physiological effects of low-frequency stimulation. The aim of this study was to investigate whether priming stimulation would enhance therapeutic response to low-frequency rTMS in patients with depression. METHOD: The study consisted of a 2-arm, double-blind, randomized, controlled trial in 60 patients with treatment-resistant depression. Right 1-Hz rTMS was provided in one continuous, 15-minute train to all subjects. The priming stimulation (twenty 5-second, 6-Hz trains) or an equivalent, sham preceded 1-Hz stimulation. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: There was a significant overall reduction in MADRS scores across the 4 weeks of the study and a significantly greater reduction in MADRS scores in the active-priming group compared with the sham-priming group. CONCLUSIONS: Low-intensity, high-frequency priming stimulation appears to enhance the response to low-frequency, right-sided rTMS treatment in patients with treatment-resistant depression.     

Insula’s functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving

Rationale

Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking.

Objectives

We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC).

Methods

Overnight-deprived smokers (n?=?24) and nonsmokers (n?=?20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC.

Results

Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI–vmPFC circuit fully mediated this alexithymia–craving relation. That is, elevated alexithymia predicted decreased aI–vmPFC rsFC and, in turn, decreased aI–vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI–vmPFC mediational effect was not observed following drug administration.

Conclusions

These results suggest that a weakened right aI–vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI–vmPFC functional coupling may be relevant factors for smoking cessation success.     

GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression.

Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II+IIIa and PV-IR neurons in layers III-VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression.     

Functional and structural connectivity of the executive control network in college binge drinkers

Binge Drinking (BD) is a pattern of excessive alcohol consumption highly prevalent among college students, and has been associated with structural and functional alterations of brain networks. Recent advances in the resting-state connectivity analysis have boosted the research of the network-level connectivity disturbances associated with many psychiatric and neurological disorders, including addiction. Accordingly, atypical functional connectivity patterns in resting-state networks such as the Executive Control Network (ECN) have been found in substance users and alcohol-dependent individuals. In this study, we assessed for the first time the ECN functional and structural connectivity in a group of 34 college students, 20 (10 women) binge drinkers (BDs) in comparison with a group of 14 (8 women) alcohol abstinent controls (AACs).Overall, our findings documented increased resting-state functional connectivity (rsFC) in the BDs left middle frontal cortex of the left ECN in comparison to the AACs, while no structural connectivity differences were observed between groups. Pearson correlations revealed a positive association between the left middle frontal gyrus rsFC and the frequency of BD episodes per month, in the BD group.These findings suggest that maintaining a pattern of acute and intermittent alcohol consumption during important stages of brain development, as the transition from adolescence to adulthood, is associated with impaired ECN rsFC despite no group differences being yet noticed in the ECN structural connectivity.     

尼莫地平联合高频重复经颅磁刺激治疗皮层下非痴呆型血管性认知障碍的临床疗效研究

目的:探讨尼莫地平联合高频重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)治疗皮层下非痴呆型血管性认知障碍的临床效果.方法:选取2018年6月至2019年6月于长沙市第三医院接受治疗的皮层下非痴呆型血管性认知障碍患者116例,采用随机数字表法分为rTM...     

重复经颅磁刺激联合米氮平治疗首发抑郁症的临床观察

目的探讨重复经颅磁刺激联合米氮平治疗首发抑郁症的疗效及安全性。方法将63例首发抑郁症的患者随机分为治疗组和对照组,治疗组33例,对照组30例。两组均应用米氮平片30mg／d治疗,治疗组在应用米氮平治疗的基础上联合重复经颅磁刺激治疗,刺激左额叶前部背外侧,每周5次,共治疗20次;对照组应用伪刺激线圈,刺激部位、次数、频率同治疗组,有振动声音,但不产生磁场效应。分别于治疗前及治疗后第1、2、4周末应用汉密尔顿抑郁量表（HAMD）、副反应量表（TESS）评价临床疗效和副反应。结果两组均完成治疗,治疗后第2周末两组患者的HAMD评分与治疗前比较,差异有统计学意义（P〈0．05或P〈0．01）;治疗组在治疗第1周末即显示出明显疗效,与对照组比较差异有统计学意义（P〈0．05）。治疗组总有效率（97％）与对照组总有效率（90％）比较,差异有统计学意义（P〈0．05）。两组均未出现明显的副反应。结论重复经颅磁刺激联合米氮平治疗首发抑郁症起效快,能增强抗抑郁效果,耐受性好。     

A double-blind,randomized parallel-group,efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder

S-adenosyl-L-methionine (SAMe) is a natural substance which constitutes the most important methyl donor in transmethylation reactions in the central nervous system. Several clinical trials have shown that SAMe possesses an antidepressant activity. This multicentre study was carried out to confirm both efficacy and safety of SAMe in the treatment of major depression. SAMe was given intramuscularly (i.m.) at a dose of 400 mg/d, double-blind, vs. 150 mg/d oral Imipramine (IMI) in patients with a diagnosis of major depressive episode, with a baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >or=18. A total of 146 patients received SAMe whereas 147 received IMI for a period of 4 wk. The two main efficacy measures were endpoint HAMD score and percentage of responders to Clinical Global Impression (CGI) at week 4. Secondary efficacy measures were the final Montgomery-Asberg Depression Rating Scale (MADRS) scores and the response rate intended as a fall in HAMD scores of at least 50% with respect to baseline. The analysis of safety and tolerability was conducted in all treated patients. SAMe and IMI did not differ significantly on any efficacy measure, either main or secondary. Adverse events were significantly less in patients treated with SAMe compared to those treated with IMI. These data show 400 mg/d i.m. SAMe to be comparable to 150 mg/d oral IMI in terms of antidepressive efficacy, but significantly better tolerated. These findings suggest interesting perspectives for the use of SAMe in depression.     

Mapping Internet gaming disorder using effective connectivity: A spectral dynamic causal modeling study

ObjectsUnderstanding the neural basis underlying Internet gaming disorder (IGD) is essential for the diagnosis and treatment of this type of behavioural addiction. Aberrant resting-state functional connectivity (rsFC) of the default mode network (DMN) has been reported in individuals with IGD. Since rsFC is not a directional analysis, the effective connectivity within the DMN in IGD remains unclear. Here, we employed spectral dynamic causal modeling (spDCM) to explore this issue.MethodsResting state fMRI data were collected from 64 IGD (age: 22.6 ± 2.2) and 63 well-matched recreational Internet game users (RGU, age: 23.1 ± 2.5). Voxel-based mean time series data extracted from the 4 brain regions within the DMN (medial prefrontal cortex, mPFC; posterior cingulate cortex, PCC; bilateral inferior parietal lobule, left IPL/right IPL) of two groups during the resting state were used for the spDCM analysis.ResultsCompared with RGU, IGD showed reduced effective connectivity from the mPFC to the PCC and from the left IPL to the mPFC, with reduced self-connection in the PCC and the left IPL.ConclusionsThe spDCM could distinguish the changes in the functional architecture between two groups more precisely than rsFC. Our findings suggest that the decreased excitatory connectivity from the mPFC to the PCC may be a crucial biomarker for IGD. Future brain-based intervention should pay attention to dysregulation in the IPL-mPFC-PCC circuits.     

Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT''s effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT''s effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, ‘normalized'') the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.     

The Montgomery Äsberg and the Hamilton ratings of depression: A comparison of measures

The 17-item Hamilton Rating Scale for Depression (HRSD₁₇) and the Montgomery Äsberg Depression Rating Scale (MADRS) are two widely used clinician-rated symptom scales. A 6-item version of the HRSD (HRSD₆) was created by Bech to address the psychometric limitations of the HRSD₁₇. The psychometric properties of these measures were compared using classical test theory (CTT) and item response theory (IRT) methods. IRT methods were used to equate total scores on any two scales. Data from two distinctly different outpatient studies of nonpsychotic major depression: a 12-month study of highly treatment-resistant patients (n = 233) and an 8-week acute phase drug treatment trial (n = 985) were used for robustness of results.

MADRS and HRSD₆ items generally contributed more to the measurement of depression than HRSD₁₇ items as shown by higher item-total correlations and higher IRT slope parameters. The MADRS and HRSD₆ were unifactorial while the HRSD₁₇ contained 2 factors. The MADRS showed about twice the precision in estimating depression as either the HRSD₁₇ or HRSD₆ for average severity of depression. An HRSD₁₇ of 7 corresponded to an 8 or 9 on the MADRS and 4 on the HRSD₆.

The MADRS would be superior to the HRSD₁₇ in the conduct of clinical trials.     

Prefrontal neuropsychological predictors of treatment remission in late-life depression.

Recent studies suggest that neuropsychological measures involving the prefrontal cortex are associated with treatment remission in late-life depression. To further explore this issue, we studied the neuropsychological performance of 110 depressed individuals aged 60 years and over who are participating in an ongoing pharmacologic treatment study. Participants were clinically depressed at entry to the study as rated by the Montgomery-Asberg Depression Rating Scale (MADRS > or = 15), at which time they also completed a neuropsychological assessment that included measures of prefrontal/executive functions. A geriatric psychiatrist treating the participant using a standardized pharmacologic treatment algorithm evaluated the participant at baseline and 3-month follow-up, completing a MADRS at both visits. Using logistic discriminative procedures to predict depression remission at 3 months while controlling for age, gender, education, ethnicity, and baseline MADRS severity, we found that perseverative responses during verbal initiation tasks significantly predicted remission status (MADRS < 7). This finding is consistent with previous single-agent treatment studies suggesting a relationship between prefrontal neuropsychological function and treatment response in late-life depression. The current results, however, appear to differentiate verbal perseveration from verbal initiation as the cognitive process that is most associated with poor treatment response. By extension, we suggest that orbitofrontal prefrontal cortex may play a role in sustaining perseverative processing in geriatric depression.     

Recent placebo-controlled acute trials in bipolar depression: focus on methodology

The completion of three recent large-scale, double-blind controlled acute trials in bipolar I depression has improved our understanding of the management of major depressive episodes associated with bipolar disorder. In contrast to the cross-over designs used in the early studies of lithium in bipolar depression, the designs utilized in these recent studies have employed random assignment to parallel arms including the use of placebo as a monotherapy in one study. The analyses of recent studies have all been conducted on intent-to-treat data, and included two types, change from baseline analyses and responder analyses. Lamotrigine monotherapy was shown to be superior to placebo with both types of analyses on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions (CGI) scales, but not the 17-item Hamilton Depression Rating Scale (HAMD) (n=195). The percentage of patients responding to placebo as a monotherapy were 29, 26 and 37%, respectively; there were no differences in switch rates (5% vs. 5%). Paroxetine augmentation was no better than placebo augmentation overall with both types analyses on the CGI and HAMD (n=117); the MADRS was not used. In patients with lithium levels < or =0.8 mequiv./l, the change from baseline analysis showed paroxetine to be superior to placebo, but responder analyses were negative; switch rates with paroxetine, imipramine, and placebo were 0, 8 and 2%. Moclobemide monotherapy was similar in efficacy to imipramine (n=156), but had a lower rate of switching (4% vs. 11%).     

Accelerated brain aging predicts impulsivity and symptom severity in depression

Multiple structural and functional neuroimaging measures vary over the course of the lifespan and can be used to predict chronological age. Accelerated brain aging, as quantified by deviations in the MRI-based predicted age with respect to chronological age, is associated with risk for neurodegenerative conditions, bipolar disorder, and mortality. Whether age-related changes in resting-state functional connectivity are accelerated in major depressive disorder (MDD) is unknown, and, if so, it is unclear if these changes contribute to specific cognitive weaknesses that often occur in MDD. Here, we delineated age-related functional connectivity changes in a large sample of normal control subjects and tested whether brain aging is accelerated in MDD. Furthermore, we tested whether accelerated brain aging predicts individual differences in cognitive function. We trained a support vector regression model predicting age using resting-state functional connectivity in 710 healthy adults aged 18–89. We applied this model trained on normal aging subjects to a sample of actively depressed MDD participants (n = 109). The difference between predicted brain age and chronological age was 2.11 years greater (p = 0.015) in MDD patients compared to control participants. An older MDD brain age was significantly associated with increased impulsivity and, in males, increased depressive severity. Unexpectedly, accelerated brain aging was also associated with increased placebo response in a sham-controlled trial of high-frequency repetitive transcranial magnetic stimulation targeting the dorsomedial prefrontal cortex. Our results indicate that MDD is associated with accelerated brain aging, and that accelerated aging is selectively associated with greater impulsivity and depression severity.Subject terms: Depression, Cognitive ageing     

Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C

BACKGROUND: Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established. AIM: To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication. METHODS: Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher's exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1-18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate. CONCLUSION: This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.     

Monitoring the response to rTMS in depression with visual analog scales

Visual analog scales (VAS) administered on a daily basis provide a fast and reliable method for assessing clinical change during transcranial magnetic stimulation (TMS). We treated 40 patients with major depression with TMS and assessed their clinical condition with VAS. Response to TMS was defined with the Hamilton rating scale for depression and the Global assessment of function scale. Nineteen patients of 40 were responders to TMS (when the whole sample was considered) whereas 17 of 29 responded when only the non-psychotic patients were considered. Patients who eventually responded to TMS demonstrated early changes in the VAS scores. We conclude that monitoring with VAS scores can detect early response to TMS.     

Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials

Objective: Selegiline transdermal system (STS) is efficacious for the treatment of major depressive disorder (MDD). This meta-analysis explores treatment effects of STS for individual symptoms of MDD derived from line-item analyses of the 28-item Hamilton Rating Scale for Depression (HAM-D28) and the Montgomery-Asberg Depression Rating Scale (MADRS). Methods: Change in score from baseline to end of treatment for each item of the HAM-D28 and MADRS was assessed using a multilevel model for meta-analysis of continuous outcome data from all five short-term, randomized, placebo-controlled efficacy trials conducted during preapproval clinical development of STS for MDD. Utilizing a random-effects model with trial effects fixed and adjusting for baseline scores, confidence intervals (95%) were computed for treatment differences between STS and placebo. Results: STS exhibited significant treatment effects on core depression symptoms (HAM-D Bech-6 items: depressed mood, guilt, work and activities, retardation, psychic anxiety, general somatic symptoms), reverse vegetative symptoms (oversleeping, overeating), motoric retardation, suicide, and genital symptoms (libido). Significant STS treatment effects were also noted for each MADRS item except for reduced sleep and appetite. The most prominent MADRS effects were improvement in sadness, lassitude, and poor concentration. Conclusions: STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.     

Modulation of frequency and duration of repetitive magnetic stimulation affects catecholamine levels and tyrosine hydroxylase activity in human neuroblastoma cells: implication for the antidepressant effect of rTMS

Transcranial magnetic stimulation (TMS), which is produced by strong non-static magnetic fields, is a non-invasive means to stimulate the cerebral cortex. Studies from recent years show that TMS affects mood in healthy subjects and improves depressive symptoms in patients with major depression. However, the relationship between the clinical efficacy of TMS and stimulation parameters is still obscure. In the present study we have investigated the effects of different stimulation frequencies and number of treatments on catecholamine turnover in SH-SY5Y cell cultures. A single session of magnetic stimulation (1.7 T) caused a significant decrease in intracellular dopamine and L-DOPA and in noradrenaline (NE) release at a rate of 3 Hz for 10 s but increased NE release at a rate of 9 Hz. These alterations were associated with a reduction (47.8%) or an increase (48%) in tyrosine hydroxylase (TH) activity after 3 and 9 Hz magnetic stimulation, respectively. The latter may be related to the known sensitivity of TH to neuronal firing rates and NE concentrations. Higher stimulation frequencies (15, 20, 45 Hz) had no effect on catecholamine metabolism. Unlike 3 Hz acute treatment, chronic treatment (3 Hz, 11 sessions, for 4 d) had no effect on monoamines and TH activity was increased by 54.5% with no change in its protein level. The results of the present study demonstrate that in tissue culture system frequency and treatment duration of the magnetic stimulation are important factors in affecting catecholamine turnover. Considering the major role of catecholamine in the pathophysiology of depression, these findings may be of relevance to the application of rTMS in humans with major depression.     

ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity

The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.