Safety was confirmed in a small trial of 6 patients with biochemical recurrence after primary therapy.24 Early phase I trials included using rV-PSA in men with biochemical recurrence after local therapy and in men with nodal or bone metastasis.25 Thirty-three men were

divided into 4 groups. All groups received 3 vaccinations at 4-week intervals. Group 1 (n = 6) received rV-PSA at 2.65 × 106 plaque-forming unit (pfu) with each vaccination, group 2 (n = 6) received 2.65 × 107 pfu, group 3 (n = 11) received 2.65 × 108 pfu, and group 4 (n = 10) was treated with 2.65 × 108 pfu + 250 μg/m2 GM-CSF in each vaccination. Inhibitors,research,lifescience,medical The rV-PSA was well tolerated. Disease stabilization, defined as a PSA level 80% below to 50% above Inhibitors,research,lifescience,medical baseline, occurred for greater than 6 months in 14 of 33 patients, with 6 patients (2 from group 3 and 4 from group 4) remaining progression free at 11 to 21 months after treatment. see more Enzyme-linked immunosorbent spot tests were performed on 7 patients, and 5 developed PSA-specific T-cell populations. The greatest increase in these T cells was seen after the first vaccination, with little subsequent response. This suggests

that repeated doses of rV-PSA were ineffective, possibly owing to the immune response against the vaccinia virus itself. In an attempt to circumvent this Inhibitors,research,lifescience,medical issue, a heterologous prime/boost approach was devised. Fowlpox virus will infect but will not replicate in mammalian cells and can transduce gene expression Inhibitors,research,lifescience,medical in infected cells for a longer period than vaccinia virus. Additionally, the lack of replication produces less immune response to the virus, allowing for

repeated vaccinations with Inhibitors,research,lifescience,medical the same agent. Thus, recombinant fowlpox virus expressing PSA was generated (rF-PSA) and used in an Eastern Cooperative Oncology Group phase II trial in men with biochemically recurrent prostate cancer.26 Sixty-four patients with no evidence of metastatic disease were randomized to 1 of 3 arms: group 1 (n = 23) received 4 rF-PSA injections, group 2 (n = 20) received 3 rF-PSA vaccinations followed by an rV-PSA second vaccination, and group 3 (n = 21) received 1 rV-PSA vaccination followed by 3 rF-PSA vaccinations. Of the 64 patients, 29 (45%) were free of biochemical progression (defined as a PSA level more than 50% above baseline) 2 years after treatment. Median time to PSA progression among the 3 arms was 13.6 months, with a trend toward prolonged time to PSA progression in Group 3. This suggests that the regimen used in group 3, using a prime/boost approach, was an improvement over rV-PSA alone. The next advancement of the vaccine model was the addition of virally expressed T-cell costimulatory molecules.

It should be pointed out that in spite of being a hypertensive patient, her blood pressure, monitored daily, stayed within the normal range of 130 mmHg/70 mmHg. Biochemical parameters, creatinine, liver function laboratory

tests, TSH and EKG showed no changes with the combined treatment. Lithaemia was 0.66 mEq/L at the sixth week. No adverse effects were reported Inhibitors,research,lifescience,medical with the exception of dry mouth and moderate constipation, both well tolerated by the patient. Discussion The combination of high doses of both selleck compound clomipramine [Gervasoni et al. 2009] and mirtazapine achieved a high level of synergy, acting at pharmacodynamic level through triple serotoninergic enhancement (reuptake inhibition by clomipramine, alpha-2 and 5-HT2 antagonistic effects of mirtazapine) and dual noradrenergic enhancement

(reuptake inhibition by clomipramine and its active metabolite desmethylclomipramine, antagonistic alpha-2 effect of mirtazapine). In addition, blockage of the 5-HT2 and 5-HT3 receptors achieved Inhibitors,research,lifescience,medical with mirtazapine can help to reduce the serotoninergic sexual (5-HT2) and digestive (5-HT3) adverse effects of clomipramine. It is also known that sustained 5-HT2 blockage improves sleep and increases the gene expression of the 5-HT1A receptor (synergy between 5-HT2 antagonism and 5-HT1A stimulation) [Ruiz-Doblado Inhibitors,research,lifescience,medical et al. 2010]. In addition, both clomipramine and mirtazapine were considered two of the most effective antidepressant drugs in a recent review of the evidence [Montgomery et al. 2007]. Furthermore, lithium enhancement has a stabilizing effect on membranes and also Inhibitors,research,lifescience,medical on sodium cellular transportation, as well as the upregulation of gene expression associated with neurotransmission Inhibitors,research,lifescience,medical via second messengers (phosphatidylinositol). Finally, partial rapid eye movement sleep deprivation, during

the second half of the night, can enhance pharmacological effect. Although its efficacy is known at the empirical level, the mechanism of action of its antidepressant effect remains unclear. Nowadays there are ‘cleaner’ combinations in treatment algorithms for resistant melancholia, such as those associating venlafaxine or duloxetine (both dual 5-HT-NA Rolziracetam antidepressants) with a second antidepressant or mood regulator [Hannan et al. 2007; De la Gándara et al. 2008; Yazici, 2009], but some works have shown that the noradrenergic effect of these new drugs may be inferior to that of clomipramine, which achieves a powerful noradrenaline reuptake inhibition due to both the drug itself and its metabolite (clomipramine + desmethylclomipramine) [Gillman, 2007]. According to our current state of knowledge, this is the first documented case of response to this combination of drugs in resistant melancholia at these doses.

In a voxel-wise analysis, Qiu et al found widespread age effects on FA across the cerebellum, temporal, frontal, and parietal lobes.47 Additionally, they found that reading scores (in Chinese and English) were associated with higher FA in a number of PXD101 regions. Lebel et al found that the developmental trajectory of measures of anisotropy and diffusivity across most tracts were best fit with an

exponential curve Inhibitors,research,lifescience,medical (Figure 2). 48 Echoing structural studies above, they found the last tracts to mature were frontotemporal connections. In one of the largest brain imaging studies to date, Kochunov et al detailed how 11 major tracts change over the lifespan (age 11 to 90) in 831 subjects.49 By charting the FA of these tracts across their subject pool, they reported the “age-at-peak” for each tract, as

well as the rate of increase/decrease, along with sex differences, in some cases. Figure 2. White matter maturation Inhibitors,research,lifescience,medical between ages 5 and 30. Age-related fractional anisotropy increases measured by tractography Inhibitors,research,lifescience,medical in 202 individuals across 10 tracts. Reproduced from ref 48: Lebel C, Walker L, Leemans A, Phillips L, Beaulieu C. Microstructural maturation … Using DTI-based connectivity analysis, Hagmann et al used graph theory to show that the efficiency of the brain’s anatomical network increased with age—as did the number of detectable connections for each brain region.50 Graph theory represents the brain as a set of nodes (brain regions) and edges (the connections Inhibitors,research,lifescience,medical between them). A number of standard parameters such as path length and modularity, to name a few, are used to describe network topology.51 Characteristic path length

measures the average path length in a network. It does not refer to the physical length of the tracts, Inhibitors,research,lifescience,medical but the number of edges, or individual “jumps,” between nodes in the network. Modularity is the degree to which a system may be subdivided into smaller networks. Graph theory can quantify more global features in brain connectivity patterns. These include network efficiency, or the degree to which the network is differentiated into modules. Using cortical connectivity matrices calculated from HARDI data, Dennis et al examined the developmental trajectory of graph theoretical measures of structural connectivity (Figure 3).52 mafosfamide Path length and modularity, among other measures, decreased with age, suggesting an increase in network integration. Interestingly, the left and right intrahemispheric networks, when analyzed separately, showed opposing age trends; some parameters increased with age in the left hemisphere, but decreased in the right. If this is corroborated in the future, it could point to different developmental processes in each hemisphere, perhaps due to the known structural asymmetry of the brain, which also increases with age.

2007). During this test, individuals are asked

to read aloud a list of 50 irregularly pronounced words. Estimated IQ based on the WTAR was used in the current analyses to control for the effects of premorbid intelligence on neurocognitive function. Premorbid IQ taps into innate intelligence and is a sensitive marker of cognitive reserve (Alexander et al. 1997). Demographic and medical characteristics The patient’s medical history and currently prescribed medications were self-reported during two interviews and confirmed by medical records when possible. Medications were categorized by class and those identified as cardiovascular medications were reviewed and confirmed by a clinical Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical cardiologist. Statistical analyses All RBANS GABA Receptor inhibitor composite scores were converted to standard scores (i.e., a distribution with a mean of 100 and a standard deviation of 15) adjusted for age using normative values. Normative data for the RBANS composite was used in order to facilitate clinical interpretation of cognitive status in the current sample. TMT A and B scores were also converted to standard scores for similar reasoning. A composite of gray matter volume and cortical thickness of each brain region including frontal, temporal, parietal,

Inhibitors,research,lifescience,medical and occipital lobes were calculated using the organization schema as described in Desikan et al. (2006). Total brain volume (TBV) and thickness consisted of the sum and average of the frontal, temporal, parietal, and occipital lobe gray

matter, respectively. All analyses Inhibitors,research,lifescience,medical examining brain volume and thickness were adjusted for intracranial volume. Lastly, a total brain perfusion composite was also computed that consisted of the mean perfusion to the left and Inhibitors,research,lifescience,medical right hemispheres of the frontal, temporal, parietal, and occipital lobe gray matter. For analyses examining regional perfusion, the average of the left and right hemispheres for each lobe was computed. One participant exhibited missing data for occipital lobe perfusion and total brain perfusion for this participant consisted of the average of the remaining lobes. There was also one case with missing data on TMT B and this case was excluded from analyses examining this cognitive test as the dependent variable. Separate multivariable hierarchical regression analyses were performed for the MMSE, each RBANS composite, aminophylline TMT A, and TMT B. For each model, demographic and medical characteristics were entered in block 1 that included: Age, sex (−1 = male; 1 = female), premorbid intelligence (as estimated by the WTAR), cardiac index, heart rate, diagnostic history of hypertension, diabetes, and atrial fibrillation (1 = positive history; 0 = negative history). Total brain cerebral perfusion was then entered into block two of each model to determine its incremental predictive validity on cognitive function.

Similarly, many studies have long no-treatment periods for observation and diagnostic purposes. Clinicians are not likely to withhold treatment from severely ill patients in whom immediate treatment is seen as an absolute necessity. Thus, only those patients who can tolerate a long no-treatment period are selleck products recruited. These patients are likely to be less severely ill. It has long been observed Inhibitors,research,lifescience,medical that severity and placebo response are inversely related. If advertising is used as the primary source of recruitment, a group of high-likelihood placebo responders, the “worried well,” arc often the ones recruited. If, on the other hand, the recruitment is largely from active clinic or

practice populations, there is likely to be preferential treatment of nonresponders under the justification that it

is inappropriate to “rock the boat” for patients that are doing well by switching to a new treatment. Study operations In large, multiple-site studies, recruitment is often set as a horse-race with enrollment Inhibitors,research,lifescience,medical concluded when the overall study sample is achieved. Payment to sites is largely on a per-patient basis. Therefore, as the study recruitment goal appears closer, there is a financial incentive to enroll subjects Inhibitors,research,lifescience,medical while enrollment is still possible. Over time, that could lead to a drift in criteria: mild symptoms are seen as more serious, and borderline eligibility gets to be considered acceptable. This erosion of severity promotes placebo responder recruitment. In combination treatment

studies, operational concerns minimize differences between pharmacological and Inhibitors,research,lifescience,medical psychosocial treatments. Typically, the approach to pharmacotherapy is rigid with fixed dosing and short duration – an approach uncharacteristic of clinical practice. Clinicians in the pharmacotherapy arm must behave robotically and in a manner unlike the way they generally work. Training and supervision are minimal. Those doing the psychosocial treatment, on the other Inhibitors,research,lifescience,medical hand, are typically highly selected, well-paid, well-trained, and closely supervised. We therefore commonly encounter trials in which expertly done psychotherapy beats poorly done pharmacotherapy, and cannot separate the operational aspects from the true clinical effect of the different treatment approaches. Outcome measures In psychiatry trials in general, Phosphatidylinositol diacylglycerol-lyase and in depression trials in particular, there is a tradition of using too many measures, most of which are rating scales or self-report forms of dubious validity and notorious unreliability. Measures are selected because they have worked in the past, and are therefore uninformed by contemporary science and knowledge of etiology or pathophysiology. There are few examples of composite, event-based measures, such as are typically used in cardiovascular trials (major adverse cardiac events, MACE), in mental health. We need to have more.

35, 36 The coronary artery origins can be assessed with 3D isotropic resolution images that are gated for both cardiac cycle and respiration.37 d. Ventricular Size and Function The majority of adults

who have undergone ASO have normal biventricular size and function. However, special attention should be paid to any regional wall motion abnormality, which may indicate a coronary artery problem. e. Myocardial Fibrosis If coronary artery occlusion results in myocardial infarction, LGE in a coronary artery territory may represent irreversible Inhibitors,research,lifescience,medical myocardial damage.19 LGE assessed by CMR can differentiate myocardial infarct from other causes of systolic Inhibitors,research,lifescience,medical myocardial dysfunction. With these components of the imaging focus in mind, here is a suggested imaging protocol for adults with TGA after an arterial switch operation (ASO): ECG-gated cine SSFP sequences LV two- and four-chamber views Ventricle short-axis stack from the base to the apex for quantitative assessment of ventricular size, function, and mass RV and LV outflow tract views RV two-chamber view Inhibitors,research,lifescience,medical STA-9090 price Branch pulmonary artery axial stack to assess for pulmonary artery

stenosis Aortic root short axis Gadolinium enhanced 3D MRA ECG-gated phase contrast sequences perpendicular to the main pulmonary artery, ascending aorta (and branch pulmonary arteries if there is concern of branch pulmonary stenosis resulting in unequal pulmonary blood flow) LGE to assess for myocardial fibrosis Coronary artery imaging with ECG and respiratory

Inhibitors,research,lifescience,medical navigator 3D SSFP Physiologically Corrected TGA Physiologically corrected transposition of the great arteries (c-TGA), also referred to as congenitally Inhibitors,research,lifescience,medical corrected TGA, L-loop TGA, or S,L,L TGA, is a congenital abnormality that may not be diagnosed until later in life. Patients with c-TGA have atrioventricular discordance and ventricular arterial discordance such that deoxygenated blood passes thru a LV and out the PA, and oxygenated blood passes to a systemic RV and then is pumped out the aorta; therefore, these patients are many not cyanotic. They are at significant risk for systemic RV dysfunction similar to patients with TGA with an atrial switch procedure, and the current adult congenital heart disease guidelines recommend imaging every year or at least every other year to assess systemic RV function.4 Additionally, many patients with c-TGA have associated cardiac anomalies including VSD, pulmonary stenosis, Ebstein anomaly, or dysplastic tricuspid valves that may have required surgery in the past. Dextrocardia may be present in up to 20% of patients with c-TGA.

98 (95% CI: 0.923-0.992), sensitivity 0.84 (95% CI: 0.743-0.911) and the accuracy was 0.87 (95% CI: 0.796-0.913). In the squamous cell carcinoma

group, detection rate was 0.89 (95% CI: 00.792-0.943), sensitivity 0.91 (95% CI: 0.754-0.972) and the accuracy was 0.84 (95% CI: 0.732-0.914). Table 2 Definitions of various parameters Table 3 When was the sentinel node biopsy done and selection criteria of patients? Heterogeneity and publication bias The heterogeneity of outcomes has been summarized in Tables 4 and ​and5.5. The Inhibitors,research,lifescience,medical reason for significant heterogeneity may be attributed to different population groups and the variable type of SLN tracer legislated for clinical use in each country. No publication bias was detected using

the Egger’s regression model. Table 4 Pooled event rate and 95% CI Table 5 Subgroup analysis for various radioisotopes used for lymphoscintigraphy Discussion SLN mapping and biopsy was Inhibitors,research,lifescience,medical first applied to melanoma, and was subsequently extended to breast cancer and, more recently, to many other solid Selleckchem FK866 tumours including oesophageal cancer (5,6,34,35,42-47). The SLN concept has revolutionized the approach Inhibitors,research,lifescience,medical to the surgical staging of both melanoma and breast cancer, and these techniques can benefit patients by avoiding various complications that may result from unnecessary prophylactic radical lymph node dissection in cases of negative SLNs for cancer metastasis. New developments in determining the sentinel node for especially early oesophageal

tumours will probably influence operative strategies in the future. Kuge et al. found direct lymphatic drainage from the submucosal plexus of the oesophagus to the thoracic duct Inhibitors,research,lifescience,medical in cadavers. Moreover, they found a long longitudinal extension of the drainage networks of the submucosal plexus suggesting that this is the explanation for skip metastases to cervical nodes (48). Especially early intramural tumours (T1 and T2) probably tend to drain Inhibitors,research,lifescience,medical lymph fluid into the longitudinal networks. Therefore, isolated distant lymph node involvement is not necessarily a sign of advanced disease. Regional Resminostat lymph nodes, on the other hand are connected with tumours invading the extramural layers (T3 and T4) through lymph vessels piercing through the oesophageal wall. In this concept regional lymph nodes would be a sign of more advanced oesophageal cancer. This was confirmed in a retrospective study by Matsubara et al. (49) In order to predict possible sites of sentinel nodes they analysed the location of initial lymph node metastasis in 329 patients after extended oesophagectomy for squamous cell carcinoma. Of the solely positive lymph nodes 82% was located in the relatively distant cervico-thoracic junction or perigastric region. When two or three positive lymph nodes were identified they were rarely confined to the intrathoracic lymph nodes.

As these cells can cross tissue barriers such as the blood brain barrier (BBB), the virus can spread unrestricted [81]. The ability of these pathogens to infect, evade the host’s phagocytic mechanisms, and replicate creating pathogen reservoirs that can disseminate throughout the body stresses the importance of the development of targeted therapeutics to macrophages and other phagocytic cells. Liposome delivery to these pathogen reservoirs has received some attention [84, 85]. Targeting strategies Inhibitors,research,lifescience,medical studied to-date include the use of negatively charged liposomes

containing PG [26, 27], sterically stabilized immunoliposomes incorporating surface anti-HLA-DR Inhibitors,research,lifescience,medical antibodies [86], tuftsin [87], galactosylated [88], and mannosylated [89]

liposomes (Table 1). Overall in these studies, the liposome encapsulation of anti-infectives was generally found to decrease cellular toxicity, modify pharmacokinetics, and improve targeting thereby enhancing the overall efficacy of the anti-infective agents. 4.2. Inflammation and Cancer Mononuclear phagocytes are recruited to sites Inhibitors,research,lifescience,medical of injury and cancer, and these sites become areas with a high macrophage presence. As inflammatory cells, macrophages release proinflammatory cytokines such as TNFα further increasing inflammation. This process can be utilized in two ways for drug targeting. Firstly, cells can be targeted Inhibitors,research,lifescience,medical and activated to Sotrastaurin mw bestow tumour suppressive properties for cancer therapy [7]. Secondly, for inflammatory disease, the inflammatory response can be reduced using anti-inflammatory drugs or cell killing to deplete monocyte/macrophage cell populations. Activation of macrophages is a means of augmenting antitumor

immune responses [4] by the induction Inhibitors,research,lifescience,medical of proinflammatory mediators such as TNFα, IL-8, and nitric oxide (NO) [28]. For instance liposomal delivery of hexadecylphosphocholine [2], JBT3002, a synthetic lipopeptide [3], the tetrapeptide (Thr-Lys-Pro-Arg) tuftsin, and Thalidomide muramyl tripeptide phosphatidylethanolamine (MTP-PE) [28] has been investigated. MTP-PE is a synthetic glycopeptide that can activate monocytes and macrophages promoting tumour regression [28]. A liposomal MTP-PE formulation (L-MTP-PE; mifamurtide) is currently in clinical trials for high risk osteosarcoma. Bisphosphonates, for example, clodronate and alendronate, are extensively used in the treatment of osteoporosis but have also shown the ability to induce apoptosis in monocytes and macrophages. Interest lies in their therapeutic potential for inflammatory disorders.

2010). Methods are identical to those reported previously (Lad et al. 2010), except

for the timing of the test. Mice were transferred to these home cages during the middle of their light cycle (between 12:30 and 13:00). Recording took place at three time points during the 24 h test (13:00–14:00; 01:00–02:00; 11:30–12:30). The first hour (13:00–14:00) following the transfer of the mice measured their behavior in response to the novel environment. The second hour (01:00–02:00) assessed their behavior during the dark phase (the active phase for mice which are nocturnal mammals), following 12 h of habituation. The last hour (11:30–12:30) measured the behavior of the mice following Inhibitors,research,lifescience,medical an extended period (>22 h) of habituation during a typically low activity phase (light phase). Four

red multi-LED cluster lamps (LED cluster red light No. 310-6757; RS Components Northants, UK) of approximate wavelength 705 nm were DNA Synthesis inhibitor placed in the test room to provide sufficient lighting Inhibitors,research,lifescience,medical for the image capture, but give the appearance of darkness to the mice given the wavelength of the lamps. Open field The open field was performed as described previously (Lad et al. 2010), except for light level which was ~30 lux. Novel Inhibitors,research,lifescience,medical object exploration Novel object exploration was performed 48 h after the open field test using the open field arena (see Lad et al. 2010 for details). During the novel object exploration task, each mouse was exposed to two identical novel objects for 5 min. The Ethovision program was utilized for both automated tracking and manual scoring. Manual scoring allowed accurate measures of exploration Inhibitors,research,lifescience,medical (frequency and duration) of each object to be made. Holeboard The holeboard (File 2001), used to measure activity Inhibitors,research,lifescience,medical and exploration in a novel arena, was run in a Tru Scan Photo Beam Activity

System (Coulbourn Instruments, Allentown, New Jersey), which consisted of an automated arena (25.4 × 25.4 × 40.6 cm) with sensor rings to track movement in the arena (light level 300 lux). The beams were spaced 1.52 cm apart providing a 0.76 cm spatial resolution. A metal floor was used, containing 16 holes (2.2 cm in diameter), evenly distributed over the floor (4 × 4 configuration). The floor others also contained sensors to detect nose pokes. Mice were placed individually in a corner of the holeboard and allowed to freely explore for 5 min. The distance traveled, number of holes visited, and time spent in the center (17.8 × 17.8 cm) were recorded using the Tru Scan Software Version 2.0 (Coulbourn Instruments). Forced swim The forced swim test (Porsolt et al. 1978) was carried out in a clear Perspex tube (49 cm high × 15 cm diameter) filled with water at room temperature (depth 40 cm). Twenty-four hours prior to the trial, a blood sample was taken to provide a baseline measure of corticosterone, see below.

Therefore, for the majority of patients, there is no advantage in increasing the dose of paroxetine above 20 mg/day. In this study,19 there were no differences

AZD0530 datasheet between paroxetine 10 mg/day and placebo on change on the HAMD total score at the end of 6 weeks. Significant differences were seen between other doses of paroxetine of 20, 30, and 40 mg/day and placebo. There were no differences between the three higher dosages of paroxetine on visual inspection of the figures of the publication.19 Sertraline The SSRI sertraline did not show significant differences in terms of clinical Inhibitors,research,lifescience,medical efficacy across a dose range of 50 to 200 mg/day, according to a major study by Fabre and Putman (Table I). 20 Therefore, for the majority of patients, there is no advantage to increase the dose of sertraline above 50 mg/day. In the study by Fabre and Putman,20 sertraline 50 mg/day, but not 100 and 200 mg/day, was more effective than placebo at end-point analysis on change Inhibitors,research,lifescience,medical on the HAMD 17 items total score on ITT-LOCF at 6 weeks. There was no statistical analysis performed between the different doses, but inspection of the data in

the publication20 suggests no differences. Evaluable patients, defined as those who Inhibitors,research,lifescience,medical had taken study medication at least up to the 11th day of the double-blind phase, with efficacy assessment performed on or after this date. With this population of 289 evaluable patients, all doses of sertraline were statistically Inhibitors,research,lifescience,medical superior to placebo on change on the HAMD total score with LOCF at the end of 6 weeks. There was no statistical analysis of the different doses, but inspection of the data in the publication20 suggests no differences; on the CGI, the percentage of responders was 58.5%, 62.7%, 58.9%, and 42.1% in the Inhibitors,research,lifescience,medical sertraline 50, 100, 200 mg/day and placebo groups, respectively. Inspection of the data in the publication20 for the 191 patients who completed

the study suggests no difference between the three doses of sertraline on change on the MADRS total score. Moreover, efficacy was similar in patients with moderate depression (HAMD score at baseline: 17 to 24) and with severe depression (HAMD score at baseline: 25 or more). A small part of this study with 30 patients had been released out 6 years earlier in a short publication,28 with the same conclusions. In a very small study in 17 patients at the start of the study and 8 at the end, Guy et al29 could not demonstrate the efficacy of sertraline 50 and 100 mg/day over placebo on the HAMD 17 items at the end of 4 weeks. No symptomatic improvement was noted for sertraline 200 or 400 mg/day. Lower dosages were better tolerated than higher dosages. Milnacipran Three fixeddose studies30’32 and one doseranging study33 were identified for milnacipran (Table II), The studies showed flat dose-response relationship between 100 and 300 mg/day; milnacipran 50 mg/day was less effective than higher doses and even than placebo.