37-39 Justifications for using placebo control groups include the fluctuating

natural course of most psychiatric illnesses, the wide variability in placebo response across patient groups, and the influence of psychosocial factors on treatment response.37 The response rates for placebo in antidepressant clinical trials range from 30% to 40%.2,3 Among patients with milder forms of depression and a relatively short episode duration, the placebo response rate Inhibitors,research,lifescience,medical is close to 50% and often indistinguishable from the response rate to antidepressants.2 Recent antidepressant clinical trials have seen a “placebo drift” in that the placebo response rate is higher than in trials conducted 30 years ago, with a slight lowering of the response to antidepressants and a substantial narrowing of the drug-placebo difference.1 Possible explanations for this observation include the fact. that patient samples in recent Inhibitors,research,lifescience,medical trials are more likely to have milder forms of depression than those in the older studies. Also, since the newer antidepressants have fewer side effects than the older ones, recent click here studies are more Inhibitors,research,lifescience,medical truly double-blind; hence a positive bias toward the active agents on the part of both patients and clinicians has less influence over the outcome.1 Rush40 points out that individuals

most likely to enter placebo-controlled trials may well be those most, likely to respond to placebos, ie, patient self-selection is a key factor (into or out of placebo-controlled studies). He further explains that individuals

most likely to agree to participate in placebocontrolled trials are those who have less severe, less complicated, less chronic, less disabling, and less treatment-resistant illnesses, hence those Inhibitors,research,lifescience,medical more likely to respond to placebos.40 Strategies to minimize Inhibitors,research,lifescience,medical placebo response in antidepressant clinical trials The substantial placebo response in depression reduces the power of clinical trials and confounds treatment decisions and the assessment of new therapies.41 The development of new antidepressant drugs is complicated by high placebo response rates, since new drugs are required to demonstrate superior effectiveness to placebo or else they below may be abandoned.42,43 Due to the paucity of objective outcome measures in depression, it is particularly difficult to prove efficacy that is superior to placebo. Thase44 argues that since a third of antidepressant published trials fail to demonstrate efficacy, new strategics are needed to systematically reduce the sources of variance. He suggests recruiting subjects with moderate and severe illnesses, and implementing a 4-week lead-in phase during which subjects receive psychocducation about handling depression; these are both steps aimed at reducing the number of patients still likely to respond to placebo once the proper trial has begun.

2010) and 15 studies from this continent were included. ECT practice was verified

from 27 Asian countries: Bangladesh, China, Hong Kong, India, Indonesia, Iran, Iraq, Israel, Japan, Jordan, South Korea, Malaysia, Myanmar, Nepal, Oman, Pakistan, Philippines, Singapore, Sri Lanka, Thailand, Turkey, United Arab Emirates, Vietnam (click here Chanpattana et al. 2010), Fiji, Kiribati, Solomon Islands Inhibitors,research,lifescience,medical (Little 2003), and Saudi Arabia (Alhamad 1999). ECT was reported not available in all countries, such as Bhutan, Brunei, Cambodia, Georgia, Laos, and Lebanon (Chanpattana et al. 2010), Micronesia and Palau (Little 2003). The countries Cyprus, Macoa, Qatar, and Maldives had also been excluded by a survey (Chanpattana et al. 2010). Overall, the included studies displayed a large heterogeneity in the presentation of rate and prevalence data and practice of ECT worldwide. On a global basis, a crude estimate (from numbers given in Appendix C, Tables C1–C5) of worldwide contemporary TPR (SD) (age < 65 years) was 2.34 (1.56); Inhibitors,research,lifescience,medical EAR (SD), 11.2 (9.0); iP (SD) 6.1 (6.9); and AvE (SD) 8 (1.4). Globally, under half of all psychiatric institutions within the same country provided ECT. Main findings of ECT utilization, parameters, and practice from the five continents are presented below. ECT Utilization Treated

person rate Overview of TPR from all countries providing such data Inhibitors,research,lifescience,medical is illustrated in Figure 2. Figure 2 Worldwide Treated Person Rates (TPR)—number of ECTs per 10,000 resident population per year. [Correction added after first online publication on 20 March 2012: The TPR column for UK (Department of Health 2007) has Inhibitors,research,lifescience,medical been changed to 1.84.] TPR (Fig. 2) varied from 0.75 in New Zealand (Ministry of Health 2005) to 4.4 in Victoria, Australia (Teh et al. 2005).

TPR in the USA Medicare population was 5.1 (5.7 women; 3.6 men) (Rosenbach et al. 1997). TPR by age groups (and therefore not included in Fig. 2) ranged from 0.0001 (<18 years) to 3.8 (>65 years) in California (Kramer 1999). TPR for the elderly (>65 years) in the Medicare population was from 2.4 to 4.2, (Rosenbach et al. 1997; Westphal et al. 1997) and varied from 3.8 West USA to 6.1 in the Inhibitors,research,lifescience,medical Northeast, as well as between rural (TPR 3.2) to large urban areas (TPR 6.0) (Rosenbach et al. 1997). TPR variations within the same State were reported from Louisiana, TPR (>65 years): 2.8 urban parishes versus 1.9 rural Terminal deoxynucleotidyl transferase parishes (Westphal et al. 1997). TPR in Europe varied between countries and regions and between individual centers (Fig. 2), with the lowest TPR 0.11 in Poland (Gazdag et al. 2009a). The within-country regional variation in Belgium (TPR 2.6–10.6) was reported as significant (Sienaert et al. 2006), which was also the case for Norway (TPR 1.83–3.44) (Schweder et al. 2011a). In South Africa, TPR was 1.26 (Mugisha and Ovuga 1991). In Asia, TPR was only reported from Thailand 1.15 (Chanpattana and Kramer 2004) and Hong Kong ranging 0.27–0.34 (Chung 2003; Chung et al. 2003; Chanpattana et al.

Cavernous malformations In spite of some reports of successful treamtent of CMs with stereotactic radiosurgery,10,30 the management of symptomatic lesions remains surgical: in a click here recent review of 97 CMs treated surgically at the Massachusetts General Hospital, only 4.1% of patients had permanent neurologic deficits and the vast majority were rendered seizure-free.9 Risk factors for increased

postoperative deficits included location within the brainstem and basal ganglia. Due to the relatively small size of these lesions and their localization within the subcortical areas making their visualization difficult on the cortical surface, neuronavigational techniques are particularly well suited for Inhibitors,research,lifescience,medical surgery of CMs. Conclusions Functional neuronavigation represents one of the most interesting advances in recent adjunctive Inhibitors,research,lifescience,medical technology in neurosurgery: the possibility of integrating functional information about anatomical localization

of eloquent areas into a 3D frameless stereotaxy system enhances the accuracy of the surgical procedure in helping localize the lesion and its immediate topographical relationships. Navigational systems are mostly represented by three different types of “pointer systems”: (i) the mechanically directed “viewing wand” type, transmitting the spatial information through an arm to the computer; (ii) instrument-based Inhibitors,research,lifescience,medical pointers using infrared light-emitting diodes and spatial sensors that transmit the information to the computer and reconstruct Inhibitors,research,lifescience,medical it as 3D images; and (iii) microscope-based pointer systems where the automated focus represents the target of the system allowing the superimposed reconstructed images to be seen directly through the microscope.16,31 The management of vascular malformations of the brain remains

Inhibitors,research,lifescience,medical to some extent controversial but the following conclusions can be drawn: small volume malformations (less than 3 cm in diameter) that have bled can be safely removed using microsurgical techniques with excellent results, and the utilization of functional neuronavigation for lesions located in eloquent areas adds even further safety in preserving function. Larger AVMs that have presented with hemorrhage many can be treated surgically after preliminary embolization but will have higher morbidity rates.32 Stereotactic radiosurgery can be offered to patients with relatively small lesions who present with symptoms other than hemorrhage, such as epilepsy, or for lesions located in the basal ganglia or brainstem. For CMs, the present trend is to remove the lesion surgically if hemorrhage has been demonstrated or if epilepsy cannot be controlled. The combined management of cerebral vascular malformations is best achieved by a well-integrated multidisciplinary team that includes neurosurgeons, interventional neuroradiologists, neurologists, and radiation oncologists.

It instructs participants to indicate how their thinking patterns change when they experience mild dysphoria. Questions are answered on a 0–4 Likert scale. The AGG and HOP subscales and the LEIDS-R total score were the primary outcome

measures for this study. The AGG and HOP reactivity subscales have been found to be strongly associated with irritability in depressed patients (Verhoeven et al. 2011) and with suicidality (Antypa et al. 2010; Verhoeven et al. 2011). The LEIDS-R total score is associated with serotonin vulnerability (response to tryptophan Inhibitors,research,lifescience,medical depletion) (Booij and Van der Does 2007) and with the interaction of serotonin transporter gene polymorphism and early-life events (Antypa and Van der Does 2010). Procedure All measures were obtained in a single session. All participants signed informed consent prior to participation and either received €10

Inhibitors,research,lifescience,medical or study credits. The research was approved by the Ethics Committee of the Institute of Psychology of Leiden University. Saliva samples were collected using Oragene Self-Collection Kits – DISC format (DNA Inhibitors,research,lifescience,medical Genotek Inc, Ottawa, Ontario, Canada); 200 μL of saliva was kept in lysis buffer (100 mmol/L NaCl, 10 mmol/L EDTA, 10 mmol/L Tris pH 8, 0.1 mg/mL proteinase K, and 0.5% w/v sodium dodecyl sulfate) until further processing. DNA isolation Genomic DNA was isolated from the samples using Inhibitors,research,lifescience,medical the Chemagic kit on a Chemagen Module I workstation (Chemagen Biopolymer-Technologie AG, Baesweiler, Germany). DNA concentrations were quantified by OD260 measurement and by agarose

gel electrophoresis. The average yield was approximately 4 μg of genomic DNA per sample. Polymerase chain reaction amplification The region of interest from the MAOA gene was amplified by triplex polymerase chain reaction (PCR) using the following primers: a 6-carboxyfluorescein-labeled Medium Resolution (MR) primer (5′-GGATAACAATTTCACACAGG-3′), forward primer (5′-ggataacaatttcacacaggACAGCCTGACCGTGGAGAAG-3′), and a reverse primer (5′-GGACCTGGGCAGTTGTGC-3′). Typical PCR reactions contained Inhibitors,research,lifescience,medical between 10 and 100 ng genomic DNA template, 1 pmol of forward primer, and 10 pmol of labeled MR and reverse primers. PCR was carried out in the presence else of 5% dimethyl sulfoxide with 0.3 U of BioThermAB polymerase (GeneCraft, Munster, Germany) in a total volume of 30 μL using the following cycling conditions: initial denaturation step of 5 min at 94°C, followed by 38 cycles of 30 sec 94°C, 30 sec 55°C, 30 sec 72°C, and a final extension step of 4 min 72°C. Metabolism inhibitor Analysis of PCR products One microliter of PCR product was mixed with LIZ-500 size standard and formamide and run on an AB 3100 genetic analyzer setup for genotyping with 50-cm capillaries. Results were analyzed using Genescan software version 3.7 (Applied Biosystems, Carlsbad, California) and alleles were scored visually.

Actually, the term extinction is used in several different ways in the literature. Extinction may refer to: (i) the experimental procedure used to produce a decrement in the fear response; (ii) the decremental effect of this procedure on the fear response, which can be measured both at the time the cue is presented in the absence of the aversive event and at a later time; or (iii) the hypothesized associative or cellular process responsible

for that effect. As suggested elsewhere,1 we will define the experimental procedure as extinction training, the decrement in the fear response measured Inhibitors,research,lifescience,medical during extinction training as within-session extinction, Inhibitors,research,lifescience,medical and the decrement measured at some interval after extinction training as extinction retention. The term extinction will be reserved for the process underlying the loss of the fear response. Extinction is not the same as forgetting Although some forgetting of the original

conditioned fear association may Inhibitors,research,lifescience,medical occur in extinction (see outstanding review),2 numerous studies show that extinction cannot fully be explained by forgetting Selleck ITF2357 because it requires exposure to the conditioned stimulus in the absence of the aversive event as opposed to the simple passage of time. Extinction is generally cue-specific Most studies show that fear extinction is cue-specific. For example, if a tone is paired with a shock and a light is paired with a shock, and then extinction

training is only given to the tone, fear of the light will be undiminished. Generalization gradients of extinction Inhibitors,research,lifescience,medical are typically seen where the magnitude of extinction is greatest to the cue given during extinction training, and less so to cues along some continuum, such as a series of different auditory frequencies that received no extinction training.3 Generalization of extinction is negligible across cues drawn from different not Inhibitors,research,lifescience,medical sensory modalities, or drawn from a single modality but differing substantially in their physical characteristics. Extinction generally is not permanent The decrement in conditioned fear responses during and shortly after extinction training generally is not permanent, as there are several instances in which extinguished fear responses are observed to reappear. Reinstatement This refers to the reappearance of a fear response following exposure to unsignaled presentations of the unconditioned stimulus after the completion of extinction training.4 Unsignaled unconditioned stimulus presentations must occur within the context in which animals ultimately are tested if a return of fear is to be observed.

S2 DGP) A number of HCPs reported that they waited for patients or family carers to raise the issues themselves: It’s very much led by the patient; if they want to know … how they are doing whatever, and be guided intuitively by them really. There are some patients who will be very open and frank with you and use all the right words but there are others that will say to you or indicate ’I know where you’re going with this and I don’t want to hear’ (HCP1. S3 DGP). Thus, to some extent, HCPs tended to rely on patients Inhibitors,research,lifescience,medical to explicitly raise issues for discussion rather than initiate these themselves. At the same time they were alert to cues from

the patient or guided by intuition as to when to introduce issues around EOLC, what depth to go into and so on. Factors mentioned in interviews with HCPs regarding judgments on timing included doing preparatory work and first building up a relationship

with the patient and family: It’s important we’ve built up a rapport with the patient … and that’s why Inhibitors,research,lifescience,medical we like early referrals so we get to know the person (HCP1. S1 DGP). Despite a preference for early referrals which enabled them to develop a relationship with the patient prior to raising sensitive and MLN8237 purchase difficult issues, HCPs reported that a significant number of referrals are made ‘late’ i.e. in a patient’s last Inhibitors,research,lifescience,medical few weeks or days of life. Discussion This study provides insights into the different perspectives of patients, family carers and HCPs relating to discussions about patients’ preferences for place of care Inhibitors,research,lifescience,medical and

death. The findings indicate that this is a complex and sensitive area for all concerned. Our focus was on the PPC (Preferred Place of Care) tool, which at the time of our study was one of the main tools for good practice in EOLC in the UK (since renamed Preferred Priorities for Care). Inhibitors,research,lifescience,medical This remains the case but the policy framework around EOLC has also placed an increasing emphasis on ACP as a means of opening discussion relating to wider range of issues to be considered about care at the end of life. already However, on the ground, ACP is still a difficult topic to broach. Guidance on ACP for HCPs [27] acknowledges that there is no ‘right time’ to introduce the topic, although it is also suggested that it is important to open up communication to discuss preferences at the earliest opportunity. Our findings have relevance here in adding to knowledge of a range of factors that contribute to the potential for reticence, evasion, reluctance by all parties involved to broach conversations to discuss ACP and EOLC needs. Not all patients wanted to discuss preferences (for place of care and/or death) with their family and/or HCPs or within an interview setting, an ambivalence that is also identified in other studies [4,10,28,29].

For the same purpose of cell-type selective CPP-mediated uptake, Kibria et al. functionalized liposomes with either RGD peptide or the tumor endothelial cell-specific peptide KYND and the octaarginine CPP and showed synergy of the combination of targeting peptide and cell penetrating peptide for liposome Gedatolisib nmr uptake in Inhibitors,research,lifescience,medical vitro with higher cell selectivity [320]. The same group later demonstrated superior antitumor

activity of doxorubicin-loaded liposomes harboring both the tumor endothelial cell-specific peptide NGR and the cell penetrating peptide tetraarginine over untargeted liposomes or single-modified doxorubicin-loaded liposomes [183]. Presentation of octaarginine at the surface of bleomycin-loaded liposomes increased apoptosis induction

in tumors and tumor growth inhibition over bleomycin-loaded liposomes devoid of the CPP [321]. Superior tumor growth inhibition was evidenced over untargeted RTN (receptor-targeted nanocomplexes, RTN) Inhibitors,research,lifescience,medical using Inhibitors,research,lifescience,medical lipopolyplexes decorated with an integrin-targeting peptide for delivery of pDNA encoding IL-2 and IL-12 to promote antitumor immunity [322, 323]. In their study, the complexes were optimized for disassembly in the target cell [323, 324]. The PEG-lipid conjugates used had an esterase-cleavable bond for endosomal escape and the integrin-targeting peptide was coupled to the polycation used for pDNA condensation by a linker cleavable by both cathepsin B and Inhibitors,research,lifescience,medical along with furin for intracellular release of the nucleic acid and high transfection efficiency. In addition to enhancing cellular uptake, TaT peptide conjugation allowed crossing of the blood brain barrier in in vitro models and increased drug delivery

of doxorubicin-loaded liposomes, resulting in prolonged survival of orthotopic glioma-bearing Inhibitors,research,lifescience,medical animals after intravenous administration [325]. 6.3. Endosomal Escape After the endocytosis, the cargo is transferred from endosomes (pH 6.5–6) to lysosomes (pH < 5) [326] in which enzymatic degradation occurs. Although PEGylation Bumetanide is required for extended blood circulation and tumor accumulation [7], this modification decreases cellular uptake and further increases endosomal degradation of the cargo, thereby reducing its activity [327, 328]. These conflicting properties of PEG have been referred to as the “PEG dilemma” [292]. The decreased endosomal pH has been exploited as a means to escape degradation using either fusogenic lipids or peptides which destabilize membranes after conformational activation at low pH, amines protonable at acidic pH for endosome swelling and rupture by a buffer effect [329–338] (Figure 4).

OROS® hydromorphone may be particularly

well suited to the long-term management of cancer pain because it provides consistent plasma concentrations, sustained analgesia, and convenient once-daily dosing. In this open-label, single treatment extension study, OROS® hydromorphone was administered to patients with moderate-to-severe chronic cancer pain who had successfully completed a previous short-term equivalence study and whose pain was controlled with a stable dose of medication. Prior opioid therapy in the previous equivalence study (OROS® hydromorphone versus CR morphine) did not affect clinical outcomes such as efficacy or safety in this study. The results demonstrate that pain control achieved Inhibitors,research,lifescience,medical with OROS® hydromorphone is maintained for up to Inhibitors,research,lifescience,medical 1 year with repeated once-daily dosing in patients with chronic cancer pain. This was shown using a variety of measures, including the BPI items pain at its worst, pain at its

least, pain on average, current pain, and pain relief, and patient and investigator global evaluations of overall treatment effectiveness. Throughout the study, pain scores were maintained at mild to moderate levels. These results support short-term studies of OROS® hydromorphone for chronic Inhibitors,research,lifescience,medical cancer pain [20-22,34]. In addition, the degree to which patients’ cancer pain interfered with their general activity, mood, ability to walk, work, relationships, sleep, and enjoyment of life was also maintained, suggesting that there was no worsening of QoL during the year. This has been demonstrated before; previous studies have shown a positive impact on QoL with CR opioid formulations [11,48]. There were no clear differences in the Inhibitors,research,lifescience,medical results when comparing patients who had received OROS® hydromorphone or CR morphine in the previous equivalence study. Although most efficacy measures were maintained at similar levels Inhibitors,research,lifescience,medical throughout the study, for most

measures, the mean scores were slightly worsened at end point Cyclosporin A compared with baseline. However, owing to the progressive nature of the disease, some deterioration is to be expected. The most commonly almost reported AEs, with an incidence of at least 10%, were nausea, constipation, vomiting, anaemia, peripheral oedema, dyspnoea, asthenia, disease progression, somnolence, and urinary tract infection. These are events typically seen with the use of strong opioids or in a chronic cancer pain population. Slightly more AEs overall and AEs considered related to study treatment were reported in patients who had previously received OROS® hydromorphone compared with CR morphine in the equivalence study; however, the clinical significance of this difference is questionable because of the degree and nature of AEs expected in an advanced cancer population. In addition, the majority of AEs were mild or moderate in severity.

From this set of 1261 subjects who did not classify for any psychiatric diagnosis, 875 agreed to donate a mouthwash. For this study 270 samples were

analyzed; they were not different with regards to the main sociodemographic variables: average age, female: male ratio, or percentage of subjects who met criteria for economic adversity from the original set from where they were chosen (data not shown). Ethical considerations This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Ethics and Scientific Committees of the Inhibitors,research,lifescience,medical National Institute of Psychiatry “Ramón de la Fuente Muñíz” (INPRFM) in Mexico City. Interviewers gave a verbal and written explanation of the study and obtained informed consent from the parent or legal guardian and the assent of

the adolescent. Childhood psychosocial adversities In addition to the psychiatric survey, information about psychosocial adverse risk factors experienced the previous years was collected. A set of 12 childhood adversities (CAs) experienced during Inhibitors,research,lifescience,medical childhood was analyzed. They were evaluated from the childhood and posttraumatic stress disorder sections of the WMH-CIDI-A as described elsewhere (Benjet et al. 2011). The selection and scoring of these measures are the same as that created for the World Mental Health Survey (Greif Green et al. 2010). All adversities were considered chronic because of reporting of multiple Inhibitors,research,lifescience,medical accounts Inhibitors,research,lifescience,medical or continued occurrence. A factor analysis showed three meaningful components in this subsample (data available on request), similar to results obtained in the whole sample (Benjet et al. 2009b): The first factor

was comprised of six CAs regarding family dysfunction, abuse and neglect, and parental maladjustment variables; criminality and substance Inhibitors,research,lifescience,medical abuse described the second factor; finally, a third factor included the report of parental divorce associated with extreme family economic adversity. On the other hand, to have experienced the death of a parent was relatively independent of being exposed to other CAs, while having a life-threatening physical illness in childhood about was also moderately independent of other adversities, although it loaded with family dysfunction adversities. http://www.selleckchem.com/products/wortmannin.html Molecular analyses High-molecular-weight DNA (23 Kb) was extracted from mouthwash samples using the Puregene DNA purification Kit (Qiagen™, Hilden, Germany). A detailed analysis on the quality of the nucleic acids obtained and the efficiency of PCR amplification achieved is available on request. Genotyping of SLC6A4 promoter VNTR (5HTT-LRP) was determined by agarose gel size fractionation as we have previously reported (Camarena et al. 2001). Gels were read in a blind fashion by two different evaluators obtaining a 100% concordance. Alleles were designated according to their relative size: S (14 repeats), L (16 repeats), with no other rare alleles detected in this sampling.

124-127 As many treatments for sleep exist, this may be a potentially modifiable risk factor for preventing IFN-MDD. This has previously been suggested for MDD,128 but may now be readily testable in patients about to be treated with IFN-α. There is also evidence that increased age may be another risk factor for IFN-MDD,129 although this is certainly not a consistent finding.130,131 Despite the fact that age itself is not modifiable, this could indicate the presence of agerelated modifiable risk factors. Related to this,

elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), prior to IFN-a Inhibitors,research,lifescience,medical therapy have been associated with subsequent IFN-MDD.132,133 Additionally, a polymorphism in IL-6 that has been associated with increased IL-6 levels is predictive of IFN-MDD.134 In the subset of people with increased IL-6 during IFN-α administration, the IL6 levels temporally predicted next month’s PI-103 purchase depression symptoms.133 Inhibitors,research,lifescience,medical This is consistent with cross-sectional studies in which elevated IL-6 levels are associated with MDD.54,132,135-140 Thus, increased IL-6 may be another plausibly modifiable target for preventive intervention in depressed individuals. Interestingly, IL-6 increases with age but can be modified by diet141 and/or Inhibitors,research,lifescience,medical exercise.142-143 Potential premorbid risk factors for IFN-MDD that may be modifiable through psychosocial interventions could include

social isolation144 and neuroticism.115,145 However, when controlling for other premorbid risk factors, the effect size for these is fairly small.146 Another risk factor may be a hyperactive stress response in the hypothalamic-pituitaryadrenal (HPA) axis.147 Given the common association between abnormalities in the HPA axis and MDD,148-150 this may also be a potentially useful predictive Inhibitors,research,lifescience,medical marker. Interestingly, HPA axis responsiveness can be therapeutically modifiable by antidepressants.154 It is therefore plausible that patients with overactive HPA responses may be the subjects who benefit

most from antidepressant prophylaxis. Consistent with this, stress-reactivity did correlate with depressive symptoms prior to IFN-α therapy147 – and thus Inhibitors,research,lifescience,medical elevated stress-reactivity may be a potential predictor of the need for ”indicated“ Ribonucleotide reductase SSRI prevention. Genetic polymorphisms within the serotonergic system have also been associated with vulnerability to IFN-MDD.134,146,155 Two studies have replicated the finding that a short allele in the serotonin transporter robustly increases risk for IFN-MDD.134,146Vulnerability to tryptophan depletion has also been associated with polymorphisms in the 5-HT reuptake transporter.59 Because IFN-MDD has been associated with lowered tryptophan levels during treatment,57,91,93-156 this suggests that differences in serotonergic tone may leave some people vulnerable to IFN-MDD. It is also plausible that these are the same subjects who may benefit from SSRI prophylaxis, a possibility that requires testing.