Large Scale Study Shows Antidepressants are More Effective than Placebo


This week an article in the Lancet has shed light on the controversy surrounding antidepressants.[1] Psychiatric disorders account for 22.8% of the global burden of disease, of which depression is the leading cause. In 2016 there were over 64 million prescriptions issued for antidepressants, which is more than double the amount issued ten years previously. Until now there has been much debate regarding the effectiveness of antidepressant drugs in treating this debilitating disorder. This study has been pivotal in providing evidence in addressing this controversy, as previous studies have not adequately examined the long term effects of antidepressants.

The study looked into 522 trials involving 116,477 patients and found that all antidepressants investigated were more effective than placebo. However, they weren’t all equally effective: It found that the drugs ranged from being a third more effective than a placebo to more than twice as effective. Interestingly, the findings showed that escitalopram, mirtazapine, paroxetine, agomelatine, and sertraline were the most efficacious in adult patients. On the other hand, reboxetine, trazodone, and fluvoxamine were found to be the least effective of the drugs tested, with effects diminishing over time. Many patients stop using antidepressants after only a few weeks, which may have contributed towards skewed results in previous investigations as many of the drugs tested are only effective after long term use. However, researchers noted that most of the data in the meta-analysis covered eight weeks of treatment, although it did not take into account problems that may emerge from longer term us of the drugs.

Overall, clinicians consider this study to be an important piece of evidence in encouraging patients to pursue treatment options for depression, including antidepressants where necessary. Hopefully, this seminal article will help remove the stigma surrounding depression and the use of antidepressants. More than ever, mental health is being acknowledged as a topic for serious discussion and in light of this article more awareness needs to be made about the treatment options for these disorders which affect one in four adults in the UK.[2]

Blog written by Rachael Besser

References

1 Cipriani, Andrea et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

2 McManus, S., Meltzer, H., Brugha, T. S., Bebbington, P. E., & Jenkins, R. (2009). Adult psychiatric morbidity in England, 2007: results of a household survey. The NHS Information Centre for health and social care.

 

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Case placement in Emeryville


I have recently returned from my PhD Case placement at the Novartis Institutes for Tropical Disease (NITD) who recently relocated to Emeryville California. NITD drug discovery is focused in 3 areas; malaria, cryptosporidiosis and kinetoplastid diseases.

My PhD project has been to identify drug-like inhibitors that inhibit an enzyme that has been identified as a target for the kinetoplastid pathogen that causes African sleeping sickness, trypanosoma brucei. Whilst on my placement at NITD I was fortunate to work alongside scientists that have been involved with identifying drug candidates against the same pathogen, and have parasite assays in place to examine the effects of drug molecules against them. I was able to culture the live parasite and it was exciting to see that the compounds that I had designed and synthesised during my PhD inhibited the growth of the parasite.
During my time at NITD I was also able to work in the research chemistry laboratories, synthesising further analogues against my enzyme target, it was a great opportunity to work in a cutting edge research environment with a variety of instruments that facilitated day to day chemistry experiments. Over the course of my placement I was able to identify new chemical analogues that showed improved potency against the parasite, that I am currently following up back at the Sussex Drug Discovery Centre.

Ryan 1

At the weekends I was able to do a bit of travelling around California, some of the highlights were visiting Yosemite national park (above), cycling over the Golden Gate Bridge and visiting Alcatraz.

Blog written by Ryan West

Beware Greeks bearing gifts


The publication that I wanted to discuss was bought to my attention whilst reading Derek Lowe’s superb blog “in the Pipeline”. I would wholeheartedly recommend readers of this particular website to read the original blog discussion of the publication there. The link to in the Pipeline article is here http://blogs.sciencemag.org/pipeline/archives/2017/10/05/beware-of-zinc-and-of-other-stuff and the link to the original article is as follows https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01071

In the publication a group at Dundee University were exploring a fragment based approach, against an enzyme which has a role in ubiquitin conjugating called Ube2T. The team had been successful in identifying a fragment hit in an earlier publication. In this first publication they had utilised differential scanning fluorimetry (otherwise known as a thermal shift assay) and followed up with biolayer interferometry, as an orthogonal technique to confirm primary hits from the DSF primary screen. To further generate confidence, ligand observed NMR was carried out.

From this work a specific fragment was chosen as the top hit and was then measured with 15N- labelled NMR and ITC measurements against which at this stage showed positive binding. At this point analogues were ordered around this fragment and this is where the project hit some rough water. None of the analogues seem to show any significant SAR, and the limited number of analogues that did bind were much weaker in potency than the original hit

In parallel, co-crystallization of the fragment against Ube2T was attempted. While this was unsuccessful in showing specific binding, it did highlight a rearrangement of the protein, and the presence of a metal ion close to the catalytic residue, this metal ion was then identified as Zn2+

As no zinc was present in the co-crystallization buffer system, the team investigated the original fragment hit compound, running a zincon colorimetric assay on the sample which was gave a positive result for the presence of zinc. The team re-ran the original ITC experiment with the fragment hit in the presence of EDTA (which should chelate all zinc present), this showed that all binding was lost. In summary, the fragment hit must have contained Zn2+ ions which was the cause of the activity.

Gareth 1

Figure A showing ITC binding experiment of Ube2T with the original fragment compound with and without EDTA present. ZnCl2 against Ube2T is also shown as a comparison.

Taken from: F. E. Morreale et al., Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements. Journal of Medicinal Chemistry60, 8183–8191 (2017).

The authors did point out that this hit was from a commercial library and one of the actions they undertook was to ask for the QC data from the supplier, at the point when the related analogues of the fragment compound did not show any activity. This obviously did not highlight the presence of the Zn2+

I did wonder when reading this publication if a different screening cascade may have identified this type of false positive, before having to get to the step of a very labour intensive co-crystallization process. For example a cell based assay might by more resilient to the presence of metal ions. However with a fragment based project, this may not be possible due to the poor affinity of fragments and also obtaining an effective concentration within the reduced DMSO tolerance of a cell based format compared to a biochemical assay. The only recommendation for this specific case, would be carry out further purification of samples, and then re-assay. It would also appear that the data from commercial suppliers is lacking and maybe that can be changed.

The authors should be commended for this work and putting it in the public domain. Drug discovery is a hard, long and quite often an unsuccessful process, and anything we can do to reduce the time following red herrings the better.

Blog written by Gareth Williams

 

 

Circular dichroism for protein characterisation


During my PhD project, I was working on a bacterial protein involved in iron transport. The secondary and tertiary information about this protein was limited and function was not well known at that time. In order to shed more light on this, I was looking for various techniques and came across ‘Circular Dichroism’ [CD], a widely used technique for analysing the secondary structure content of the protein of interest in solution. Circular dichroism measures the difference in the absorption of left and right circularly polarised light by chiral molecules. It is also a great technique to study the protein-ligand interactions.

The secondary structure composition is associated with characteristic spectra based on the absorption due to the peptide bond in the far ultraviolet [UV] CD region (180-260 nm) whereas tertiary structure features are influenced by the spectrum in the near UV region (260-320 nm) with absorption being due to aromatic residues [2]. In this category, synchrotron radiation circular dichroism spectroscopy [3] [SRCD] also became popular which provided more structural information with the available options for measuring the spectra to lower wavelengths, with improved signal to noise ratio levels.

I came across an article in Nature Scientific Reports indicating more advancement in this area by the introduction of High-throughput SRCD [HT-SRCD] using multi-well plates [1] which was interesting. The paper describes the features provided by Beamline B23 of Diamond Light Source, Oxford, UK for setting up the HT-SRCD using multi-well plates. It also describes examples for high-throughput measurements carried out using multi-well systems. In short, this HT-SRCD could be a potential resource for studying the protein folding, conformational changes in protein structure induced by ligands, buffers and other components as well as secondary structure determination on a high-throughput scale.

Blog written by Mohan Rajasekaran

  1. Hussain, R., Javorfi, T., Rudd, T. R., and Siligardi, G. (2016) High-throughput SRCD using multi-well plates and its applications. Scientific reports 6, 38028
  2. Kelly, S. M., Jess, T. J., and Price, N. C. (2005) How to study proteins by circular dichroism. Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics 1751, 119-139
  3. Wallace, B. A., and Janes, R. W. (2010) Synchrotron radiation circular dichroism (SRCD) spectroscopy: an enhanced method for examining protein conformations and protein interactions. Biochemical Society transactions 38, 861-873