Volume 20 - Issue 8

November 2016

Davide Amato, Editor-in-chief

Jackie Rose, Guest Editor

In This Issue...

  1. D2 drugs do not work equally for all patients and for all symptoms. Why should novel drugs do so?
  2. Grant Writing Tips:  Thoughts on R01 Applications
  3. IBNS @ SfN2016
  4. 2017 Travel Award Applications & Abstract Submissions
  5. Join NOW to get 2016 membership rates!
  6. Trending Science
  7. Japanese Basics
  8. Call for News

D2 drugs do not work equally for all patients and for all symptoms.
Why should novel drugs do so?
By Anissa Abi-Dargham

Note: Dr. Abi-Dargham is the IBNS 2017 Bench-to-Bedside plenary speaker at the IBNS Annual Meeting in Hiroshima, Japan.  View her short bio, below.

The field of therapeutics in schizophrenia has proceeded with a seemingly rational approach to drug development over the last few decades. Pharmaceutical companies tested very targeted theories, which had been raised based on clinical and preclinical observations. They developed drugs to test these specific theories, and tested them elegantly and successfully in animal models. Unfortunately, the humans were a lot more challenging than the mice. Promising new targets failed when tested in patients. These included well thought out and promising glutamatergic targets, both to reduce glutamate transmission, or to increase NMDA glutamatergic function, targets for the PDE10 enzyme, the nicotinic alpha7 receptors, among others. So what went wrong? The testing in humans was blind to the precise human brain pathology in the specific patients who participated in these trials.

Treatment in schizophrenia was influenced by the success of D2 drugs. Despite the fact that not all patients have hyperdopaminergia (1), and despite the fact that not all symptom clusters in schizophrenia relate to hyperdopaminergia, nevertheless, D2 drugs provide a statistically significant therapeutic effect in most trials that include all patients without distinction. But this may not apply to other mechanisms that may not be as generalized across patients. While the majority of patients with schizophrenia may present a combination of D2 hypersensitivity and enhanced presynaptic dopamine release, it may be that other disturbances are present in fewer subjects.

For future drug development to succeed we may need to shift strategies. Going forward, therapeutic trials may need to address specific functional domains, rather than schizophrenia as a whole; and they need to target subgroups of patients within these domains that display certain abnormalities in markers of brain function, neurochemistry or neurocircuitry, rather than all patients with schizophrenia. As an illustration to this point, we have recently uncovered a widespread deficit in dopamine release in extrastriatal regions of the brain in patients with schizophrenia (2). This may relate to cortical dysfunction and cognitive deficits. Patients at the extreme end of the distribution may benefit from a dopamine enhancing strategy. We have little direct information obtained in patients about most other systems. Trials include subjects who receive new drugs without knowing whether a subject has the particular alteration that the drug is attempting to fix.

We need to better understand the brain pathology in the illness, and develop biomarkers that will allow us to deliver targeted treatments to only those who need them. Is this attainable? Not soon, not easily, and not without increased funding, but the hope is that more emphasis will be placed on novel imaging techniques to explore brain pathology and develop, validate and implement the use of biomarkers in therapeutic trials. The ultimate goal is to use these biomarkers to subgroup patients according to specific pathological findings that are targeted by specific interventions.  In the future a patient may undergo a series of tests or scans that will determine which classes of drugs or which other non-pharmacological interventions, such as brain stimulation approaches, may be beneficial. This would move the field from a rational therapeutics development to a rational therapeutics testing.

      1. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, et al. (2000): Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 97:8104-8109.

       2. Slifstein M, van de Giessen E, Van Snellenberg J, Thompson JL, Narendran R, Gil R, et al. (2015): Deficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia: A Positron Emission Tomographic Functional Magnetic Resonance Imaging Study. JAMA Psychiatry.


Anissa Abi-Dargham, MD, is a Professor of Psychiatry and Vice Chair for Research in the Department of Psychiatry in Stony Brook University, NY. She was born in Beirut, Lebanon, where she went to Medical School in Saint Joseph’s University. She moved to the US in 1985, did her residency at the University of Tennessee in Memphis, TN, followed by a research fellowship at the National Institute for Mental Health. She then joined the Faculty at Yale University, and moved to Columbia University in 1996, where she spent most of her career. She retains an appointment as Professor Emerita of Psychiatry in the Department of Psychiatry at Columbia University. She is a newly elected member of the National Academy of Medicine.

Anissa Abi-Dargham is an expert in the areas of molecular imaging, pharmacology, schizophrenia and addiction.  She uses Positron Emission Tomography imaging to study the neurobiology of these disorders. Her research has resulted in seminal findings describing the complex alterations of dopamine transmission in schizophrenia and their relationship to clinical symptoms, cognition and response to treatment. More recently she built a multidisciplinary team with expertise in neurocomputational and neurocognitive disciplines.  She has received funding from NIMH, NIDA and NIAAA, as well as various pharmaceutical companies and charitable foundations. She is Associate Editor for Neuropsychopharmacology, Deputy Editor for Biological Psychiatry, Past President of the Brain Imaging Council for SNM, President-Elect for the American College of Neuropsychopharmacology and she serves on the scientific boards of Schizophrenia International Research Society, the Brain and Behavior Research Foundation and Research Forum.  She is also a member of the NIMH Board of Scientific Counselors.

Grant Writing Tips:  Thoughts on R01 Applications
by Jared W. Young & Jill L. Silverman

Writing your first R01 application is daunting, frightening and exhilarating all at the same time.  There is no underestimating how difficult that first application is to start with the blank screen in front of you.  You may be fortunate to have started with successful F- or K-award grant or pilot mechanism applications and therefore have some idea of the process.  The step to an independent investigator is however, an enormous one, opening yourself up to criticism like you’ve never been dealt earlier in the hands of your mentors. 

We thought it would be refreshing to disseminate pieces advice handed down to us over the years, which were invaluable and would behoove any aspiring independent investigator to take heed.  These pieces will hopefully invigorate rather than discourage aspiring newly, independent academic principal investigators.  We have outlined these components in what we believe to chronological order.  Naturally, if you have the best idea, the most innovative techniques, and are inherently a wonderful writer, this information may not be required.  In most situations, rarely is one person the “total package” as an early stage investigator. 

These pieces of advice are based on the premise that you already have a significantly impactful idea for your application, based on sound preliminary evidence, that you have the ability and resources to execute, in the environment (i.e., institution) you find yourself. 


Naturally, you cannot start your application unless you have a clear set of ideas you wish to test (i.e., aims).  The idea should not only be based on reading from the literature, but also from your preliminary findings.  In fact, preliminary evidence is vital to such a large application, it first must be provided to the reviewers to demonstrate such a proposal should be considered.  You must prove your experiments are viable.  Putting your ideas to paper well in advance of the application deadline (e.g., 12 months in advance) will give you plenty of time to identify what key experiments must be conducted to prove that key experiments are sustainable.  Such preparation also means that you can have your application written in plenty of time prior to the deadline.  Preferably, at least 1 month ahead of submission so that it can be read by others (see Support below) for feedback on legibility and clarity (see Clarity below).  Importantly, you should always leave time to go away from the application (e.g., for a week) and work on other items.  You will always see your application differently when you re-review yourself with fresh eyes.  This preparation gives you the chance to serve as a reviewer for yourself and spot any major or minor potential confounds.

Time is the best gift you can give yourself.


While your idea is germinating, you should also enlist support from your network.  The first level should come from colleagues in the field that have experience in this area, who can perhaps provide you with an example of successful applications.  Hopefully, by this point you will have been a Co-Investigators on a successful R01 application and be able to enlist the support and experience of the PI.  Such support does not however, need to be limited to your immediate group.  You can ask the support of colleagues in the field that have been successful, and/or are on study sections for their advice.  The level of support can vary from thoughts on your major premise, to actually reviewing the application for clarity.  Support from statisticians will also be vital, to review your proposed statistical analyses as well as the power analyses you have provided to support the feasibility of your project.  Finally, support can also come from those close to you but not directly in the field.  Your application may be read by someone that is not an expert in your field, so having a friend read your application for clarity of idea is central.  While academics are all busy, having at least 5 people read your aims, will give you great insight.  The aims page is only a single page and often the most critical.  If the aims are not clear and not dependent on one another, a reviewer may not be enthused to carefully read your 12 pages, when they have 8 others to review.


When you submit your application, you get the feeling that it is your “baby”.  You will spend so much time on it and know you want to cover every possible angle.  A common complaint of novel R01 applications is that they are complex and attempt to do too much.  If your approach is not simple enough for your non-expert friend to understand, it is likely the reviewers will have difficulty also.  There are some techniques you can adhere to that will aid in the clarity of your manuscript, making the reviewers’ job as easy as possible is essential.  These reviewers give up a fair amount of their time and get a lot of applications to review, so communicating your idea as simply as possible is key.  Don’t let the “sexy” of your innovation confuse your “expert” reviewer, it will not go over be favorably.  When you present your hypotheses, write them extremely clearly, and plainly stated.  Write them the format that would make the analysis obvious.  In fact even before you present your hypotheses, can your idea - all the aims - be put into a graphic that would appear on the first page?  If you can, do it!  This cartoon aids the reviewer whenever they get lost in your “masterpiece.”   Additionally, you will be presenting figures demonstrating your preliminary data.  If you can add a figure to each page, the reviewer won’t be faced with dense text.  Adding tables can also assist in legibility.  Finally, adding spaces between paragraphs provides clear delineation of ideas.  While these suggestions are indeed superficial and stylistic, you should cater to the reviewer and help them find your application understandable, readable and clear, so they feel their time is well spent.  Commonly, reviewers will say “I wanted to like this application because of the science but I could not get through its density.”  I (JS) taped this comment to my monitor at one point as a constant reminder.

Biosketch & other key items

You will certainly be tempted to focus on the research strategy section of the application.  Bear in mind however, this section is number 12, there are many other aspects of the application to be completed.  Working on experienced others to come up with a budget well ahead of time is key, can you afford to do what you promised?  Reviewers will evaluate the capability of completing the proposal in the allotted time.  In addition, do you have the skills and demonstrable leadership capabilities to conduct these experiments?  You can convey these two aspects from preparation of your Biosketch.  The new format enables on you to highlight key research areas that make you qualified to apply for this application.  Publications in the area are vital, but so is evidence that you have the independence to complete such work.  At the same time however, you must also convey your ability to work with any researchers listed as Co-Investigator.  Additionally, the Specific Aims, Summary, and Narrative sections will be your first opportunity to communicate your ideas to the reviewers.  Do not leave these sections to the end, work on them in concert with the application.  There should be time when Co-Investigators, or friends, will be reviewing the main body of the application.  Work on these sections while the main body of the text is in another’s hands.


It seems most applications will be as Investigator Initiated proposals.  If you can however, identify RFAs (request for applications) or Proposals which will identify research targets that the NIH group is interested in supporting.  Being responsive to such requests will increase the likelihood of funding even with lower scores.  Keeping an eye on those announcements and in touch with Program Officers within NIH will aid in this approach.  That is not to say Investigator Initiated proposals cannot also target key areas of interest from NIH.  In fact, commenting within the application how it addresses key areas of concern for one of the NIH domains may result in it being reviewed more favorably. 

As mentioned above, these pieces of advice come with the forewarning that most importantly the research area you propose must be worthy of researching (significance) and the idea be viable.  Using those items as a solid foundation for your proposal, and the suggestions above as the dressing, will hopefully aid in improving your chances.  Worst case scenario, there is always the chance to resubmit. 

IBNS @ SfN2016

As we have been for over 25 years, the IBNS was present at the 2016 Society for Neuroscience conference in San Diego, California, USA, last month.  Our members were extremely active in the IBNS exhibit booth and welcomed many new potential members, providing information on our Society and upcoming annual meeting.

The annual IBNS Social at SfN was attended by over 125 members and those interested in the organization.  View some of the photos of both events below:



2017 Travel Award Applications & Abstract Submissions

Join the International Behavioral Neuroscience Society (IBNS) for the 26th Annual Meeting on June 26-30, 2017. Hear from best in our fields of study, establish network with scientists and researchers from all over the world, show case your work and visit Hiroshima, Japan, a vibrant city with a rich culture.

The 2017 Travel Award Application for IBNS Student and Post-Doctoral members is now available online. For more information, visit Awards.  All applications are due by January 23, 2017.

Abstracts are also now being accepted through February 21, 2017, for poster or oral presentation at the Hiroshima meeting.  If you intend to present a only in poster format, you have until March 27, 2017, to submit your abstract using the 2017 Abstract Form.

Join NOW to get 2016 membership rates!

2017 IBNS membership forms are available online now.  However, as of January, all membership rates will increase, so join now to take advantage of the lower rates!  Find out about our membership options on the Membership webpage.


Trending Science

In this column, we will share the latest research, interesting scientific articles and news you can use.

Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior 

Researchers from Harvard characterize how a small subset of dopamine receptor expressing neurons in the serotonergic raphe nuclei account for male aggression in mice.  Read more here...

Japanese Basics

(excerpt from Mami Suzuki's Guide to Bowing in Japan)

First, bow when someone bows to you. This excludes the people who greet you in shops and hand out fliers on the street, but should be pretty fool-proof otherwise.

Second, when in doubt, bow to 30°. This will be acceptable in nearly every situation, as it shows a good balance of respect and familiarity.

Third, use age and titles to determine how long you bow, perform longer bows when bowing to someone of more senior age or position.

If all else fails, simply hold your bow a bit longer than the person you're bowing to or, if you're in a group situation, than the person who is your closest superior.

Call for News

IBNS would like to share your relevant developments with the organization. If you are a member of IBNS and have an achievement or topic that you would like considered for the next edition of IBNS News, please email the details, along with a headshot photo of yourself, to the IBNS Central Office no later than Friday, December 16, 2017.

We look forward to hearing your recent, newsworthy events!

IBNS Central Office | 1123 Comanche Path, Bandera, TX 78003 | [email protected]


Join the International Behavioral Neuroscience Society (IBNS) for the 26th Annual Meeting on June 26-30, 2017. Hear from best in our fields of study, establish network with scientists and researchers from all over the world, show case your work and visit Hiroshima, Japan, a vibrant city with a rich culture.