Sharp Brains: Brain Fitness and Cognitive Health News

Neuroplasticity, Brain Fitness and Cognitive Health News


Personalized Medicine in Psychiatry: from DSM to brain-based RDoC, iSPOT‑D and biomarkers

(Edi­tor’s Note: this is Part 2 of the new 3‑part series writ­ten by Dr. Evian Gor­don draw­ing from his par­tic­i­pa­tion at the Per­son­al­ized Med­i­cine World Con­gress on Jan­u­ary, 23, 2012 at Stan­ford Uni­ver­si­ty.)

Most Per­son­al­ized Med­i­cine research in Psy­chi­a­try using mol­e­c­u­lar mea­sures alone have failed to repli­cate. Whilst dis­ap­point­ing, this is not sur­pris­ing, since 80% of human 25,000 genes have some effect on the brain.

There are there­fore grow­ing efforts expand­ing Genom­ic Bio­mark­ers in Psy­chi­a­try to Neu­roimag­ing (all Brain-based bio­log­i­cal and cog­ni­tive mea­sures). Some approach­es tar­get Gene+Brain Com­bi­na­tion Bio­mark­ers to spe­cif­ic neu­ro­trans­mit­ter “Cir­cuits. For exam­ple the Sero­tonin cir­cuit: since SSRIs impact upon this Amyg­dala-Ante­ri­or Cin­gu­late-Raphe Nucleus–BDNF mol­e­c­u­lar mod­u­la­tion cir­cuit.

What­ev­er the approach, the goal is to shed light on bio­log­i­cal­ly rel­e­vant char­ac­ter­is­tics of the patient and then increas­ing­ly elu­ci­date which of these pre­dict a spe­cif­ic treat­ment response.

Diverse groups are shap­ing this bio­mark­er land­scape for psy­chi­a­try, includ­ing DSM‑5, NIMH and many trans­la­tion­al neu­ro­science groups.

I pre­sent­ed a dis­til­la­tion of these in my PMWC pre­sen­ta­tion:

  • The need for neu­ro­bi­o­log­i­cal infor­ma­tion to “val­i­date” con­structs of Psy­chi­atric dis­or­ders;
  • The need for mul­ti­ple com­ple­men­tary Gene+Brain mea­sures across scale;
  • A Neu­rode­vel­op­men­tal con­text, with empha­sis on the age of onset and peak peri­ods when Psy­chi­a­try insta­bil­i­ties man­i­fest;
  • A Dimen­sion­al con­text of Psy­chi­atric Dis­or­ders, where under­ly­ing neu­ro­bi­ol­o­gy is con­tin­u­ous from nor­mal­i­ty to dis­or­der;
  • Large Data­bas­es of norms for age and lon­gi­tu­di­nal clin­i­cal out­comes with clear end-points that can confirm/disconfirm Bio­mark­er treat­ment pre­dic­tions;
  • A trans­la­tion­al approach that links basic mech­a­nism of Psy­chopathol­o­gy to tar­get­ed Bio­mark­ers that pre­dict who is most like­ly to respond best to what inter­ven­tion.

These empha­sizes are reflect­ed in the move to the DSM‑5 and the “Research Domain Research Cri­te­ria (RDoC) ini­ti­atve launched by the Nation­al Insti­tute of Men­tal Health.

The goal of DSM‑5 to expand “signs and symp­toms” clas­si­fi­ca­tion to incor­po­rate bio­log­i­cal mea­sures, is cap­tured to some extent by this quote from Task Force Chair, David Kupfer:

As we grad­u­al­ly build on our knowl­edge of men­tal dis­or­ders, we begin bridg­ing the gap between what lies behind us (pre­sumed eti­olo­gies based on phe­nom­e­nol­o­gy) and what we hope lies ahead (iden­ti­fi­able patho­phys­i­o­log­ic eti­olo­gies).” Amer­i­can J Psy­chi­a­try, 168 (7): 672–674, 2011.

The DSM pro­vides a con­sis­tent frame­work for clin­i­cal com­mu­ni­ca­tion. But it was devel­oped at a time of lim­it­ed knowl­edge in brain sci­ence. Its cur­rent lim­i­ta­tion in Per­son­al­ized treat­ment pre­dic­tion reflects this knowl­edge gap and the grow­ing call for flesh­ing out the clin­i­cal real­i­ty of co-mor­bid­i­ty and het­ero­gene­ity by con­nect­ing them with mean­ing­ful bio­log­i­cal enti­ties.

RDoC is a com­ple­men­tary approach (Insel et al. 2010. Amer­i­can J Psy­chi­a­try, 1020; 167 (7): 748–751). One of its goals will be to inform new edi­tions of clas­si­fi­ca­tion sys­tems. But the breadth of its impli­ca­tions con­struc­tive­ly chal­lenges all cur­rent con­ven­tion­al approach­es in Psy­chi­a­try.

RDoC is a Frame­work of 5 orga­niz­ing ‘Domains’ that cut across tra­di­tion­al dis­or­der clas­si­fi­ca­tions. The Research Domain Cri­te­ria (RDoc) are:

Neg­a­tive Valence Sys­tems (Threat and Anx­i­ety);
Pos­i­tive Valence Sys­tems (Rewards and Habits);
Cog­ni­tive Sys­tems (atten­tion, per­cep­tion, work­ing mem­o­ry);
Sys­tems for Social Process­es (iden­ti­fi­ca­tion of facial expres­sion, The­o­ry of Mind);
Arousal/Regulatory Sys­tems (State and Trait dynam­ics).

By expli­cat­ing RDoC, NIMH seeks to elu­ci­date the under­pin­ning bio­log­i­cal mech­a­nisms across scale (from genes to cir­cuits and behav­ior) of these 5 domains. This is antic­i­pat­ed to lead to new mol­e­c­u­lar and neu­roimag­ing drug dis­cov­ery tar­gets, accel­er­ate a new cul­ture of research strate­gies (suc­ceed or fail fast; stan­dard­iza­tion, inte­gra­tion, data shar­ing) and pro­vide fun­da­men­tal­ly new bio-behav­ioral approach­es to clas­si­fy­ing (and treat­ing) men­tal dis­or­ders.

Using stan­dard­ized meth­ods to advance Per­son­al­ized Med­i­cine in Psy­chi­a­try

One approach to inte­grat­ing bio­mark­ers with clin­i­cal knowl­edge in Psy­chi­a­try is the use of stan­dard­ized mea­sure­ment to link each type of infor­ma­tion.

Brain Resource has a flag­ship study under­way that uses stan­dard­ized meth­ods to iden­ti­fy bio­mark­ers of per­son­al­ized treat­ment for depres­sion: the inter­na­tion­al Study to Pre­dict Opti­mized Treat­ment for Depres­sion (iSPOT‑D).

iSPOT‑D uses the stan­dard bat­tery of mea­sures estab­lished by Brain Resource, and used to set up the inter­na­tion­al data­base. These mea­sures include:

Mol­e­c­u­lar (Genet­ic vari­ants);
Brain Imag­ing (struc­tur­al and func­tion­al scans) ;
Phys­i­ol­o­gy (EEG, Evoked Poten­tials, heart rate and skin con­duc­tance);
Cog­ni­tive and Emo­tion­al behav­ior;
Self-report­ed expe­ri­ence.

iSPOT‑D is using these mea­sures to iden­ti­fy bio­mark­ers that pre­dict these end points:

  • Over­all Response to the med­ica­tion (No/Yes: defined by symp­tom remis­sion);
  • Dif­fer­ent respons­es to the 3 most com­mon­ly employed anti­de­pres­sives in the U.S. (Esc­i­talo­pram; Ser­tra­line; Ven­lafax­ine-XR);
  • Dose (For Exam­ple Ven­lafax­ine: SSRI 150mg);
  • Side effects;
  • Long Term Remis­sion.

These pro­to­cols have been pub­lished (For details, see: Williams, Rush, Koslow, Wis­niews­ki, Coop­er, Nemeroff, Schatzberg, Gor­don, Tri­als, 4, 2011).

iSPOT‑D will have 2,000 patients with Major Depres­sion Dis­or­der (MDD). The goal is to deter­mine the best bio­mark­ers for treat­ment pre­dic­tion in the 3 med­ica­tions. Data for the first 1,000 par­tic­i­pants is cur­rent­ly in analy­sis.

The need for bio­mark­ers in Psy­chi­a­try

The need for iden­ti­fy­ing bio­mark­ers is enor­mous, and depres­sion is a strik­ing exam­ple of this need.

The cost of depres­sion in the U.S. is $43.7 bil­lion per year, and $83 bil­lion when lost work pro­duc­tiv­i­ty is fac­tored in. Each year, over 60 mil­lion pre­scrip­tions are writ­ten for esc­i­talo­pram, ser­tra­line and ven­lafax­ine-XR. Retails sales for these med­ica­tions total $6 bil­lion.

The exam­ple below serves to illus­trate the impli­ca­tions of dis­cov­er­ing Bio­mark­ers that pre­dict treat­ment response for the 3 most com­mon­ly used anti­de­pres­sants in the U.S.:

Let’s assume the cur­rent 1 in 3 chance of being pre­scribed the right anti­de­pres­sive treat­ment first time can be improved by 25% (from 33% to 42%). That means that around 2m peo­ple (10% of the 19m suf­fer­ing depres­sion in the U.S.) will ben­e­fit from sav­ing at least one incor­rect pre­scrip­tion. The iSPOT med­ica­tions rep­re­sent a 40% mar­ket share so that implies 800,000 peo­ple (assum­ing sim­ple aver­ages) will ben­e­fit from this sav­ing. Assum­ing an aver­age $50 pre­scrip­tion cost per patient, this implies a direct med­ica­tion cost sav­ing of $40m. This of course ignores the flow on costs of clin­i­cal con­sul­ta­tion time, pro­duc­tiv­i­ty loss­es and over­all patient suf­fer­ing when get­ting the wrong med­ica­tion. Adding the cost of even 1 lost day and 1 inef­fi­cient clin­i­cal vis­it mean and these sav­ings can increase ten fold (assum­ing $500 cost to an employ­er for one lost day and $100 for a clin­i­cal vis­it). It also ignores the ben­e­fit that a patient that reach­es a solu­tion faster will have high­er com­pli­ance tak­ing the med­ica­tion and data has shown that this leads to over­all reduced med­ical expen­di­tures of more than $1,000 pa (“Recov­ery from Depres­sion, Work Pro­duc­tiv­i­ty, and Health Care Costs Among Pri­ma­ry Care Patients, Gre­go­ry E. Simon, MD, et al. Gen­er­al Hos­pi­tal Psy­chi­a­try 22, 153–162, 2000).

Find­ing the right bio­mark­ers for each per­son is an impor­tant way to get the right med­ica­tion for each patient quick­ly.


To Be Con­tin­ued…

New Series on Per­son­al­ized Med­i­cine and the Brain:

  • Mon­day, Feb­ru­ary 13th: The State of Per­son­al­ized Med­i­cine
  • Mon­day, Feb­ru­ary 20th: Per­son­al­ized Med­i­cine in Psy­chi­a­try (above)
  • Mon­day, Feb­ru­ary 27th: Work­ing with Health Care Indus­try Stake­hold­ers Towards Brain-based Per­son­al­ized Med­i­cine
– Dr Evian Gor­don is the Exec­u­tive Chair­man of theBrain Resource Com­pany.  He ini­tially drew upon  his sci­ence and med­ical back­ground to estab­lish the inter­dis­ci­pli­nary Brain Dynam­ics Cen­ter, in 1986.  Through the Brain Dynam­ics Cen­ter and its col­lab­o­ra­tive net­works, Dr Gor­don estab­lished an “inte­gra­tive neu­ro­science” approach, ground­ed in the use of stan­dard­ized meth­ods across mul­ti­ple types of data. Using this approach, Dr Gor­don found­ed the “Brain Resource Com­pany”, that cre­ated the first inter­na­tional data­base on the human brain. The data­base is the asset which under­pins the devel­op­ment of new tools for brain health and its per­son­al­ized appli­ca­tion in the mar­ket, such as assess­ments of brain health, deci­sion sup­port sys­tems, and per­son­al­ized train­ing pro­grams. Brain Resource has also sup­ported the for­ma­tion of a non-prof­it 501c3 Foun­da­tion, called ‘BRAIN­net” (, through which sci­en­tists have access to many of these datasets for inde­pen­dent research.

Leave a Reply...

Loading Facebook Comments ...

Leave a Reply

Categories: Cognitive Neuroscience, Technology

Tags: , , , , , , , , , , , , , , , , , , , , , , , , , ,

About SharpBrains

As seen in The New York Times, The Wall Street Journal, BBC News, CNN, Reuters,  SharpBrains is an independent market research firm tracking how brain science can improve our health and our lives.

Search in our archives

Follow us and Engage via…

RSS Feed

Watch All Recordings Now (40+ Speakers, 12+ Hours)