Molecular Psychiatry (2006) 11, 11–17

& 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00
www.nature.com/mp

PERSPECTIVE

Cure therapeutics and strategic prevention: raising the bar

for mental health research
TR Insel1 and EM Scolnick2
1
NIMH, Bethesda, MD, USA and 2Broad Institute of MIT and Harvard, Cambridge, MA, USA

Mental disorders cause more disability than any other class of medical illness in Americans
between ages 15 and 44 years. The suicide rate is higher than the annual mortality from
homicide, AIDS, and most forms of cancer. In contrast to nearly all communicable and most
non-communicable diseases, there is little evidence that the morbidity and mortality from
mental disorders have changed in the past several decades. Mental health advocates,
including psychiatric researchers, have pointed to stigma as one of the reasons for the lack of
progress with mental illnesses relative to other medical illnesses. This review considers how
the expectations and goals of the research community have contributed to this relative lack of
progress. In contrast to researchers in cancer and heart disease who have sought cures and
preventions, biological psychiatrists in both academia and industry have set their sights on
incremental and marketable advances, such as drugs with fewer adverse effects. This essay
argues for approaches that can lead to cures and strategies for prevention of schizophrenia
and mood disorders.
Molecular Psychiatry (2006) 11, 11–17. doi:10.1038/sj.mp.4001777
Keywords: recovery; remission; prevention; pathophysiology, drug development

Introduction research has generally sought incremental advances.

Health care 100 years ago was dominated by acute,
infectious diseases.1 Chronic infectious and non-
infectious diseases, such as tuberculosis, syphilis,
leprosy, and the mental illnesses were frequently
confined to large public institutions where treatments
were largely custodial. After 100 years in this country,
most acute infectious illnesses are preventable or
curable. In 2005, we find ourselves in the era of
chronic illnesses.2 Many of the chronic illnesses of
1905, such as leprosy, syphilis, and (until recently)
tuberculosis, have become so rare as to be unknown
by young physicians. The conspicuous exception in
this history of progress is mental illness. In spite of
new medications and psychosocial treatments, men-
tal illnesses, such as schizophrenia and mood
disorders, are as much of a public health challenge
now as they were a century ago. Mental illnesses are
increasingly recognized to be chronic and disabling,
belonging to a group of serious medical illnesses that
includes heart disease, cancer, and diabetes. How-
ever, as we argue throughout this essay, researchers
continue to approach mental illnesses as fundamen-
tally different from these other medical diseases.
While the goals of biomedical research for heart
disease, diabetes, and cancer are generally cure and
prevention, very little research for the mental ill-
nesses has set the bar this high. Mental illness
Correspondence: Dr TR Insel, NIMH – Room 8235, 6001 Executive
Blvd., Bethesda, MD 20892, USA.
E-mail: insel@mail.nih.gov
Here we ask: What would be a strategy for seeking a
cure for a mental disorder? What are the impediments
to raising the bar? How can we ensure that less than
100 years from now schizophrenia, mood disorders,
and autism will join the ranks of leprosy, syphilis,
and tuberculosis?
The public health challenge
As a starting point, it is important to recognize the
challenge. Mental illnesses are common, chronic, and
disabling. The recent National Comorbidity Survey-
Replication (NCS-R) study used a population-based
approach to estimate the prevalence of mood, anxiety,
and substance use disorders in a household survey.3
Even leaving out schizophrenia, 6% of this household
population was identified as having a ‘serious’
disorder, defined as a suicide attempt with serious
lethal intent, work disability or substantial limita-
tions, or being out of role for at least 30 days in the
past year. As the NCS-R did not count some of the
most severely disabled who are in hospitals, prisons,
or homeless, the 6% estimate must be considerably
lower than the rate of severe disability from mental
illness in the general population. Indeed, schizophre-
nia affects roughly 1% of the population; most people
with this disorder are unemployed, unmarried, and
on public assistance.4 Autism spectrum disorder, also
not counted in the NCS-R, has been estimated to
affect between 0.3 and 0.6% of children, many with a
 Cure therapeutics and strategic prevention
TR Insel and EM Scolnick

12
lifelong absence of language and severe social little progress on some of the most serious mental
deficits.5 disorders. While we are seeing recent reductions in
In an attempt to quantify the public health burden deaths from cardiac disease, AIDS, certain cancers,
of each of the major medical illnesses, the World and even homicide, the mortality rate as measured by
Health Organization launched the Burden of Disease the number of suicides has changed little in the past
study. This study, which used the metric of ‘dis- century.7 Are we reducing morbidity? The epidemio-
ability-adjusted life years’ to take into account the logical data on prevalence and severity are not
duration as well as the severity of the disability, encouraging. Clearly, more people are receiving
identified mental illness as the number one source of treatment over the past decade, but there is little
disability from all non-communicable medical causes evidence thus far that this has led to reductions in
in developed nations.6 Relative to other major sources disability.10
of morbidity and mortality, such as heart disease,
cancer, and stroke, mental illnesses are chronic and
Progress: the glass half full
they strike early in life. In the 15–44-year-age bracket,
depression and substance abuse disorders account for This sober accounting of the state of mental health
more than 50% of the disability from all medical care neglects substantial progress in many areas. For
causes. Indeed, as shown in Table 1, all of the top five the most common major illnesses, we now have
sources of medical disabilities are mental disorders in medical and psychosocial interventions of proven
this age bracket in the US and Canada. efficacy in randomized, controlled trials. Exceptions
It is also clear that these illnesses account for include anorexia nervosa and autism where we still
considerable mortality. There are approximately lack large-scale, controlled trials. However, even for a
30 000 suicides in the US each year, with 90% related chronic, disabling illness like schizophrenia, we have
to a mental disorder.7 This is greater than the number medications that predictably reduce most of the
of deaths from homicide (18 000), AIDS (20 000), and positive symptoms, allowing patients to leave hospi-
all but three forms of cancer (lung, breast, and colon). tals. Many patients with mood disorders will respond
While suicide is usually associated with depression, to treatment and some will recover completely.
the relative risk of death from suicide is increased How does this availability of effective treatments
nearly 10-fold in schizophrenia and 50-fold in square with the persistent morbidity and mortality of
anorexia nervosa.8,9 these disorders? The traditional answer is that we fail
What is perhaps most surprising in looking at at service delivery, that is, too few patients receive
morbidity and mortality data is that we have made so evidence-based interventions. There are good data to
support this argument. The PORT study demonstrated
the low rate of use of several evidence-based
treatments for schizophrenia.11 A recent meta-analy-
Table 1 Defining the public health burden at the beginning
sis of 28 studies demonstrates that family psycho-
of the 21st century
education can reduce relapse in schizophrenia by
Causes of disability by illness category (all ages) 50%, but only 31% of patients receive this relatively
Mental illness 26.1 cost-effective intervention.12,13 The NCS-R study
Alcohol and drug use 11.5 reports that only 50% of those with depression
Respiratory diseases 7.6 receive any treatment and approximately 20% receive
Musculoskeletal diseases 6.8 minimally adequate care.10 Cognitive behavioral
Sense organ diseases 6.4 treatment has been demonstrated to be an effective
Cardiovascular diseases 5.0 psychotherapy for mood and anxiety disorder, but a
Dementias 4.8
recent survey documents that the majority of psy-
Injuries 4.7
Digestive diseases 3.4
chotherapy training programs in the US do not
provide adequate training in this or any other
Causes of disability by specific illness (ages 15–44 years) evidence-based treatment (Weissman, 2005, personal
Unipolar depression 28.1 communication).
Alcohol use 15.4
Drug use 4.8
Bipolar disorder 3.7 Limitations: the glass half empty
Schizophrenia 3.4 While there can be little doubt that we have not fully
Hearing loss (adult onset) 2.4 utilized the available treatments, it is important to
Migraine 2.3
recognize that the available treatments are insuffi-
Asthma 2.3
Iron-deficient anemia 2.2
cient. To repeat an oft-used metaphor from the history
Diabetes mellitus 2.2 of polio, while we can continue to make more and
better iron lungs available, we also need to go after the
Values represent percent of disability due to either class or vaccine. All current medical treatments for mental
specific illness. Disability defined by WHO as years lost due illnesses are palliative, none are even proposed as
to disability for all medical illnesses (excluding commu- cures. Yes, too few people receive evidence-based
nicable diseases).6 palliative care. However, to stretch the polio meta-

Molecular Psychiatry

phor, we have not yet gone after the vaccine. Indeed,
while the recent President’s New Freedom Commis-
sion on Mental Health Care proclaimed ‘recovery’ as
the goal of mental health care, few research studies
have aimed for ‘recovery’ as an outcome.14
In fairness, researchers may avoid the term ‘recov-
ery’ because it is difficult to quantify. Remission has
been a more widely accepted term, with several
attempts to provide consensus definitions of remis-
sion in mood disorders and schizophrenia.15–17
Resnick et al.18 have recently described two defini-
tions of recovery: recovery as an outcome (which
might be defined as remission over an extensive
duration) and recovery as an orientation (defined as
life satisfaction, hope and optimism, knowledge
about mental illness and services, and empower-
ment). While the latter definition of recovery may be
more achievable with the provision of current
services as envisioned by the President’s New Free-
dom Commission, we suspect this goal would fall far
short of what most researchers in cancer or heart
disease would accept as success. We suggest that in
mental illnesses as in other medical illnesses, we
need to aim for a goal of recovery defined by a
complete and permanent remission. In other areas of
medicine, this approach has been called ‘cure
therapeutics’ (URL: www.jdrf.org).
If cure therapeutics is the goal, how insufficient are
today’s treatments for mental illnesses? For some
disorders such as autism and anorexia nervosa, we
simply lack biomedical treatments for the core
symptoms. For others, such as schizophrenia, current
treatments target only select symptoms. Neuroleptics,
both conventional and atypical antipsychotics, re-
duce psychotic symptoms but may not treat the
cognitive deficits or negative symptoms of schizo-
phrenia.19 While five decades of research have shown
that antipsychotics have greater efficacy than placebo
for reducing hallucinations and delusions in schizo-
phrenia, the effectiveness of these drugs remains
disappointing. The recent Clinical Antipsychotic
Treatment Intervention Effectiveness (CATIE) trial
demonstrated that only about one in four patients
with chronic schizophrenia continued either a first or
second generation antipsychotic throughout an 18-
month trial.20 An analysis of the 1490 patients who
began this trial revealed that less than 10% met cross-
sectional criteria for symptomatic and functional
remission at the 18-month end point (S Scott,
personal communication). Of course the patients in
CATIE were chronically ill and partially treatment
resistant, so a low rate of recovery should not be
surprising. However, even in a 5-year follow-up of
118 schizophrenic patients after their first episode of
psychosis, only 13.7% met criteria for full remission
lasting 2 years or more.21 Schizophrenia remains a
chronic, disabling disorder, just as it was a century
ago. We know that psychosocial interventions, such
as supported employment and family psychoeduca-
tion, reduce relapse and may help patients to achieve
a life in the community. Surprisingly, we do not know
Cure therapeutics and strategic prevention
TR Insel and EM Scolnick
13
how many or which patients with schizophrenia will
recover with the optimal combined application of
current medical and psychosocial interventions. And
our expectations continue to be limited. For instance,
the recent consensus definition of remission for
schizophrenia developed by an American Psychiatric
Association working group does not even include a
requirement of improved functioning, which many
patients and families view as the essence of recov-
ery.17
Are treatments for mood disorders much better?
Antidepressants, the third most commonly prescribed
class of medications in the US, have been shown to
reduce the symptoms of major depressive disorder,
but these drugs are generally better than placebo only
after 6 weeks of administration and in most studies,
patients on medication continue to have substantial
depressive symptoms.22 A consensus definition of
remission published in 1991 has helped the field to
measure remission as a target in the treatment of
major depressive disorder. How often do SSRIs result
in remission? In a large-scale effectiveness study of
the SSRI citalopram less than a third of patients met
criteria for remission (defined as a 17 item Hamilton
Rating Score < 8 or last observed QIDS-SR16 of < 6)
after 12 weeks of treatment.23 Placebo was not used as
a comparison for this trial, so it is not clear how many
of these patients would have recovered without active
medication. However, even accepting that roughly
one-third meet criteria for remission, is the treatment
sufficient? In an illness characterized by intense
emotional suffering, hopelessness, and suicidal idea-
tion, should we be satisfied with treatments that
require several weeks to be effective and will not lead
to remission in the majority of patients? Would our
colleagues in medicine be satisfied with these out-
comes for an illness characterized by intense pain,
high morbidity, and a 4% mortality rate?
In considering the shortcomings of current treat-
ments, one can hardly ignore the absence of progress
in developing medications with new mechanisms.
While scores of new antipsychotics and antidepres-
sants have been introduced over the past three
decades to reduce side effects or improve efficacy,
virtually all of these ‘new’ medication are simply
variations on old themes. In contrast to other areas of
medicine, there have been few medications with new
mechanisms of action developed in the past three
decades for schizophrenia and depression (Figure 1).
In fact, after more than three decades, we do not truly
know the mechanisms or targets for the first genera-
tion medications, so one can hardly be certain if
newer atypical antipsychotics or SSRIs represent
compounds with different mechanisms of action or
simply chemical analogues with fewer or different
side effects.24
A different approach
Whether one focuses on the glass as half full or half
empty, there can be little doubt that we need a
Molecular Psychiatry
 Cure therapeutics and strategic prevention
14
16
14
# of Mechanistically
Distinct Drugs
12
10
8
6
4
2
0
1950s
Depression Schizophrenia
Figure 1 Drug development in the past 50 years. While
pharmacologic research in cardiovascular medicine and
other areas of medicine has developed medications with
new mechanisms of action, psychiatry has enjoyed less
innovation in terms of drug development. Over the past 50
years, new medications for schizophrenia and depression
have been almost exclusively based on existing medications
without developing compounds that have either new
clinical targets (e.g. the cognitive deficits in schizophrenia
or suicidal behavior in depression) or new molecular
mechanisms (beyond dopamine receptor blockade for
schizophrenia or monoamine transporter or enzyme block-
ers for depression).
different approach for medication development for
mental disorders. For the past five decades, the
biological study of mental illness has been dominated
by the study of the action of the available drugs. In
retrospect, this might have been productive if the
drugs targeted the core pathophysiology of the
disorders. Certainly, the study of insulin action has
been useful for developing new approaches to
diabetes and research on adrenergic pharmacology
has been helpful for cardiovascular medicine. How-
ever, as we have just reviewed, the available medica-
tions in psychiatry are insufficient for treating the
disorders. Indeed, after five decades, we need to
recognize that we may never get from neuropharma-
cology to the pathophysiology of mental disorders.
The canonical approach to treatment development
in psychiatry is essentially a recipe for developing
‘me-too’ compounds, as the entire process is based on
developing drugs modeled on an existing, insufficient
drug (Figure 2). In other areas of medicine, from heart
disease to cancer, treatment development begins by
defining pathophysiology (Figure 2). Through cell
biology (identifying the tyrosine kinase for myeloid
cell division) or epidemiology (recognizing the role of
cholesterol in heart disease), the process begins with
target identification.
How will we identify new targets for mental
disorders? This will happen just as it is happening
in the rest of medicine, through research on the core
mechanism of these diseases. There are three key
steps in this process. First, comprehensive studies of
people with these disorders, using genomics, tran-
scriptomics, and proteomics, should identify cellular
pathways that are affected. This will undoubtedly be
more difficult than in other areas of medicine, but
genetics is already providing some hints. The study of
Molecular Psychiatry
TR Insel and EM Scolnick
Psychiatric Medications Modern Drug Discovery
Clinical observation Molecular pathophysiology
Mechanism of action Small molecule screening
Present Animal studies Animal studies
Heart Disease
Clinical trial Clinical trial
Figure 2 Pathways for drug development. The traditional
pathway for medication development in psychiatry has
begun with a serendipitous clinical observation of efficacy
followed by intensive study of the drug’s actions. Based on
neuropharmacology, new drugs have been developed with
greater specificity or potency and these, in turn, are tested
in animal studies and clinical trials. This is a recipe for
developing new drugs that will mimic existing drugs. The
modern approach to drug development begins with identi-
fying a molecular or cellular target based on pathophysiol-
ogy, then uses high throughput screening of small molecule
libraries to detect potential hits that can be refined by
medicinal chemistry into drugs for testing in animals and
ultimately adapted for clinical trials.
the serotonin transporter promoter demonstrates that
the short allele is associated with an increase in the
vulnerability to depression.25,26 This allele also is
associated with a reduction in the volume of Area 25
in the ventromedial prefrontal cortex, a region with
one of the most intense serotonergic innervations in
the forebrain.27 Along with reduced volume of this
brain region, the short allele is associated with a
functional dissociation of this region from the
amygdala during the processing of negative affect.27
Understanding how this allele alters development of
Area 25 and affects functional connectivity in the
forebrain could serve as a starting point for defining
targets for major depressive disorder.
However, the search for genomic variations asso-
ciated with mental illness is really just beginning.
With the recent completion of the human haplotype
map and the advent of rapid genotyping capacity, we
should finally make rapid progress identifying some
of the vulnerability genes and thus critical pathways
for the pathophysiology of the major mental ill-
nesses.28 In other complex genetic diseases, such as
age-related macular degeneration, this strategy is
already revealing new targets that would not have
been suspected based on decades of descriptive
research.29
A second step, the use of in vitro screening, will be
critical for identifying new compounds. What we
have learned elsewhere in medicine is that target
identification is a long and high-risk process with
many false leads. It is also the easy part, in that

cellular pathways frequently have specific pressure
points for modifying function and these may be
implicated in many diseases. The second step,
developing small molecules that affect these pressure
points, may prove more difficult. Indeed, this step has
historically been ceded to the pharmaceutical indus-
try. The recent creation of a molecular library screen-
ing centers network (MLSCN) in universities and the
NIH has, for the first time, encouraged academic
investigators to engage in the early phase of identify-
ing small molecules for influencing specific cellular
pathways.30 The MLSCN uses a library of small
molecules, an array of assays recommended by the
field, and high throughput screening centers to
identify ‘hits’ for any given target. Of course, there
will be a vast amount of medicinal chemistry
necessary to translate a ‘hit’ in a small molecule
screen into a drug, but this network promises to
increase the number and the range of targets that can
be interrogated. One might expect that early years of
this project will largely be focused on cancer and
metabolic targets, but the advent of targets for mental
disorders should allow rapid development of new
compounds for cell biology, some of which may
graduate to medications with novel mechanisms of
action.
Once new compounds are available from in vitro
screening, they can be tested in whole animals.
Whereas ‘animal models’ in psychiatry have largely
been developed to simulate psychopathology and
validated by their response to existing medications,
drug discovery models are created based on a
pathologic mechanism and used to search for new
targets and ultimately new compounds. For instance,
the identification of the role of specific genes in
Alzheimer’s disease has led to the creation of flies,
fish, and mice with homologous alleles, a similar
phenotype, and a model system for testing new
interventions.31 While similar progress has been
reported in a number of neurodevelopmental dis-
orders recently, including Fragile X and Rett syn-
drome, we have not yet seen the first ‘animal model’
of a psychiatric disorder in which various genetic
lesions are used to develop the phenotype.32,33
Finally, new compounds can be tested in clinical
trials. Trials may increasingly be public rather than
private. The NIH Roadmap as part of its effort to re-
engineer clinical research has proposed the develop-
ment of a national network of clinical trialists who
can move quickly to test the efficacy and the
effectiveness of new treatments. Networks have
already been developed in pediatric cancer and cystic
fibrosis, such that nearly every patient becomes a
participant. The NIMH effectiveness trials, such as
CATIE, STAR-D, and STEP-BD may represent the
beginning of such a network for mental illness.
Prevention
Our discussion to this point has focused on the
development of new medications that could be cures.
Cure therapeutics and strategic prevention
TR Insel and EM Scolnick
15
The approach described above has proven effective
for acute myeloid leukemia. The discovery of a single
tyrosine kinase, BCR-ABL, with effects on myeloid
transformation led to a small molecule, imitiab, that
has already revolutionized treatment of leukemia and
other blood disorders.34 This spectacular success is
notable because it lays out a pathway of discovery
that could lead to cures of many illnesses based on an
understanding of pathophysiology, identifying targets
for intervention, and developing effective small
molecules. It is also notable because it is relatively
rare in medicine.
The great public health success stories of the past
century are largely stories of prevention. From
sanitation to vaccines to smoking cessation to the
use of statins, we have proven much more successful
at pre-empting disease than curing it. What do we
need to pre-empt or prevent mental disorders? As
with sanitation, there are undoubtedly public health
interventions that will change social norms and
improve functioning. For instance, a nurse visitation
program for new mothers reduces antisocial behavior
in their offspring even 15 years after the interven-
tion.35 This is an important contribution but there is
no evidence that such public health interventions
reduce morbidity and mortality of schizophrenia,
mood disorders, or autism. Psychiatry will need to
develop strategies for prevention for each of these
disorders.
Two recent approaches offer promise. Most people
with schizophrenia have symptoms of this illness for
more than 18 months before they become overtly
psychotic.36 Studies of the prodrome have reported a
strategy to identify those who will go on to have a
psychotic break with 86% sensitivity and 91%
specificity.37 Analogous to identifying those at risk
for myocardial infarction, one can imagine that early
intervention could pre-empt the psychotic break and
prevent the long-term disability of this illness. In
cardiology, biomarkers (plasma lipids), family history,
and functional imaging are all critical for identifying
risk, and statins, exercise, and even surgical inter-
ventions are essential for prevention. In schizophre-
nia, we lack biomarkers and imaging has not yet been
developed for clinical use. Also, we do not know if
either medication or psychosocial interventions will
pre-empt a psychotic break. Nevertheless, we have an
opportunity to develop a strategy for pre-emption that
could have an impact as great as or even greater than a
new, effective class of drugs.
In many ways, PTSD is a disorder defined by a
failure of recovery. Following trauma, an acute
emotional response is expected and potentially
adaptive. Whereas, most individuals recover from
trauma, a small percentage subsequently develop
PTSD, the actual percentage resulting from a complex
mix of individual vulnerability and the nature of the
trauma. Identifying who is at risk for PTSD could
focus intervention efforts, much as we do now in
cardiovascular disease. Shalev and co-workers have
tested a transcriptional approach to identify a finger-
Molecular Psychiatry
 Cure therapeutics and strategic prevention
TR Insel and EM Scolnick
16
print for susceptibility; others have recommended
specific clinical features of the early stress response
that indicate a high likelihood for subsequent
PTSD.38,39 We do not yet have the equivalent of
cholesterol or Thallium imaging for PTSD, but the
model clearly has promise as there are several
behavioral and medical interventions that might pre-
empt the development of PTSD.40,41
Note that both of these examples require a better
understanding of the pathophysiology of mental
disorders, not for developing interventions but for
identifying risk. As in the rest of medicine, genomics
will be essential, but we will need epidemiology and
developmental neuroscience to understand how these
illnesses develop if we are to pre-empt them.
Conclusion
Mental illnesses are among the most disabling of
medical illnesses. Currently evidence-based medical
and psychosocial treatments are not delivered to the
majority of patients who would benefit. These
palliative treatments are necessary but not sufficient.
Even with optimal care, many patients with mental
illness will not recover, where recovery is defined as
permanent remission. Patients need rapid, effective
treatments that target the core pathophysiology of
these illnesses. And they need tools for early detec-
tion and preventive interventions. Psychiatric re-
search can develop new diagnostic markers and
treatments, but this will require defining the patho-
physiology of these illnesses. We now have the
research tools necessary. Now is the time for research
to set an ambitious goal of finding cures and
preventive interventions for these disabling illnesses.
References
1 Kennedy M. A Brief History of Disease, Science and Medicine, The
Writers Collective, Cranston, Rhode Island, 2004.
2 Zerhouni E. Translational and clinical science–time for a new
vision. N Engl J Med 2005; 353: 1621–1623.
3 Kessler RC, Chiu W, Demler O, Walters E. Prevalence, severity, and
comorbidity of 12-month DSM-IV disorders in the national
comorbidity survey replication (NCS-R). Arch Gen Psychiatr
2005; 62: 617–627.
4 Lauriello J, Bustillo JR, Keith SJ. Schizophrenia: scope of the
problem. In: Sadock BJ, Sadock VA (eds). Comprehensive Textbook
of Psychiatry, 8th edn. Lippincott Williams & Wilkins: Philadel-
phia, 2004, pp 1345–1353.
5 Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C,
Murphy C. Prevalence of autism in a US metropolitan area. JAMA
2003; 289: 49–55.
6 WHO Report. 2002; http://www.who.int/healthinfo/bodestimates/
en/.
7 Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE (eds).
Reducing Suicide: A National Imperative. Board on Neuroscience
and Behavioral Health, Institute of Medicine Publisher: Washing-
ton, DC, 2002.
8 Heila H, Haukka J, Suvisaari J, Lonnqvist J. Mortality among
patients with schizophrenia and reduced psychiatric hospital care.
Psychol Med 2005; 35: 725–732.
9 Keel PK, Dorer DJ, Eddy KT, Franko D, Charatan DL, Herzog DB.
Predictors of mortality in eating disorders. Arch Gen Psychiatr
2003; 60: 179–183.
Molecular Psychiatry
10 Kessler R, Berglund P, Demler O, Jin R, Koretz D, Merikangas K et
al. The epidemiology of major depressive disorder. JAMA 2003;
289: 3095–3105.
11 Lehman AF, Steinwachs DM. Patterns of usual care for schizo-
phrenia: initial results from the Schizophrenia Patient Outcomes
Research Team (PORT) client survey. Schizophr Bull 1998; 24: 11–
20.
12 McFarlane WR, Dixon L, Lukens E, Lucksted A. Family psychoe-
ducation and schizophrenia: a review of the literature. J Marital
Fam Ther 2003; 29: 223–245.
13 Resnick SG, Rosenheck HA, Dixon L, Lehman AF. Correlates of
family contact with the mental health system: allocation of a scare
resource. Ment Health Serv Res 2005; 2: 113–121.
14 The President’s New Freedom Commission on Mental Health.
Achieving the Promise: transforming mental health care in
America, Final Report, July 2003.
15 Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW et
al. Conceptualization and rationale for consensus definitions of
terms in major depressive disorder. Remission, recovery, relapse,
and recurrence. Arch of Gen Psychiatr 1991; 48: 851–885.
16 Nierenberg AA, Wright EC. Evolution of remission as the new
standard in the treatment of depression. J Clin Psychiatr 1999;
60(Suppl 22): 7–11.
17 Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR,
Weinberger DR. Remission in schizophrenia: proposed criteria and
rationale for consensus. Am J Psychiatr 2005; 162: 441–449.
18 Resnick S, Rosenbeck R, Lehman A. An exploratory analysis of
correlates of recovery. Psychiatr Serv 2004; 55: 540–547.
19 Hyman S, Fenton W. Medicine. What are the right targets for
psychopharmacology? Science 2003; 299: 350–351.
20 Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA,
Perkins DO et al. Effectiveness of antipsychotic drugs in patients
with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.
21 Robinson DG, Woerner MG, McMeniman M, Mendelowitz A,
Bilder RM. Symptomatic and functional recovery from a first
episode of schizophrenia. Am J Psychol 2004; 161: 473–479.
22 Tamminga C, Nemeroff C, Blakely R, Brady L, Carter C, Davis K et
al. Developing novel treatments for mood disorders: accelerating
discovery. Biol Psychiatr 2002; 52: 589–609.
23 Trivedi M, Rush J, Wisniewski S, Nierenberg A, Warden D, Ritz L
et al. Outcomes with citalopram for depression using measure-
ment-based care in STAR*D: implications for clinical research and
practice. Am J Psychiatr, in press.
24 Zipursky RB, Christensen BK, Daskalakis Z, Epstein I, Roy P,
Furimsky I et al. Treatment response to olanzapine and haloper-
idol and its association with dopamine D receptor occupancy in
first-episode psychosis. Can J Psychiatr 2005; 50: 462–469.
25 Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H.
et al. Influence of life stress on depression: moderation by a
polymorphism in the 5-HTT gene. Science 2003; 301: 386–389.
26 Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The
interaction of stressful life events and a serotonin transporter
polymorphism in the prediction of episodes of major depression: a
replication. Arch Gen Psychiatr 2005; 62: 529–535.
27 Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA,
Munoz KE, Kolachana BS et al. 5-HTTLPR polymorphism impacts
human cingulate-amygdala interactions: a genetic susceptibility
mechanism for depression. Nat Neurosci 2005; 6: 828–834.
28 The International HapMap Consortium. A haplotype map of the
human genome. Nature 2005; 436: 1299–1320.
29 Edwards AO, Ritter R, Abel K, Manning A, Panhuysen C, Farrer L.
Complement factor H polymorphism and age-related macular
degeneration. Science 2005; 308: 421–424.
30 Austin C, Brady L, Insel T, Collins F. Molecular biology: NIH
molecular libraries initiative. Science 2004; 306: 1138–1139.
31 Billings LM, Oddo S, Green KN, McGaugh JL, Laferla FM.
Intraneuronal Abeta causes the onset of early Alzheimer’s
disease-related cognitive deficits in transgenic mice. Neuron
2005; 45: 675–688.
32 Zarnescu DC, Shan G, Warren ST, Jin P. Come fly with us: toward
understanding fragile X syndrome. Genes Brain Beh 2005; 6: 385–
392.
33 Neul J, Zoghbi H. Rett syndrome: a prototypical neurodevelop-
mental disorder. Neuroscientist 2004; 10: 118–128.

34 Druker BJ. Imatinib as a paradigm of targeted therapies. Adv
Cancer Res 2004; 91: 1–30.
35 Olds D, Henderson C, Cole R, Eckenrode J, Kitzman H, Luckey D et
al. Long-term effects of nurse home visitation on children’s
criminal and antisocial behavior. JAMA 1998; 280: 1238–1244.
36 Owens C, Miller P, Lawrie S, Johnstone E. Pathogenesis of
schizophrenia: a psychopathological perspective. Br J Psychiatr
2005; 186: 386–393.
37 Yung AR, Phillips LJ, Yuen HP, Francey SM, McFarlane SM,
Hallgren M et al. Psychosis prediction: 12-month follow up of a
high risk (‘prodromal’) group. Schizophr Res 2003; 60: 21–32.
38 Segman RH, Gtoltser-Dubner T, Friedman N, Kaminski N, Shalev
A. Peripheral blood mononuclear cell gene expression profiles
Cure therapeutics and strategic prevention
TR Insel and EM Scolnick
17
identify emergent post-traumatic stress disorder among trauma
survivors. Mol Psychiatr 2005; 10: 500–513.
39 Yehuda R, Bryant R, Marmar C, Zohar J. Pathological responses
to terrorism. Neuropsychopharmacology 2005; 30: 1793–
1805.
40 Foa EB, Cahill SP, Boscarino JA, Hobfoll SE, Lahad M,
McNally RJ et al. Social, psychological, and psychiatric
interventions following terrorist attacks: recommendations for
practice and research. Neuropsychopharmacology 2005; 30:
1806–1817.
41 Nemeroff C, Bremner JD, Foa EB, Mayberg HS, North CS, Stein
MB. Posttraumatic stress disorder: a state-of-the-science review.
J Psychiatr Res 2005, in press.
Molecular Psychiatry