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Review
Psychiatric Disorders:
Diagnosis to Therapy
John H. Krystal1,2,* and Matthew W. State3,*
1Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA
2VA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT 06516, USA
3Department of Psychiatry and Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, CA 94143, USA
Recent findings in a range of scientific disciplines are challenging the conventional wisdom
regarding the etiology, classification, and treatment of psychiatric disorders. This Review focuses
on the current state of the psychiatric diagnostic nosology and recent progress in three areas:
genomics, neuroimaging, and therapeutics development. The accelerating pace of novel and
unexpected findings is transforming the understanding of mental illness and represents a hopeful
sign that the approaches and models that have sustained the field for the past 40 years are yielding
to a flood of new data and presaging the emergence of a new and more powerful scientific paradigm.
The observation that the apparently identical mutation in one leveraging the identification of Mendelian mutations, namely
gene or genomic interval can lead to psychosis, language impair- knocking out a gene of interest and exploring the resulting, and
ment, social deficits, epilepsy, or some combination of these often the most overtly dramatic, phenotype(s) (Figure 1A).
phenotypes certainly challenges this view. Instead, it suggests This approach will require some re-evaluation given (1) the
that some significant portion of genetic risk impairs fundamental sheer number of risk alleles already identified; (2) the very small
(‘‘non-diagnosis-specific’’) processes in brain development and effect sizes conferred particularly by common variation; (3) the
functioning, and that the emergence of diverse clinical (or sub- polygenic nature of risk reflected in studies of both common
clinical) phenotypes in these cases results from inputs other and rare variants (Purcell et al., 2009, 2014); (4) the observation
than the identified ‘‘etiological’’ germline genetic variant, even that many common risk alleles are both heterozygous and fall
when this is found to carry relatively large risks (State and Levitt, outside of coding regions; (5) the widely varied psychiatric
2011; State and Sestan, 2012). These additional factors plausibly outcomes emerging from identical or similar mutations; and,
include epigenetic mechanisms, stochastic events, environ- particularly for neurodevelopmental disorders, (6) the common
mental variables, polygenic modifiers, somatic mutation, the observation of biological pleiotropy, in which a single gene
microbiome, and immune function, among others. Clarifying may encode the same or multiple protein isoforms serving
the nature and relative contribution of these inputs remains a multiple functions across development (Figure 1B).
considerable challenge. However, there is little question that A recent spate of studies focusing on systems biological
success in gene discovery combined with advancing ‘‘omics’’ approaches has emerged in part as a response to these types
technologies, an increasingly nuanced understanding of the of challenges. The underlying rationale for such studies is that
characteristics of many of these variables, and the development identifying points of convergence among multiple risk genes
of large-scale and epidemiologically based study cohorts may be a necessary valuable prelude to dissecting specific dis-
along with the ability to ascertain groups of individuals based ease-related mechanisms. An initial wave of these studies have
on mutation status, irrespective of clinical diagnosis, will help relied on protein-protein interaction databases, gene ontologies,
resolve these critically important questions. and expression analyses in normal versus pathological tissue to
Moreover, with the caveat that reliable gene discovery in organize various risk or candidate genes and identify areas of
psychiatry is still in its infancy, the recent findings are challenging shared biology (O’Roak et al., 2012; Pinto et al., 2010; Voineagu
not only psychiatric nosology but also some aspects of the et al., 2011) (Figure 2). More recently, studies focusing on autism
conventional wisdom regarding translational neuroscience. The and schizophrenia have attempted to incorporate develop-
standard ‘‘bottom-up’’ paradigm in psychiatry for moving from mental variables by leveraging human brain expression data
gene discovery to the identification of treatment target has relied from the Brainspan project (Gulsuner et al., 2013; Parikshak
largely on an approach that has historically been successful in et al., 2013; Willsey et al., 2013).
All of these approaches have revealed a marked degree of a thousand risk alleles might suggest the need for a thousand
convergence, particularly given the expected scale of locus het- different treatments. Moreover, recent studies have broadened
erogeneity. This is certainly good news for those concerned that the view of the range of possible points of intersection for diverse
is estimated that over 20% of hospitalized patients diagnosed response within 24 hr, and response lasting for up to 2 weeks
with bipolar disorder may eventually die by suicide. Conse- (Berman et al., 2000). This pattern stands in marked contrast
quently, there is tremendous urgency in identifying novel treat- to the characteristics of standard treatments for depression,
ment targets and mechanisms in order to respond to the need which have been comprehensively described in the NIMH
for more and more effective treatments. STAR*D study: a 7 week interval, on average, to remission in
In the current era, where scientific discovery and innovation are treatment-responsive patients and a 10%–15% response rate
occurring across a range of relevant disciplines, new treatments for treatment-resistant patients following medication changes
seem to be emerging from many levels of investigation, including in those who initially failed a trial of a serotonin uptake inhibitor
clinical observations, neuroimaging findings, and animal models (Gaynes et al., 2009).
(Figure 3). Interestingly, despite the recent wave of discovery Within a decade, there were more than a dozen replications of
in genetics and genomics, one strategy that has not yet defini- the therapeutic effects of ketamine. These documented promi-
tively succeeded in psychiatry is the direct translation from ge- nent reductions in suicidal ideation, response rates in the
netic variation to biology to treatment, despite efforts to apply 50%–80% range (including in electroconvulsive therapy nonre-
this strategy to Alzheimer’s disease (antibodies to Abeta pro- sponders), a third of patients sustaining response from a single
tein, gamma secretase inhibitors, beta secretase inhibitors) and dose for 2 weeks, and preliminary evidence that the antidepres-
autism (metabotropic glutamate receptor-5 antagonists). sant responses of a single dose could be sustained by repeated
Though, particularly with regard to psychiatric illness, this effort ketamine dosing (Aan Het Rot et al., 2012). Further, a growing list
has only recently been underway in earnest. To illustrate alternate of studies of NMDAR antagonists or NMDAR-negative allosteric
paths that have led to recent exciting therapeutic advances, this modulators, including S-ketamine, CP101,606 (NR2B-selective),
Review highlights the development of new rapid-acting antide- lanicemine (AZD6765, NR2B-selective), and GlyX13 (NR2B par-
pressants, which emerged from clinical observation; the devel- tial agonist), provided further evidence that ketamine’s effects
opment of drugs to enhance synaptic neuroplasticity to improve were mediated primarily by its actions at NMDAR.
the efficacy of pharmacotherapy, based on animal models; and Preclinical insights into the antidepressant effects of ketamine
the development of neurostimulation treatments that developed have helped to identify a broader class of antidepressants that
as a consequence of neuroimaging studies of depression. may converge on common signaling mechanisms (Krystal
Rapid-acting antidepressant medications may become the et al., 2013). The antidepressant effects of ketamine appear to
first fundamentally new class of pharmacotherapies for psy- be mediated, at least in part, by the ability to increase glutamate
chiatry in several decades (Krystal et al., 2013). The prototype release, perhaps overcoming suppression of mGluR2 receptors
for this class of medications, ketamine, was identified in by elevations in extrasynaptic glutamate noted earlier, and
academia through basic-science-informed human experimenta- to stimulate a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
tion (Berman et al., 2000). Ketamine is an uncompetitive NMDA acid (AMPA) receptors, raising BDNF levels, increasing insertion
glutamate receptor antagonist that was first studied in humans of AMPA receptor subunits into cell members, enhancing
as a probe for the neurobiology of schizophrenia (Krystal et al., signaling via Akt/mTOR, and enhancing the rapid growth of func-
2003). In an attempt to extend this work to the study of depres- tional dendritic spines (Li et al., 2010). This process appears to
sion, and informed by preclinical descriptions of antidepressant be enhanced by the blockade of extrasynaptic NMDARs, which
effects of these drugs (Skolnick et al., 2009; Trullas and Skolnick, reduces the phosphorylation of ELF2 and disinhibits elevations
1990), a pilot study (published in 2000) was conducted in pa- in BDNF (Autry et al., 2011; Hardingham and Bading, 2010).
tients with treatment-resistant symptoms. The study reported The articulation of these mechanisms through which ketamine
the following: clinical improvement in patients within 4 hr of may function has helped to show that other putative rapid-
a single dose, 50% of patients meeting criteria for clinical acting antidepressant may similarly work through a common
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