U.S. patent application number 13/093543 was filed with the patent office on 2012-04-19 for methods and compositions for the treatment of psychotic disorders through the identification of the olanzapine poor response predictor gene signature.
This patent application is currently assigned to SUREGENE, LLC. Invention is credited to Mark D. Brennan, Bharat Mehrotra, Timothy L. Ramsey.
Application Number | 20120094854 13/093543 |
Document ID | / |
Family ID | 43880434 |
Filed Date | 2012-04-19 |
United States Patent
Application |
20120094854 |
Kind Code |
A1 |
Ramsey; Timothy L. ; et
al. |
April 19, 2012 |
METHODS AND COMPOSITIONS FOR THE TREATMENT OF PSYCHOTIC DISORDERS
THROUGH THE IDENTIFICATION OF THE OLANZAPINE POOR RESPONSE
PREDICTOR GENE SIGNATURE
Abstract
Methods and compositions relate to genetic markers of psychotic
disorders, e.g., schizophrenia (SZ), are provided. For example, in
certain aspects methods for determinations of a OPRP genetic
signature are described. Furthermore, the invention provides
methods and compositions involving treatment of psychotic disorders
using the genetic signature.
Inventors: |
Ramsey; Timothy L.;
(Shelbyville, KY) ; Mehrotra; Bharat; (Louisville,
KY) ; Brennan; Mark D.; (Jeffersonville, IN) |
Assignee: |
SUREGENE, LLC
Jeffersontown
KY
|
Family ID: |
43880434 |
Appl. No.: |
13/093543 |
Filed: |
April 25, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12903891 |
Oct 13, 2010 |
7932042 |
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13093543 |
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Current U.S.
Class: |
506/9 ; 435/6.1;
435/6.11 |
Current CPC
Class: |
C12Q 2600/106 20130101;
C12Q 1/6883 20130101 |
Class at
Publication: |
506/9 ; 435/6.1;
435/6.11 |
International
Class: |
C40B 30/04 20060101
C40B030/04; C12Q 1/68 20060101 C12Q001/68 |
Goverment Interests
[0001] This invention was made with government support under SBIR
grant MH078437 awarded by National Institutes of Mental Health. The
government has certain rights in the invention.
Claims
1-17. (canceled)
18. A method for genotyping a subject to determine the presence of
a haplotype comprising the steps of: (a) obtaining a biological
sample comprising genetic material of the subject, wherein the test
subject is undergoing or is to undergo anti-psychotic
pharmacotherapy; (b) determining the presence of an Olanzapine Poor
Response Predictor (OPRP) genetic signature in the biological
sample, wherein the OPRP genetic signature is defined as a genotype
comprising a homozygous genotype for the T allele at rs11960832 and
either a homozygous or heterozygous genotype for the T allele at
rs7975477.
19. The method of claim 18, further comprising recording the
determination of the genetic signature in a tangible medium.
20. The method of claim 19, wherein the tangible medium comprises a
computer-readable disk, a solid state memory device, or an optical
storage device.
21. The method of claim 18, further comprising extracting DNA from
the biological sample.
22. The method of claim 18, wherein the genetic material is
analyzed by SNP genotyping or sequencing.
23. The method of claim 18, further comprising reporting the
determination to the subject, a health care payer, a physician, a
pharmacist, a pharmacy benefits manager, or an electronic
system.
24. The method of claim 18, wherein the determining step is carried
out through the use of an array or a kit comprising a plurality of
primers or probes specific for the OPRP genetic signature, wherein
the OPRP genetic signature is defined as a genotype comprising a
homozygous genotype for the T allele at rs11960832 and either a
homozygous or heterozygous genotype for the T allele at
rs7975477.
25. The method of claim 18, wherein the test subject is undergoing
or is to undergo antipsychotic treatment with olanzapine,
risperidone, quetiapine, ziprasidone, or perphenzazine.
Description
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to the field of
psychotic disorders, such as schizophrenia. More particularly, it
concerns genetic markers of antipsychotic response, for example,
genes and genetic markers that influence or predict a person's
likely response to antipsychotic medications.
[0004] 2. Description of Related Art
[0005] Numerous drugs exist to treat psychotic disorders, such as
schizophrenia (SZ), related SZ-spectrum disorders (including
schizotypal personality disorder (SPD) and schizoaffective disorder
(SD)), and bipolar disorders (BD). Most of these drugs fall into
one of two categories, typical (first generation) and atypical
(second generation).
[0006] Although head to head studies of large groups of patients,
either in the acute phase or outpatient treatment, show that most
atypical antipsychotic drugs are equally efficacious for positive
symptoms, there are individual differences in response to specific
drugs based on differences in drug pharmacology and metabolism,
combined with genetic differences between patients. There are
currently no proven ways to identify which antipsychotic drug is
optimal for a given patient. Thus, patients switch from one drug to
another when response is not considered to be adequate or side
effects are intolerable. This switching of medication incurs a
variety of increased costs, both economic and patient and caregiver
hardship. Moreover, the limited or partial response that is often
seen with antipsychotics leads to polypharmacy, where physicians
prescribe two or more antipsychotic drugs plus mood stabilizers
and/or antidepressants. Polypharmacy increases medication costs and
significantly increases the likelihood of adverse advents and drug
interactions (Stahl and Grady, 2006). On average, each patient may
change medications three times for finding one that works.
Additionally, the current drug have significant side-effects. This
combination of side-effects and limited efficacy create a vast
unmet need for selecting the optimal antipsychotic for each
patient.
[0007] Pharmacogenomics, using genetic variation to predict altered
response and side-effects profiles, will be important for enhanced
patient care going forward. There continues to exist, therefore, a
need to identify specific genetic variations that are associated
with psychotic disorders such as schizophrenia.
SUMMARY OF THE INVENTION
[0008] The invention is in part based on the finding that a genetic
signature, which the inventors refer to as the Olanzapine Poor
Response Predictor (OPRP), is a biomarker that can be used for
selecting a more appropriate antipsychotic treatment plan for that
particular subject. For example, the inventors have discovered that
patients that are OPRP negative respond better than patients that
are OPRP positive when treated with olanzapine, and that OPRP
negative patients respond better to olanzapine than to other
antipsychotics. Thus, prior determination of a patient's OPRP
status can aid in the development of an optimal antipsychotic
treatment regimen. One aspect of the invention involves a method
for obtaining genetic information about a test subject comprising
(a) obtaining a biological sample comprising genetic material of a
test subject, wherein the test subject is undergoing or is to
undergo anti-psychotic pharmacotherapy; (b) determining whether the
genetic material comprises an Olanzapine Poor Response Predictor
(OPRP) genetic signature, determining the Olanzapine Poor Response
Predictor (OPRP) genetic signature status of the subject, wherein
the OPRP genetic signature is defined as a genotype comprising a
homozygous genotype for the T allele at rs11960832 and either a
homozygous or heterozygous genotype for the T allele at rs7975477,
to thereby obtain the genetic information.
[0009] Thus, an aspect of the invention involves determining
whether genetic material of the subject comprises a ORRP genetic
signature. Of course, to meet the need to transfer and store
genetic information, the results of the determination will
preferably be recorded and maintained in a tangible medium, such as
a computer-readable disk, a solid state memory device, an optical
storage device or the like, more specifically, a storage device
such as a hard drive, a Compact Disk (CD) drive, a floppy disk
drive, a tape drive, a random access memory (RAM), etc.
[0010] One preferred manner of obtaining the genetic signature
information involves analyzing the genetic material of the subject
to determine the presence or absence of the OPRP genetic signature.
This can be accomplished, for example, by testing the subject's
genetic material through the use of a biological sample. In certain
embodiments, the methods set forth will thus involve obtaining a
biological sample from the subject and testing the biological
sample to identify whether an OPRP genetic signature is present.
The biological sample may be any biological material that contains
DNA or RNA of the subject, such as a nucleated cell source.
Non-limiting examples of cell sources available in clinical
practice include hair, skin, nucleated blood cells, buccal cells,
any cells present in tissue obtained by biopsy or any other cell
collection method. The biological sample may also be obtained from
body fluids, including without limitation blood, saliva, sweat,
urine, amniotic fluid (the fluid that surrounds a fetus during
pregnancy), cerebrospinal fluid, feces, and tissue exudates at the
site of infection or inflammation. DNA may be extracted from the
biologic sample such as the cell source or body fluid using any of
the numerous methods that are standard in the art.
[0011] Determining whether the genetic material exhibits an OPRP
genetic signature can be by any method known to those of ordinary
skill in the art, such as genotyping (e.g., SNP genotyping) or
sequencing. Techniques that may be involved in this determination
are well-known to those of ordinary skill in the art. Examples of
such techniques include allele specific oligonucleotide
hybridization, size analysis, sequencing, hybridization, 5'
nuclease digestion, single-stranded conformation polymorphism
analysis, allele specific hybridization, primer specific extension,
and oligonucleotide ligation assays. Additional information
regarding these techniques is discussed in the specification
below.
[0012] For genetic signature determinations, the sequence of the
extracted nucleic acid of the subject may be determined by any
means known in the art, including but not limited to direct
sequencing, hybridization with allele-specific oligonucleotides,
allele-specific PCR, ligase-PCR, HOT cleavage, denaturing gradient
gel electrophoresis (DDGE), and single-stranded conformational
polymorphism (SSCP) analysis. Direct sequencing may be accomplished
by any method, including without limitation chemical sequencing,
using the Maxam-Gilbert method, by enzymatic sequencing, using the
Sanger method; mass spectrometry sequencing; and sequencing using a
chip-based technology. In particular embodiments, DNA from a
subject is first subjected to amplification by polymerase chain
reaction (PCR) using specific amplification primers. In some
embodiments, the method further involves amplification of a nucleic
acid from the biological sample. The amplification may or may not
involve PCR. In some embodiments, the primers are located on a
chip.
[0013] The subject can be any subject, such as a mammal.
Non-limiting examples of mammals include mice, rats, rabbits, dogs,
cats, sheep, goats, non-human primates (chimpanzees, baboons,
monkeys), cows, horses, pigs, and humans. In specific embodiments,
the subject is a human. For example, in some embodiments the human
is a subject who has or is suspected to have a psychotic disorder,
such as schizophrenia, schizotypal personality disorder (SPD),
schizoaffective disorder (SD), or bipolar disorder (BD). The
subject can be a human (e.g., a patient having, suspected to have,
or at risk of, a psychotic disorder). In one embodiment, the
subject is a patient having previously diagnosed a psychotic
disorder (e.g., a patient suffering from early, intermediate or
aggressive a psychotic disorder). In some embodiments, the subject
is of Caucasian (CA) descent, i.e., has one or more ancestors who
are CA. In some embodiments, the subject is of African American
(AA) descent, i.e., has one or more ancestors who are AA.
[0014] Moreover, the inventors contemplate that the genetic
structure and sequence, including SNP profiles, of individual
subjects will at some point be widely or generally available, or
will have been developed by an unrelated third party. In such
instances, there will be no need to test or analyze the subject's
biological material again. Instead, the genetic information will in
such cases be obtained simply by analyzing the sequencing or
genotyping outcome of the subject, for example, a SNP profile, a
whole or partial genome sequence, etc. These outcomes can then be
obtained from or reported by a sequencing or a genotyping service,
a laboratory, a scientist, or any genetic test platforms.
[0015] In some further aspects, the method may further comprise
reporting the determination to the subject, a health care payer, an
attending clinician, a pharmacist, a pharmacy benefits manager, or
any person that the determination may be of interest.
[0016] In certain embodiments, there is also provided a method for
treating a human subject having or suspected of having a psychotic
disorder, comprising a) selecting a subject that has been
determined to have the OPRP genetic signature, defined as a
genotype comprising a homozygous genotype for the T allele at
rs11960832 and either a homozygous or heterozygous genotype for the
T allele at rs7975477, wherein if the subject comprises the OPRP
genetic signature, the subject is less likely to exhibit a
favorable response to olanzapine, and treating the subject with an
anti-psychotic treatment other than olanzapine; and b) selecting a
subject that has been determined not to have the OPRP genetic
signature, wherein if the subject does not comprise the OPRP
genetic signature, the subject is more likely to exhibit a
favorable response to olanzapine, and treating the subject with
olanzapine.
[0017] In certain embodiments, there is also provided a method of
developing a pharmacotherapeutic treatment plan for a subject
having or suspected of having a psychotic disorder comprising
determining the OPRP status of the patient, wherein a) if the human
subject comprises the OPRP genetic signature, the subject is less
likely to exhibit a favorable response to olanzapine; and b) if the
subject does not comprise the OPRP genetic signature, the subject
is more likely to exhibit a favorable response to olanzapine; and
developing the pharmacotherapeutic treatment plan. For example, if
the subject does not comprise an OPRP genetic signature, then the
method may further comprise treating the subject with olanzapine.
If the subject does comprise the OPRP genetic signature, then the
method may further comprise treating the subject with an
anti-psychotic treatment other than olanzapine, such as treating
with risperidone, quetiapine, ziprasidone or perphenazine. In some
embodiments, the psychotic disorder may be schizophrenia.
[0018] Certain aspects of the invention may involve a method for
treating a subject having a psychotic disorder and determined not
to have an OPRP genetic signature, comprising treating the subject
with olanzapine. In some further aspects, the invention may include
a method for treating a subject having a psychotic disorder and
determined to have an OPRP genetic signature, comprising treating
the subject with a non-olanzapine anti-psychotic treatment.
[0019] Certain aspects of the invention may involve a method for
treating a subject comprising selecting a subject that is
determined to have an OPRP genetic signature and developing an
appropriate treatment plan. Other aspects of the invention may
involve a method for treating a subject comprising selecting a
subject that is determined not to have an OPRP genetic signature
and developing an appropriate treatment plan. Prior determination
of a patient's an OPRP genetic signature status may be obtained
from or reported by a sequencing or a genotyping service, a
laboratory, a scientist, or any genetic test platforms.
[0020] Certain aspects of the present invention also contemplate
the preparation of kits or arrays for use in accordance with the
present invention. Suitable kits include various reagents for use
in accordance with the present invention in suitable containers and
packaging materials, including tubes, vials, and shrink-wrapped and
blow-molded packages. Such an array or a kit may comprise a
plurality of primers or probes specific for an OPRP genetic
signature. The array may be a genotyping chip. Also a tangible,
computer-readable medium comprising a SNP profile of a subject may
also be provided, wherein the SNP profile exhibits the presence or
absence of an OPRP genetic signature.
[0021] Embodiments discussed in the context of methods and/or
compositions of the invention may be employed with respect to any
other method or composition described herein. Thus, an embodiment
pertaining to one method or composition may be applied to other
methods and compositions of the invention as well.
[0022] As used herein the specification, "a" or "an" may mean one
or more. As used herein in the claim(s), when used in conjunction
with the word "comprising", the words "a" or "an" may mean one or
more than one.
[0023] The use of the term "or" in the claims is used to mean
"and/or" unless explicitly indicated to refer to alternatives only
or the alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." As used herein "another" may mean at least a second or
more.
[0024] Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0025] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWING
[0026] The following drawing forms part of the present
specification and is included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to this drawing in combination with the
detailed description of specific embodiments presented herein.
[0027] FIG. 1: An exemplary embodiment of risk management involving
OPRP genetic signature determination.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0028] Choosing the correct antipsychotic medication for patients
suffering from severe neuropsychiatric illnesses is a major
challenge. Fewer than one in three patients suffering from
schizophrenia and related disorders will have a robust improvement
in symptoms on the first antipsychotic drug prescribed. One out of
three patients will be resistant to commonly used drugs.
Furthermore, the metabolic side-effects of antipsychotic drugs,
most commonly seen with olanzapine and clozapine, result in low
compliance, with 50% of patients discontinuing drug use within 6
months of prescription, leading to relapse (return of psychosis)
and hospitalization.
[0029] Therefore, methods and compositions of the present invention
will help to meet this challenge by assisting physicians, patients,
lab, or pharmacists with selection or recommendation of appropriate
antipsychotic medication. Specifically, the present inventors have
used an OPRP genetic signature for related psychotic disorders for
pharmacogenomic applications, i.e., assessing the impact of genetic
variation on drug response. Examples of variation in drug response
include any of the following efficacy, side-effect profile,
treatment maintenance and discontinuation rates, return to work
status, hospitalizations, suicidality, total healthcare cost,
social functioning scales, response to non-pharmacological
treatments, and dose response curves. Efficacy includes but is not
limited to the following definition: .gtoreq.10% decrease in Total
PANSS score. Side-effect profile includes one or more of weight
gain, metabolic dysfunction, lipid dysfunction, movement disorders,
and extrapyramidal symptoms.
[0030] Further embodiments and advantages of the invention are
described below.
I. DEFINITIONS
[0031] As defined herein, "Schizophrenia" or "SZ" includes the
SZ-spectrum disorders, Schizotypal Personality Disorder (SPD) and
Schizoaffective Disorder (SD), as well as Schizophrenia under the
narrower, DSM-IV definition.
[0032] As used herein, a "genetic signature" is a mutually
exclusive set of genotypes comprising a group of markers (e.g.,
polymorphisms). As used herein, the term "polymorphism" refers to
the condition in which there is a variation in the DNA sequence
between some members of a species. A genetic signature can consist
of a variety of genetic markers, including indels (insertions or
deletions of the DNA at particular locations on the chromosome);
single nucleotide polymorphisms (SNPs) in which a particular
nucleotide is changed; microsatellites; and minisatellites.
[0033] As used herein, a "OPRP genetic signature" refers to a
genetic signature comprising homozygous genotype for the T allele
at SNP marker rs11960832, i.e., rs11960832(T)/rs11960832(T)
homozygosity, in combination with either a homozygous or
heterozygous genotype for the T allele at marker rs7975477, i.e.,
rs7975477(T)/rs7975477(T) homozygosity or rs7975477(T)/rs7975477(C)
heterozygosity.
[0034] The term "chromosome" as used herein refers to a gene
carrier of a cell that is derived from chromatin and comprises DNA
and protein components (e.g., histones). The conventional
internationally recognized individual human genome chromosome
numbering identification system is employed herein. The size of an
individual chromosome can vary from one type to another with a
given multi-chromosomal genome and from one genome to another. In
the case of the human genome, the entire DNA mass of a given
chromosome is usually greater than about 100,000,000 base pairs.
For example, the size of the entire human genome is about
3.times.10.sup.9 base pairs.
[0035] The term "gene" refers to a DNA sequence in a chromosome
that codes for a product (either RNA or its translation product, a
polypeptide). A gene contains a coding region and includes regions
preceding and following the coding region (termed respectively
"leader" and "trailer"). The coding region is comprised of a
plurality of coding segments ("exons") and intervening sequences
("introns") between individual coding segments.
[0036] The term "probe" refers to an oligonucleotide. A probe can
be single stranded at the time of hybridization to a target. As
used herein, probes include primers, i.e., oligonucleotides that
can be used to prime a reaction, e.g., a PCR reaction.
[0037] The term "label" or "label containing moiety" refers in a
moiety capable of detection, such as a radioactive isotope or group
containing same, and nonisotopic labels, such as enzymes, biotin,
avidin, streptavidin, digoxygenin, luminescent agents, dyes,
haptens, and the like. Luminescent agents, depending upon the
source of exciting energy, can be classified as radioluminescent,
chemiluminescent, bioluminescent, and photoluminescent (including
fluorescent and phosphorescent). A probe described herein can be
bound, e.g., chemically bound to label-containing moieties or can
be suitable to be so bound. The probe can be directly or indirectly
labeled.
[0038] The term "direct label probe" (or "directly labeled probe")
refers to a nucleic acid probe whose label after hybrid formation
with a target is detectable without further reactive processing of
hybrid. The term "indirect label probe" (or "indirectly labeled
probe") refers to a nucleic acid probe whose label after hybrid
formation with a target is further reacted in subsequent processing
with one or more reagents to associate therewith one or more
moieties that finally result in a detectable entity.
[0039] The terms "target," "DNA target," or "DNA target region"
refers to a nucleotide sequence that occurs at a specific
chromosomal location. Each such sequence or portion is preferably
at least partially, single stranded (e.g., denatured) at the time
of hybridization. When the target nucleotide sequences are located
only in a single region or fraction of a given chromosome, the term
"target region" is sometimes used. Targets for hybridization can be
derived from specimens which include, but are not limited to,
chromosomes or regions of chromosomes in normal, diseased or
malignant human cells, either interphase or at any state of meiosis
or mitosis, and either extracted or derived from living or
postmortem tissues, organs or fluids; germinal cells including
sperm and egg cells, or cells from zygotes, fetuses, or embryos, or
chorionic or amniotic cells, or cells from any other germinating
body; cells grown in vitro, from either long-term or short-term
culture, and either normal, immortalized or transformed; inter- or
intraspecific hybrids of different types of cells or
differentiation states of these cells; individual chromosomes or
portions of chromosomes, or translocated, deleted or other damaged
chromosomes, isolated by any of a number of means known to those
with skill in the art, including libraries of such chromosomes
cloned and propagated in prokaryotic or other cloning vectors, or
amplified in vitro by means well known to those with skill; or any
forensic material, including but not limited to blood, or other
samples.
[0040] The term "hybrid" refers to the product of a hybridization
procedure between a probe and a target. The term "hybridizing
conditions" has general reference to the combinations of conditions
that are employable in a given hybridization procedure to produce
hybrids, such conditions typically involving controlled
temperature, liquid phase, and contact between a probe (or probe
composition) and a target. Conveniently and preferably, at least
one denaturation step precedes a step wherein a probe or probe
composition is contacted with a target. Guidance for performing
hybridization reactions can be found in Ausubel et al. (2003).
Aqueous and nonaqueous methods are described in that reference and
either can be used. Hybridization conditions referred to herein are
a 50% formamide, 2.times.SSC wash for 10 minutes at 45.degree. C.
followed by a 2.times.SSC wash for 10 minutes at 37.degree. C.
[0041] Calculations of "identity" between two sequences can be
performed as follows. The sequences are aligned for optimal
comparison purposes (e.g., gaps can be introduced in one or both of
a first and a second nucleic acid sequence for optimal alignment
and non-identical sequences can be disregarded for comparison
purposes). The length of a sequence aligned for comparison purposes
is at least 30%, e.g., at least 40%, 50%, 60%, 70%, 80%, 90% or
100%, of the length of the reference sequence. The nucleotides at
corresponding nucleotide positions are then compared. When a
position in the first sequence is occupied by the same nucleotide
as the corresponding position in the second sequence, then the
molecules are identical at that position. The percent identity
between the two sequences is a function of the number of identical
positions shared by the sequences, taking into account the number
of gaps, and the length of each gap, which need to be introduced
for optimal alignment of the two sequences.
[0042] The comparison of sequences and determination of percent
identity between two sequences can be accomplished using a
mathematical algorithm. In some embodiments, the percent identity
between two nucleotide sequences is determined using the GAP
program in the GCG software package, using a Blossum 62 scoring
matrix with a gap penalty of 12, a gap extend penalty of 4, and a
frameshift gap penalty of 5.
[0043] As used herein, the term "substantially identical" is used
to refer to a first nucleotide sequence that contains a sufficient
number of identical nucleotides to a second nucleotide sequence
such that the first and second nucleotide sequences have similar
activities. Nucleotide sequences that are substantially identical
are at least 80%, e.g., 85%, 90%, 95%, 97% or more, identical.
[0044] The term "nonspecific binding DNA" refers to DNA which is
complementary to DNA segments of a probe, which DNA occurs in at
least one other position in a genome, outside of a selected
chromosomal target region within that genome. An example of
nonspecific binding DNA comprises a class of DNA repeated segments
whose members commonly occur in more than one chromosome or
chromosome region. Such common repetitive segments tend to
hybridize to a greater extent than other DNA segments that are
present in probe composition.
[0045] As used herein, the term "stratification" refers to the
creation of a distinction between subjects on the basis of a
characteristic or characteristics of the subjects. Generally, in
the context of clinical trials, the distinction is used to
distinguish responses or effects in different sets of patients
distinguished according to the stratification parameters. In some
embodiments, stratification includes distinction of subject groups
based on the presence or absence of an OPRP genetic signature
described herein. The stratification can be performed, e.g., in the
course of analysis, or can be used in creation of distinct groups
or in other ways.
[0046] As used herein, "Typical" antipsychotics refer to so called
first generation or classical antipsychotics. This class of drugs
was first developed in the 1950s. Some examples include:
Chlorpromazine (Largactil, Thorazine), Fluphenazine (Prolixin),
Haloperidol (Haldol, Serenace), Molindone, Thiothixene (Navane),
Thioridazine (Mellaril), Trifluoperazine (Stelazine), Loxapine
(Loxapac, Loxitane), Perphenazine, Prochlorperazine (Compazine,
Buccastem, Stemetil), Pimozide (Orap), Zuclopenthixol (Clopixol).
This class of drug can cause serious adverse events, particularly
Tardive Dyskinesia, a movement disorder.
[0047] As used herein, "Atypical" antipsychotics refer to a newer
class of antipsychotic drugs first introduced in the 1990s. This
class of drugs includes the following examples:
[0048] Clozapine (Clozaril) (FDA-approval: 1990) Available in oral
tablets and dissolving tablets (FazaClo).
[0049] Risperidone (Risperdal) (FDA-approval: 1993) Available in
oral tablets, dissolving tablets, liquid form, and extended release
intramusclar injection.
[0050] Olanzapine (Zyprexa) (FDA-approval: 1996) Available in oral
tablets, dissolving tablets, and intramuscular injection.
[0051] Quetiapine (Seroquel) (FDA-approval: 1997) Available only in
oral tablets.
[0052] Ziprasidone (Geodon) (FDA-approval: 2001) Available in oral
capsules and intramuscular injection.
[0053] Aripiprazole (Abilify) (FDA)-approval: 2002) Available in
oral tablets and dissolving tablets.
[0054] Paliperidone (Invega) (FDA)-approval: 2006) Available in
extended-release oral tablets.
[0055] Asenapine FDA has accepted NDA as of Nov. 26, 2007.
[0056] Iloperidone (Fanapta or Zomaril) FDA has accepted NDA as of
Nov. 27, 2007.
[0057] Sertindole (Serlect) (Not approved by the FDA for use in the
USA).
[0058] Zotepine (Not approved by the FDA for use in the USA).
[0059] Amisulpride (Not approved by the FDA for use in the
USA).
[0060] Bifeprunox (Not approved by the FDA for use in the USA).
[0061] Melperone Approved in Europe. Currently in clinical trial in
the USA
[0062] Atypicals have a superior side-effect profile for the
serious adverse event Tardive Dyskinesia. However, the atypicals
can cause metabolic disturbances leading to weight gain and
metabolic syndrome.
[0063] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Methods
and materials are described herein for use in the present
invention; other, suitable methods and materials known in the art
can also be used. The materials, methods, and examples are
illustrative only and not intended to be limiting. All
publications, patent applications, patents, sequences, database
entries, and other references mentioned herein are incorporated by
reference in their entirety. In case of conflict, the present
specification, including definitions, will control.
II. OPRP GENETIC SIGNATURE
[0064] In certain aspects, the present invention involves
determination of an OPRP genetic signature and use of the specific
genetic signature to optimize treatments for psychotic disorders.
For example, the invention may enhance drug safety and improve
treatment outcome.
[0065] The synaptic vesicle glycoprotein 2C gene (SV2C) is located
on chromosome 5q (from 75,379,305 to 75,621,416 bp Consortium Human
Build 37 (GRCh37), Primary_Assembly; source: available on the world
wide web at www.ncbi.nlm.nih.gov/gene/22987). It encodes the SV2C
protein, which is expressed in the brain and interacts with
synaptotagmin 1 to regulate neurotransmitter release in a variety
of synapses (Lazzell et al., 2004: Schivell et al., 2005; Xu et
al., 2001; Janz et al., 1999). Determination of the genotype of SNP
marker rs11960832, which is located within the SV2C gene, comprises
one aspect of the OPRP genetic signature test.
[0066] The mannosyl(alpha-1,3-)-glycoprotein
beta-1,4-N-acetylglucosaminyltransferase, isozyme C (putative) gene
(MGAT4C) is located on chromosome 12 q (from 86,373,037 to
87,232,681 bp Consortium Human Build 37 (GRCh37), Primary Assembly;
source: available on the world wide web at
www.ncbi.nlm.nih.gov/gene/25834). It encodes the MGAT4C protein and
is expressed in the fetal and adult brain (Furukawa et al., 1999).
Determination of the genotype of SNP marker rs7975477, which is
located within the MGAT4C gene, comprises one aspect of the OPRP
genetic signature test.
[0067] The OPRP genetic signature was selected as the biomarker of
interest based on results showing associations between this genetic
signature and response to antipsychotic drugs. The inventors used
samples from the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE), a large federally funded clinical trial
designed to assess the efficacy of antipsychotics in a real world
setting (Lieberman et al., 2005; Stroup et al., 2003), to explore
gene-based differential responses of patients suffering from
schizophrenia and related disorders (schizoaffective disorder and
bipolar disorder) to atypical antipsychotic drugs.
[0068] The OPRP genetic signature occurs at a frequency of
approximately 6.5% in Caucasians and 23.5% in African
Americans.
III. DETERMINATION OF OPRP GENETIC SIGNATURE
[0069] The invention includes methods for determination of the OPRP
genetic signature in order to select optimal treatments.
Homozygosity for a SNP within the SV2C gene, i.e., SNP
rs11960832(T)/rs11960832(T) homozygosity, in combination with
either a homozygous or heterozygous T allele at marker rs7975477
within the MGAT4C gene, i.e., rs7975477(T)/rs7975477(T)
homozygosity or rs7975477(T)/rs7975477(C) heterozygosity, can be
used to determine a OPRP genetic signature as defined above. Using
the exemplary SNP markers (i.e., rs11960832 and rs7975477) or SNPS
in linkage disequilibrium with the exemplary SNPs, one can
determine the presence or absence of an OPRP genetic signature.
Using the genetic signature, one can assign subjects to specific
categories based on the evaluation of the genetic signature present
in the subject and select optimal treatments (atypical
antipsychotic, typical antipsychotic, and/or psychosocial
intervention) for patients.
[0070] Determining an OPRP genetic signature can, but need not,
include obtaining a sample comprising DNA from a subject, and/or
assessing the identity, presence or absence of one or more genetic
markers for the OPRP genetic signature in the sample. The
individual or organization who determines the genetic signature
need not actually carry out the physical analysis of a sample from
a subject; the genetic signature can include information obtained
by analysis of the sample by a third party. Thus the methods can
include steps that occur at more than one site. For example, a
sample can be obtained from a subject at a first site, such as at a
health care provider or at the subject's home in the case of a
self-testing kit. The sample can be analyzed at the same or a
second site, e.g., at a laboratory, a sequencing or genotyping
facility, or other testing facility. Determining a genetic
signature can also include or consist of reviewing a subject's
medical history or test results, where the medical history or test
results includes information regarding the identity, presence or
absence of one or more genetic markers in the subject.
[0071] Samples that are suitable for use in the methods described
herein contain genetic material, e.g., genomic DNA (gDNA).
Non-limiting examples of sources of samples include urine, blood,
cells, and tissues. The sample itself will typically consist of
nucleated cells (e.g., blood or buccal cells), tissue, etc.,
removed from the subject. The subject can be an adult, a child, a
fetus, or an embryo. In some embodiments, the sample is obtained
prenatally, either from a fetus or an embryo or from the mother
(e.g., from fetal or embryonic cells in the maternal circulation).
Methods and reagents are known in the art for obtaining,
processing, and/or analyzing samples. In some embodiments, the
sample is obtained with the assistance of a health care provider,
e.g., to draw blood. In some embodiments, the sample is obtained
without the assistance of a health care provider, e.g., where the
sample is obtained non-invasively, such as a sample comprising
buccal cells that is obtained using a buccal swab or brush, or a
mouthwash sample.
[0072] The sample may be further processed before the detecting
step. For example, DNA in a cell or tissue sample can be separated
from other components of the sample. The sample can be concentrated
and/or purified to isolate DNA. Cells can be harvested from a
biological sample using standard techniques known in the art. For
example, cells can be harvested by centrifuging a cell sample and
resuspending the pelleted cells. The cells can be resuspended in a
buffered solution such as phosphate-buffered saline (PBS). After
centrifuging the cell suspension to obtain a cell pellet, the cells
can be lysed to extract DNA, e.g., gDNA. See, e.g., Ausubel et al.,
2003, supra. All samples obtained from a subject, including those
subjected to any sort of further processing, are considered to be
obtained from the subject.
[0073] OPRP genetic signature may be determined by any methods
known in the art, e.g., gel electrophoresis, capillary
electrophoresis, size exclusion chromatography, sequencing, and/or
arrays to detect the presence or absence of the marker(s) of the
genetic signature. Amplification of nucleic acids, where desirable,
can be accomplished using methods known in the art, e.g., PCR.
[0074] Methods of nucleic acid analysis to detect polymorphisms
and/or polymorphic variants include, e.g., microarray analysis.
Hybridization methods, such as Southern analysis, Northern
analysis, or in situ hybridizations, can also be used (see Ausubel
et al., 2003). To detect microdeletions, fluorescence in situ
hybridization (FISH) using DNA probes that are directed to a
putatively deleted region in a chromosome can be used. For example,
probes that detect all or a part of a microsatellite marker can be
used to detect microdeletions in the region that contains that
marker.
[0075] Other methods include direct manual sequencing (Church and
Gilbert, 1988; Sanger et al., 1977; U.S. Pat. No. 5,288,644);
automated fluorescent sequencing; single-stranded conformation
polymorphism assays (SSCP); clamped denaturing gel electrophoresis
(CDGE); two-dimensional gel electrophoresis (2DGE or TDGE);
conformational sensitive gel electrophoresis (CSGE); denaturing
gradient gel electrophoresis (DGGE) (Sheffield et al., 1989),
mobility shift analysis (Orita et al., 1989), restriction enzyme
analysis (Flavell et al., 1978; Geever et al., 1981); quantitative
real-time PCR (Raca et al., 2004); heteroduplex analysis; chemical
mismatch cleavage (CMC) (Cotton et al., 1985); RNase protection
assays (Myers et al., 1985); use of polypeptides that recognize
nucleotide mismatches, e.g., E. coli mutS protein; allele-specific
PCR, for example. See, e.g., U.S. Patent Publication No.
2004/0014095, to Gerber et al., which is incorporated herein by
reference in its entirety. In some embodiments, the sequence is
determined on both strands of DNA.
[0076] In order to detect polymorphisms and/or polymorphic
variants, it will frequently be desirable to amplify a portion of
genomic DNA (gDNA) encompassing the polymorphic site. Such regions
can be amplified and isolated by PCR using oligonucleotide primers
designed based on genomic and/or cDNA sequences that flank the
site. See e.g., PCR Primer: A Laboratory Manual; McPherson et al.,
2000; Mattila et al., 1991; Eckert et al., 1991; and U.S. Pat. No.
4,683,202. Other amplification methods that may be employed include
the ligase chain reaction (LCR) (Wu and Wallace, 1989, Landegren et
al., 1988), transcription amplification (Kwoh et al., 1989),
self-sustained sequence replication (Guatelli et al., 1990), and
nucleic acid based sequence amplification (NASBA). Guidelines for
selecting primers for PCR amplification are well known in the art.
See, e.g., McPherson et al. (2000). A variety of computer programs
for designing primers are available, e.g., `Oligo` (National
Biosciences, Inc, Plymouth Minn.), MacVector (Kodak/IBI), and the
GCG suite of sequence analysis programs (Genetics Computer Group,
Madison, Wis. 53711).
[0077] In one example, a sample (e.g., a sample comprising genomic
DNA), is obtained from a subject. The DNA in the sample is then
examined to determine a OPRP genetic signature as described herein.
The genetic signature can be determined by any method described
herein, e.g., by sequencing or by hybridization of the gene in the
genomic DNA, RNA, or cDNA to a nucleic acid probe, e.g., a DNA
probe (which includes cDNA and oligonucleotide probes) or an RNA
probe. The nucleic acid probe can be designed to specifically or
preferentially hybridize with a particular polymorphic variant.
[0078] In some embodiments, a peptide nucleic acid (PNA) probe can
be used instead of a nucleic acid probe in the hybridization
methods described above. PNA is a DNA mimetic with a peptide-like,
inorganic backbone, e.g., N-(2-aminoethyl)glycine units, with an
organic base (A, G, C, T or U) attached to the glycine nitrogen via
a methylene carbonyl linker (see, e.g., Nielsen et al., 1994). The
PNA probe can be designed to specifically hybridize to a nucleic
acid comprising a polymorphic variant of the OPRP genetic
signature.
[0079] In some embodiments, restriction digest analysis can be used
to detect the existence of a polymorphic variant of a polymorphism,
if alternate polymorphic variants of the polymorphism result in the
creation or elimination of a restriction site. A sample containing
genomic DNA is obtained from the individual. Polymerase chain
reaction (PCR) can be used to amplify a region comprising the
polymorphic site, and restriction fragment length polymorphism
analysis is conducted (see Ausubel et al., supra). The digestion
pattern of the relevant DNA fragment may indicate the presence or
absence of a particular polymorphic variant of the OPRP genetic
signature and may be therefore indicative of the presence or
absence of the OPRP genetic signature.
[0080] Sequence analysis can also be used to detect specific
polymorphic variants. A sample comprising DNA or RNA is obtained
from the subject. PCR or other appropriate methods can be used to
amplify a portion encompassing the polymorphic site, if desired.
The sequence is then ascertained, using any standard method, and
the presence of a polymorphic variant is determined.
[0081] Allele-specific oligonucleotides can also be used to detect
the presence of a polymorphic variant, e.g., through the use of
dot-blot hybridization of amplified oligonucleotides with
allele-specific oligonucleotide (ASO) probes (see, for example,
Saiki et al., 1986). An "allele-specific oligonucleotide" (also
referred to herein as an "allele-specific oligonucleotide probe")
is typically an oligonucleotide of approximately 10-50 base pairs,
preferably approximately 15-30 base pairs, that specifically
hybridizes to a nucleic acid region that contains a polymorphism.
An allele-specific oligonucleotide probe that is specific for a
particular polymorphism can be prepared using standard methods (see
Ausubel et al., supra).
[0082] Generally, to determine which of multiple polymorphic
variants is present in a subject, a sample comprising DNA is
obtained from the individual. PCR can be used to amplify a portion
encompassing the polymorphic site. DNA containing the amplified
portion may be dot-blotted, using standard methods (see Ausubel et
al., supra), and the blot contacted with the oligonucleotide probe.
The presence of specific hybridization of the probe to the DNA is
then detected. Specific hybridization of an allele-specific
oligonucleotide probe (specific for a polymorphic variant
indicative of susceptibility to altered pharmacological response)
to DNA from the subject may determine a OPRP genetic signature.
[0083] In some embodiments, fluorescence polarization
template-directed dye-terminator incorporation (FP-TDI) is used to
determine which of multiple polymorphic variants of a polymorphism
is present in a subject (Chen et al., 1999). Rather than involving
use of allele-specific probes or primers, this method employs
primers that terminate adjacent to a polymorphic site, so that
extension of the primer by a single nucleotide results in
incorporation of a nucleotide complementary to the polymorphic
variant at the polymorphic site.
[0084] Real-time pyrophosphate DNA sequencing is yet another
approach to detection of polymorphisms and polymorphic variants
(Alderborn et al., 2000). Additional methods include, for example,
PCR amplification in combination with denaturing high performance
liquid chromatography (dHPLC) (Underhill et al., 1997).
[0085] The methods can include determining the genotype of a
subject with respect to both copies of the polymorphic site present
in the genome. For example, the complete genotype may be
characterized as -/-, as -/+, or as +/+, where a plus sign
indicates the presence of the polymorphic variant of interest, such
as rs11960832(T) or rs7975477(T), and a minus sign indicates the
absence of the polymorphic variant of interest and/or the presence
of the other or wild type sequence at the polymorphic site. If
multiple polymorphic variants exist at a site, this can be
appropriately indicated by specifying which ones are present in the
subject. Any of the detection means described herein can be used to
determine the genotype of a subject with respect to one or both
copies of the polymorphism present in the subject's genome.
[0086] In some embodiments, it is desirable to employ methods that
can detect the presence of multiple polymorphisms (e.g.,
polymorphic variants at a plurality of polymorphic sites) in
parallel or substantially simultaneously. Oligonucleotide arrays
represent one suitable means for doing so. Other methods, including
methods in which reactions (e.g., amplification, hybridization) are
performed in individual vessels, e.g., within individual wells of a
multi-well plate or other vessel may also be performed so as to
detect the presence of multiple polymorphic variants (e.g.,
polymorphic variants at a plurality of polymorphic sites) in
parallel or substantially simultaneously according to certain
embodiments of the invention.
IV. PSYCHOTIC DISORDERS
[0087] Certain aspects of the invention can use OPRP genetic
signature status to optimize treatments for psychotic disorders,
such as schizophrenia (SZ), schizotypal personality disorder (SPD),
schizoaffective disorder (SD), and/or bipolar disorders (BD).
[0088] Schizophrenia and bipolar disorder are life-long, severely
disabling mental illnesses. The clinical criteria for these
neuropsychiatric illnesses have continued to evolve through a
consensus process organized by the American Psychiatric Association
(APA) and published in its Diagnostic and Statistical Manual (DSM)
I-IV (American Psychiatric Assoc. Diagostic and Statistical Manual
of Mental Disorders, 1994). The inventors disclose here some of the
key features of both illnesses as currently conceived, with the
full awareness that there is strong evidence for overlap between
these disorders in genetic risk factors and response to treatment.
Nevertheless, all indications are that DSM-V, which is currently
being developed by the APA, will maintain this distinction more or
less in the current form. Also because FDA indications for
treatment have been and may continue to be given for drugs for each
disorder separately, having genetic information which pertains to
classification and prediction of response to treatment is of
considerable value.
[0089] Schizophrenia and bipolar disorder share some common
clinical features while differing on others. Schizophrenia is
characterized by psychotic symptoms (delusions, hallucinations),
disorganized thinking and cognitive impairment and poor social and
work function. Additionally, some schizophrenia patients can have
severe negative symptoms, including blunted affect and social and
emotional withdrawal. Bipolar Disorder is characterized by two main
types of mood disturbances, with depression being the most common
type and mania, or hypomania less frequent. Psychotic disorders may
be present in either the manic or depressive mood phases. Both
disorders have a high risk for suicide attempts and
completions.
[0090] Schizophrenia usually begins in the late teens and early
20's. It affects about 1% of the population. Conversely, bipolar
disorder most often occurs in the 3.sup.rd and 4.sup.th decades of
life. Bipolar (BP) Type I affects about 1.5% of the population. BP
type II and BP Not Otherwise Specified (NOS) afflict another 2-4%
of the population. Life-long drug treatment is often required to
minimize the number of acute episodes, the need for hospitalization
or assisted living, and to optimize daily functioning. Suicide
occurs in 5% of schizophrenia cases and 10% of bipolar disorder
cases. Patients with schizophrenia or bipolar disorder can have
"acute" episodes which are characterized by abrupt and large
increases in psychotic symptoms. Often, these episodes occur after
a period of non-compliance with medication. Both are generally
treated with one or more classes of psychotropic medications.
Atypical antipsychotic drugs treat psychosis and mood disturbances.
Additionally, mood stabilizers such as lithium or valproate treat
the manic phase of bipolar disorder, and antidepressants and
atypical antipsychotic drugs target the depressive phase.
Antipsychotics and mood stabilizers are often used together for
"maintenance" treatment to prevent relapse.
[0091] A. Schizophrenia (SZ)
[0092] SZ is considered a clinical syndrome, and is probably a
constellation of several pathologies. Substantial heterogeneity is
seen between cases; this is thought to reflect multiple overlapping
etiologic factors, including both genetic and environmental
contributions. A diagnosis of SZ is typically indicated by chronic
psychotic symptoms, e.g., hallucinations and delusions.
Disorganization of thought and behavior are common and are
considered distinguishing factors in the diagnosis of SZ. Patients
typically have some subtle impairments in cognition. Reduced
emotional experience and expression, low drive, and impaired speech
are observed in a subgroup of patients. Cognitive, emotional and
social impairments often appear early in life, while the psychotic
symptoms typically manifest in late adolescence or early adulthood
in men, a little later in women.
[0093] A diagnosis of SZ can be made according to the criteria
reported in the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision, American Psychiatric
Association, 2000 (referred to herein as DSM-IV) as follows:
[0094] Diagnostic Criteria for SZ--All six criteria must be met for
a diagnosis of SZ.
[0095] A. Characteristic symptoms: Two (or more) of the following,
each present for a significant portion of time during a one month
period (or less if successfully treated):
[0096] (1) delusions; (2) hallucinations; (3) disorganized speech
(e.g., frequent derailment or incoherence); (4) grossly
disorganized or catatonic behavior; (5) negative symptoms, e.g.,
affective flattening, alogia, or avolition.
[0097] Only one criterion A symptom is required if delusions are
bizarre or hallucinations consist of a voice keeping up a running
commentary on the person's behavior or thoughts, or two or more
voices conversing with each other.
[0098] B. Social/occupational dysfunction: For a significant
portion of the time since the onset of the disturbance, one or more
major areas of functioning such as work, interpersonal relations,
or self-care are markedly below the level achieved prior to the
onset (or when the onset is in childhood or adolescence, failure to
achieve expected level of interpersonal, academic, or occupational
achievement).
[0099] C. Duration: Continuous signs of the disturbance persist for
at least 6 months. This 6-month period must include at least 1
month of symptoms (or less if successfully treated) that meet
Criterion A (i.e., active-phase symptoms) and may include periods
of prodromal or residual symptoms. During these prodromal or
residual periods, the signs of the disturbance may be manifested by
only negative symptoms or two or more symptoms listed in Criterion
A present in an attenuated form (e.g., odd beliefs, unusual
perceptual experiences).
[0100] D. Schizoaffective and Mood Disorder Exclusion:
Schizoaffective Disorder and Mood Disorder With Psychotic Features
have been ruled out because either (1) no major depressive, manic,
or mixed episodes have occurred concurrently with the active-phase
symptoms; or (2) if mood episodes have occurred during active-phase
symptoms, their total duration has been brief relative to the
duration of the active and residual periods.
[0101] E. Substance/General Medical Condition Exclusion: The
disturbance is not due to the direct physiological effects of a
substance (e.g., a drug of abuse, a medication) or a general
medical condition.
[0102] F. Relationship to a Pervasive Developmental Disorder: If
the patient has a history of Autistic Disorder or another Pervasive
Developmental Disorder, the additional diagnosis of SZ is made only
if prominent delusions or hallucinations are also present for at
least a month (or less if successfully treated).
[0103] B. Schizoaffective Disorder (SD)
[0104] SD is characterized by the presence of affective (depressive
or manic) symptoms and schizophrenic symptoms within the same,
uninterrupted episode of illness.
[0105] The DSM-IV Criteria for a diagnosis of schizoaffective
disorder is as follows:
[0106] An uninterrupted period of illness during which, at some
time, there is either (1) a Major Depressive Episode (which must
include depressed mood), (2) a Manic Episode, or (3) a Mixed
Episode, concurrent with symptoms that meet (4) Criterion A for SZ,
above.
[0107] A. Criteria for Major Depressive Episode
[0108] At least five of the following symptoms must be present
during the same 2-week period and represent a change from previous
functioning; at least one of the symptoms is either (1) depressed
mood or (2) loss of interest or pleasure.
[0109] (1) depressed mood most of the day, nearly every day, as
indicated by either subjective report (e.g., feels sad or empty) or
observation made by others (e.g., appears tearful). In children and
adolescents, this can be an irritable mood.
[0110] (2) markedly diminished interest or pleasure in all, or
almost all, activities most of the day, nearly every day (as
indicated by either subjective account or observation made by
others)
[0111] (3) significant weight loss when not dieting or weight gain
(e.g., a change of more than 5% of body weight in a month), or
decrease or increase in appetite nearly every day. (In children,
failure to make expected weight gains is considered).
[0112] (4) insomnia or hypersomnia nearly every day
[0113] (5) psychomotor agitation or retardation nearly every day
(observable by others, not merely subjective feelings of
restlessness or being slowed down)
[0114] (6) fatigue or loss of energy nearly every day
[0115] (7) feelings of worthlessness or excessive or inappropriate
guilt (which may be delusional) nearly every day (not merely
self-reproach or guilt about being sick)
[0116] (8) diminished ability to think or concentrate, or
indecisiveness, nearly every day (either by subjective account or
as observed by others)
[0117] (9) recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a specific plan, or a suicide
attempt or a specific plan for committing suicide
[0118] In addition, the symptoms do not meet criteria for a Mixed
Episode. The symptoms cause clinically significant distress or
impairment in social, occupational, or other important areas of
functioning. The symptoms are not due to the direct physiological
effects of a substance (e.g., a drug of abuse, a medication) or a
general medical condition (e.g., hypothyroidism).
[0119] The symptoms are not better accounted for by Bereavement,
i.e., after the loss of a loved one, the symptoms persist for
longer than 2 months, or are characterized by marked functional
impairment, morbid preoccupation with worthlessness, suicidal
ideation, psychotic symptoms, or psychomotor retardation.
[0120] B. Criteria for Manic Episode
[0121] A manic episode is a distinct period of abnormally and
persistently elevated, expansive, or irritable mood, lasting at
least one week (or any duration, if hospitalization is
necessary).
[0122] During the period of mood disturbance, three (or more) of
the following symptoms have persisted (four if the mood is only
irritable) and have been present to a significant degree:
[0123] (1) inflated self-esteem or grandiosity
[0124] (2) decreased need for sleep (e.g., feels rested after only
3 hours of sleep)
[0125] (3) more talkative than usual or pressure to keep
talking
[0126] (4) flight of ideas or subjective experience that thoughts
are racing
[0127] (5) distractibility (i.e., attention too easily drawn to
unimportant or irrelevant external stimuli)
[0128] (6) increase in goal-directed activity (either socially, at
work or school, or sexually) or psychomotor agitation
[0129] (7) excessive involvement in pleasurable activities that
have a high potential for painful consequences (e.g., engaging in
unrestrained buying sprees, sexual indiscretions, or foolish
business investments)
[0130] The symptoms do not meet criteria for a Mixed Episode. The
mood disturbance is sufficiently severe to cause marked impairment
in occupational functioning or in usual social activities or
relationships with others, or to necessitate hospitalization to
prevent harm to self or others, or there are psychotic features.
The symptoms are not due to the direct physiological effects of a
substance (e.g., a drug of abuse, a medication, or other treatment)
or a general medical condition (e.g., hyperthyroidism).
[0131] C. Criteria for Mixed Episode
[0132] A mixed episode occurs when the criteria are met both for a
Manic Episode and for a Major Depressive Episode (except for
duration) nearly every day during at least a 1-week period. The
mood disturbance is sufficiently severe to cause marked impairment
in occupational functioning or in usual social activities or
relationships with others, or to necessitate hospitalization to
prevent harm to self or others, or there are psychotic
features.
[0133] The symptoms are not due to the direct physiological effects
of a substance (e.g., a drug of abuse, a medication, or other
treatment) or a general medical condition (e.g.,
hyperthyroidism).
[0134] D. Criterion A of SZ
[0135] See above.
[0136] E. Types of SD
[0137] The type of SD may be may be specifiable, as either Bipolar
Type, if the disturbance includes a Manic or a Mixed Episode (or a
Manic or a Mixed Episode and Major Depressive Episodes), or
Depressive Type, if the disturbance only includes Major Depressive
Episodes.
[0138] F. Associated Features
[0139] Features associated with SD include Learning Problems,
Hypoactivity, Psychotic, Euphoric Mood, Depressed Mood,
Somatic/Sexual Dysfunction, Hyperactivity, Guilt/Obsession,
Odd/Eccentric/Suspicious Personality, Anxious/Fearful/Dependent
Personality, and Dramatic/Erratic/Antisocial Personality.
[0140] C. Schizotypal Personality Disorder (SPD)
[0141] A diagnosis of SPD under the criteria of the DSM-IV is
generally based on a pervasive pattern of social and interpersonal
deficits marked by acute discomfort with, and reduced capacity for,
close relationships as well as by cognitive or perceptual
distortions and eccentricities of behavior, beginning by early
adulthood and present in a variety of contexts, as indicated by
five (or more) of the following:
[0142] (1) ideas of reference (excluding delusions of
reference)
[0143] (2) odd beliefs or magical thinking that influences
behavior
[0144] (3) inconsistent with subcultural norms (e.g.,
superstitiousness, belief in clairvoyance, telepathy, or "sixth
sense;" in children and adolescents, bizarre fantasies or
preoccupations)
[0145] (4) unusual perceptual experiences, including bodily
illusions
[0146] (5) odd thinking and speech (e.g., vague, circumstantial,
metaphorical, overelaborate, or stereotyped)
[0147] (6) suspiciousness or paranoid ideation
[0148] (7) inappropriate or constricted affect
[0149] (8) behavior or appearance that is odd, eccentric, or
peculiar
[0150] (9) lack of close friends or confidants other than
first-degree relatives
[0151] (10) excessive social anxiety that does not diminish with
familiarity and tends to be associated with paranoid fears rather
than negative judgments about self
[0152] SPD is diagnosed if the symptoms do not occur exclusively
during the course of SZ, a Mood Disorder With Psychotic Features,
another Psychotic Disorder, or a Pervasive Developmental Disorder,
and the disturbance is not due to the direct physiological effects
of a substance (e.g., a drug of abuse, a medication) or a general
medical condition.
[0153] Associated features of SPD include Depressed Mood and
Odd/Eccentric/Suspicious Personality.
[0154] D. Bipolar Disorder (BD)
[0155] Bipolar disorder is also known as manic-depression or
manic-depressive disorder. This condition is characterized by mood
that alternates between two emotional extremes, or poles: the
sadness of depression and the euphoria of mania (see symptoms of
mania below).
[0156] Between these emotional swings, there are periods when a
person's mood is quite normal. When a person is in the depressed
phase of bipolar illness, he or she will have the same symptoms as
those found in major depressive disorder. The depressive episodes
can often be severe. While in a manic phase, a person experiences
mood that is extremely elevated, expansive, or irritable. Mania can
seriously impair one's normal judgment. When manic, a person is
prone towards reckless and inappropriate behavior such as engaging
in wild spending sprees or having promiscuous sex. He or she may
not be able to realize the harm of his/her behavior and may even
lose touch with reality.
[0157] There are two primary types of bipolar disorder:
[0158] Bipolar I Disorder is diagnosed when a person has had at
least one manic or mixed episode, often along with a major
depressive episode. It affects equal numbers of men and women in
approximately 0.4% to 1.6% of the population.
[0159] Bipolar II Disorder is diagnosed when a person has had a
major depressive episode along with at least one hypomanic episode.
It affects more women than men in about 0.5% of the population.
[0160] People with bipolar disorder experience a wide range of
feelings depending on the phase of the illness is present. During a
phase of depression, a person will have many of the symptoms of a
major depressive episode. He or she may have despondent mood, a
loss of energy, feelings of worthlessness or guilt, or problems
with concentration. Thoughts of suicide are not uncommon. In fact,
10% to 15% of those with bipolar disorder may die by suicide. If
the depression is severe, a person may need to be hospitalized for
his or her own safety. For those who go through a phase of
hypomania, the experience usually feels quite good. If a person's
mood and spirit lightens, he or she will be more outgoing and
notice more energy and enhanced self-esteem. Lots of ideas come
with ease and a person may feel compelled towards greater activity
and productivity. A person in a hypomanic phase may also feel more
powerful and omnipotent.
[0161] The manic phase is the most extreme part of bipolar
disorder. A person becomes euphoric, ideas come much too fast, and
concentration is nearly impossible. Anger, irritability, fear, and
a sense of being out of control are overwhelming. A person's
judgment is impaired, and he or she may behave recklessly without a
sense of consequence. Some people lose touch with reality and
experience delusions and hallucinations. When this happens, people
often need to be hospitalized for their own safety. If a person
with bipolar disorder experiences a severe manic episode, he or she
may be abusive to children, spouses, or engage in other violent
behaviors. There may also be problems with attendance and
performance at school or work, as well as significant difficulties
in personal relationships.
[0162] The cycles of bipolar disorder may be different for each
person. Oftentimes a person may first experience depression. Then
depression may be replaced with manic symptoms and the cycle
between depression and mania may continue for days, weeks, or
months. Between phases of depression and mania some people return
to their normal mood. Some others have several periods of either
depression or mania. Still others may experience several bouts of
depression with infrequent phases of hypomania, or repeated manic
episodes with occasional depressive periods. A portion of people,
roughly 10% to 20% may only experience mania, while others can have
both depression and mania at the same time.
[0163] For at least 90% of those who have bipolar disorder the
condition is recurrent. They will experience future symptoms of the
cycles of mania and depression. Approximately 60%-70% of manic
episodes may happen just before or after a depressive episode, and
this pattern may happen in a particular way for each person. Most
people return to a regular level of functioning between episodes,
while some (about 20%-30%) may continue to have some problems with
mood stability and social and occupational functioning.
[0164] Bipolar I disorder affects equal numbers of males and
females, however there does appear to be a gender difference in the
onset of the illness. Females are more likely to experience a first
episode of depression, while males tend to have a first episode
that is manic. Women who have bipolar I or II disorder and who have
children may be at a higher risk of experiencing bipolar episodes
within several months of giving birth.
[0165] A first episode of mania is most likely to occur when a
person is in his/her teens or twenties. If a person develops
bipolar disorder for the first time after 40 years of age, he or
she should be evaluated for the possibility of a medical illness or
substance use.
[0166] People who have immediate relatives with bipolar I disorder
have a higher risk of developing a mood disorder themselves. For
these people the rate of developing bipolar II disorder or major
depression is 4%-24% and bipolar I disorder is 1%-5%.
[0167] Of adolescents who have recurrent major depressive episodes,
about 10%-15% of them will likely develop bipolar disorder.
[0168] Diagnostic Criteria of Bipolar I Disorder
[0169] Summarized from the Diagnostic and Statistical Manual of
Mental Disorders-Fourth Edition
[0170] A. A person experiences a current or recent episode that is
manic, hypomanic, mixed, or depressed.
[0171] To be a manic episode, for at least one week a person's mood
must be out of the ordinary and continuously heightened,
exaggerated, or irritable.
[0172] At least three of the following seven symptoms have been
significant and enduring. If the mood is only irritable, then four
symptoms are required.
[0173] Self-esteem is excessive or grandiose.
[0174] The need for sleep is greatly reduced.
[0175] Talks much more than usual.
[0176] Thoughts and ideas are continuous and without a pattern or
focus.
[0177] Easily distracted by unimportant things.
[0178] An increase in purposeful activity or productivity, or
behaving and feeling agitated.
[0179] Reckless participation in enjoyable activities that create a
high risk for negative consequences (e.g., extensive spending
sprees, sexual promiscuity).
[0180] The persons' symptoms do not indicate a mixed episode.
[0181] The person's symptoms are a cause of great distress or
difficulty in functioning at home, work, or other important areas.
Or, the symptoms require the person to be hospitalized to protect
the person from harming himself/herself or others. Or, the symptoms
include psychotic features (hallucinations, delusions).
[0182] The person's symptoms are not caused by substance use (e.g.,
alcohol, drugs, medication), or a medical disorder.
[0183] B. Unless this is a first single manic episode there has
been at least one manic, mixed, hypomanic, or depressive
episode.
[0184] For a major depressive episode a person must have
experienced at least five of the nine symptoms below for the same
two weeks or more, for most of the time almost every day, and this
is a change from his/her prior level of functioning. One of the
symptoms must be either (a) depressed mood, or (b) loss of
interest.
[0185] Depressed mood. For children and adolescents, this may be
irritable mood.
[0186] A significantly reduced level of interest or pleasure in
most or all activities.
[0187] A considerable loss or gain of weight (e.g., 5% or more
change of weight in a month when not dieting). This may also be an
increase or decrease in appetite. For children, they may not gain
an expected amount of weight.
[0188] Difficulty falling or staying asleep (insomnia), or sleeping
more than usual (hypersomnia).
[0189] Behavior that is agitated or slowed down. Others should be
able to observe this.
[0190] Feeling fatigued, or diminished energy.
[0191] Thoughts of worthlessness or extreme guilt (not about being
ill).
[0192] Ability to think, concentrate, or make decisions is
reduced.
[0193] Frequent thoughts of death or suicide (with or without a
specific plan), or attempt of suicide.
[0194] The persons' symptoms do not indicate a mixed episode.
[0195] The person's symptoms are a cause of great distress or
difficulty in functioning at home, work, or other important
areas.
[0196] The person's symptoms are not caused by substance use (e.g.,
alcohol, drugs, medication), or a medical disorder.
[0197] The person's symptoms are not due to normal grief or
bereavement over the death of a loved one, they continue for more
than two months, or they include great difficulty in functioning,
frequent thoughts of worthlessness, thoughts of suicide, symptoms
that are psychotic, or behavior that is slowed down (psychomotor
retardation).
[0198] C. Another disorder does not better explain the episode.
[0199] Diagnostic Criteria of Bipolar II Disorder
[0200] Summarized from the Diagnostic and Statistical Manual of
Mental Disorders-Fourth Edition
[0201] A. The person currently has, or in the past has had at least
one major depressive episode:
[0202] For a major depressive episode a person must have
experienced at least five of the nine symptoms below for the same
two weeks or more, for most of the time almost every day, and this
is a change from his/her prior level of functioning. One of the
symptoms must be either (a) depressed mood, or (b) loss of
interest.
[0203] Depressed mood. For children and adolescents, this may be
irritable mood.
[0204] A significantly reduced level of interest or pleasure in
most or all activities.
[0205] A considerable loss or gain of weight (e.g., 5% or more
change of weight in a month when not dieting). This may also be an
increase or decrease in appetite. For children, they may not gain
an expected amount of weight.
[0206] Difficulty falling or staying asleep (insomnia), or sleeping
more than usual (hypersomnia).
[0207] Behavior that is agitated or slowed down. Others should be
able to observe this.
[0208] Feeling fatigued, or diminished energy.
[0209] Thoughts of worthlessness or extreme guilt (not about being
ill).
[0210] Ability to think, concentrate, or make decisions is
reduced.
[0211] Frequent thoughts of death or suicide (with or without a
specific plan), or attempt of suicide.
[0212] The persons' symptoms do not indicate a mixed episode.
[0213] The person's symptoms are a cause of great distress or
difficulty in functioning at home, work, or other important
areas.
[0214] The person's symptoms are not caused by substance use (e.g.,
alcohol, drugs, medication), or a medical disorder.
[0215] The person's symptoms are not due to normal grief or
bereavement over the death of a loved one, they continue for more
than two months, or they include great difficulty in functioning,
frequent thoughts of worthlessness, thoughts of suicide, symptoms
that are psychotic, or behavior that is slowed down (psychomotor
retardation).
[0216] B. The person currently has, or in the past has had at least
one hypomanic episode:
[0217] For a hypomanic episode a person's mood must be out of the
ordinary and continuously heightened, exaggerated, or irritable for
at least four days.
[0218] At least three of the following seven symptoms have been
significant and enduring. If the mood is only irritable, then four
symptoms are required.
[0219] Self-esteem is excessive or grandiose.
[0220] The need for sleep is greatly reduced.
[0221] Talks much more than usual.
[0222] Thoughts and ideas are continuous and without a pattern or
focus.
[0223] Easily distracted by unimportant things.
[0224] An increase in purposeful activity or productivity, or
behaving and feeling agitated.
[0225] Reckless participation in enjoyable activities that create a
high risk for negative consequences (e.g., extensive spending
sprees, sexual promiscuity).
[0226] The episode is a substantial change for the person and
uncharacteristic of his or her usual functioning.
[0227] The changes of functioning and mood can be observed by
others.
[0228] The person's symptoms are NOT severe enough to cause
difficulty in functioning at home, work, or other important areas.
Also, the symptoms neither require the person to be hospitalized,
nor are there any psychotic features.
[0229] The person's symptoms are not caused by substance use (e.g.,
alcohol, drugs, medication), or a medical disorder. C. The person
has never experienced a manic or mixed episode. D. Another disorder
does not better explain the episode. E. The symptoms are a cause of
great distress or difficulty in functioning at home, work, or other
important areas.
[0230] E. Psychiatric Endophenotypes in SZ
[0231] A number of endophenotypes, i.e., intermediate phenotypes,
that may more closely reflect biological mechanisms behind SZ, have
been suggested, such as prepulse inhibition, structural
abnormalities evident in MRI scans, specific domains of cognition
(e.g., executive function), fine motor performance, working memory,
etc.
[0232] Endophenotypes can also include clinical manifestations such
as hallucinations, paranoia, mania, depression,
obsessive-compulsive symptoms, etc., as well as response or lack of
response to drugs and comorbidity for substance and alcohol abuse.
See, e.g., Kendler et al. (1995); Gottesman and Gould (2003);
Cadenhead, 2002; Heinrichs (2004); and Zobel and Maier (2004).
There is now evidence that some candidate genes that were
identified using DSM-IV type categorical definitions for "affected"
individuals may influence specific endophenotypes, see, e.g., Baker
et al. (2005); Cannon et al. (2005); Gothelf et al. (2005);
Hallmayer et al. (2005); Callicott et al. (2005); Gornick et al.
(2005).
[0233] F. Use of PANSS (Positive and Negative Syndrome Scale) Score
for Differential Diagnosis and Evaluation of Clinical Response
[0234] The Positive and Negative Syndrome Scale (PANSS) is a
comprehensive psychometric scale used to classify psychopathology
for severe neuropsychiatric diseases, including SZ. It measures a
number of psychiatric endophenotypes or dimensions using
quantitative scales based on the scoring of patients by clinicians.
It is widely used to classify patients into specific subtypes, and
is commonly used for measuring the improvement of symptoms in
response to clinical interventions (Kay et al., 1987; Kay et al.,
1989; Leucht et al., 2005).
[0235] Detailed information on PANSS and Scoring Criteria can be
found in the art, e.g., on the world wide web at panss.org, or in
the book by Kay (1991) which is incorporated herein in its entirety
by reference. Based on these sources, the methodology is summarized
briefly below.
[0236] PANSS comprises 30 individual subscales. Seven constitute a
Positive Symptom Scale, seven the Negative Symptom Scale, and the
remaining 16 items make up a General Psychopathology Scale. The
scores for these scales are arrived at by summation of ratings
across component items. Therefore, the potential ranges are 7 to 49
for the Positive and Negative Scales, and 16 to 112 for the General
Psychopathology Scale (Source: The PANSS Institute).
[0237] Each of the 30 items is accompanied by a specific definition
as well as detailed anchoring criteria for all seven rating points.
These seven points represent increasing levels of psychopathology,
as follows:
[0238] 1--absent
[0239] 2--minimal
[0240] 3--mild
[0241] 4--moderate
[0242] 5--moderate severe
[0243] 6--severe
[0244] 7--extreme
[0245] The PANSS Individual subscales are described below.
[0246] P1. DELUSIONS--Beliefs which are unfounded, unrealistic and
idiosyncratic.
[0247] P2. CONCEPTUAL DISORGANISATION--Disorganized process of
thinking characterized by disruption of goal-directed sequencing,
e.g., circumstantiality, loose associations, tangentiality, gross
illogicality or thought block.
[0248] P3. HALLUCINATORY BEHAVIOUR--Verbal report or behaviour
indicating perceptions which are not generated by external stimuli.
These may occur in the auditory, visual, olfactory or somatic
realms.
[0249] P4. EXCITEMENT--Hyperactivity as reflected in accelerated
motor behaviour, heightened responsivity to stimuli, hypervigilance
or excessive mood lability.
[0250] P5. GRANDIOSITY--Exaggerated self-opinion and unrealistic
convictions of superiority, including delusions of extraordinary
abilities, wealth, knowledge, frame, power and moral
righteousness.
[0251] P6. SUSPICIOUSNESS/PERSECUTION--Unrealistic or exaggerated
ideas of persecution, as reflected in guardedness, ad distrustful
attitude, suspicious hypervigilance or frank delusions that others
mean harm.
[0252] P7. HOSTILITY--Verbal and nonverbal expressions of anger and
resentment, including sarcasm, passive-aggressive behavior, verbal
abuse and assualtiveness.
[0253] N1. BLUNTED AFFECT--Diminished emotional responsiveness as
characterized by a reduction in facial expression, modulation of
feelings and communicative gestures.
[0254] N2. EMOTIONAL WITHDRAWAL--Lack of interest in, involvement
with, and affective commitment to life's events.
[0255] N3. POOR RAPPORT--Lack of interpersonal empathy, openness in
conversation and sense of closeness, interest or involvement with
the interviewer. This is evidenced by interpersonal distancing and
reduced verbal and nonverbal communication.
[0256] N4. PASSIVE/APATHETIC SOCIAL WITHDRAWAL--Diminished interest
and initiative in social interactions due to passivity, apathy,
anergy or avolition. This leads to reduced interpersonal
involvements and neglect of activities of daily living.
[0257] N5. DIFFICULTY IN ABSTRACT THINKING--Impairment in the use
of the abstract-symbolic mode of thinking, as evidenced by
difficulty in classification, forming generalizations and
proceeding beyond concrete or egocentric thinking in
problem-solving tasks.
[0258] N6. LACK OF SPONTANEITY AND FLOW OF CONVERSATION--Reduction
in the normal flow of communication associated with apathy,
avolition, defensiveness or cognitive deficit. This is manifested
by diminished fluidity and productivity of the verbal interactional
process.
[0259] N7. STEREOTYPED THINKING--Decreased fluidity, spontaneity
and flexibility of thinking, as evidenced in rigid, repetitious or
barren thought content.
[0260] G1. SOMATIC CONCERN--Physical complaints or beliefs about
bodily illness or malfunctions. This may range from a vague sense
of ill being to clear-cut delusions of catastrophic physical
disease.
[0261] G2. ANXIETY--Subjective experience of nervousness, worry,
apprehension or restlessness, ranging from excessive concern about
the present or future to feelings of panic.
[0262] G3. GUILT FEELINGS--Sense of remorse or self-blame for real
or imagined misdeeds in the past.
[0263] G4. TENSION--Overt physical manifestations of fear, anxiety,
and agitation, such as stiffness, tremor, profuse sweating and
restlessness.
[0264] G5. MANNERISMS AND POSTURING--Unnatural movements or posture
as characterized be an awkward, stilted, disorganized, or bizarre
appearance.
[0265] G6. DEPRESSION--Feelings of sadness, discouragement,
helplessness and pessimism.
[0266] G7. MOTOR RETARDATION--Reduction in motor activity as
reflected in slowing or lessening or movements and speech,
diminished responsiveness of stimuli, and reduced body tone.
[0267] G8. UNCOOPERATIVENESS--Active refusal to comply with the
will of significant others, including the interviewer, hospital
staff or family, which may be associated with distrust,
defensiveness, stubbornness, negativism, rejection of authority,
hostility or belligerence.
[0268] G9. UNUSUAL THOUGHT CONTENT--Thinking characterized by
strange, fantastic or bizarre ideas, ranging from those which are
remote or atypical to those which are distorted, illogical and
patently absurd.
[0269] G10. DISORIENTATION--Lack of awareness of one's relationship
to the milieu, including persons, place and time, which may be due
to confusion or withdrawal.
[0270] G11. POOR ATTENTION--Failure in focused alertness manifested
by poor concentration, distractibility from internal and external
stimuli, and difficulty in harnessing, sustaining or shifting focus
to new stimuli.
[0271] G12. LACK OF JUDGEMENT AND INSIGHT--Impaired awareness or
understanding of one's own psychiatric condition and life
situation. This is evidenced by failure to recognize past or
present psychiatric illness or symptoms, denial of need for
psychiatric hospitalization or treatment, decisions characterized
by poor anticipation or consequences, and unrealistic short-term
and long-range planning
[0272] G13. DISTURBANCE OF VOLITION--Disturbance in the willful
initiation, sustenance and control of one's thoughts, behavior,
movements and speech.
[0273] G14. POOR IMPULSE CONTROL--Disordered regulation and control
of action on inner urges, resulting in sudden, unmodulated,
arbitrary or misdirected discharge of tension and emotions without
concern about consequences.
[0274] G15. PREOCCUPATION--Absorption with internally generated
thoughts and feelings and with autistic experiences to the
detriment of reality orientation and adaptive behavior.
[0275] G16. ACTIVE SOCIAL AVOIDANCE--Diminished social involvement
associated with unwarranted fear, hostility, or distrust.
[0276] Each patient's disease manifestation and process is unique.
PANSS provides a structured, objective way of describing the
various aspects of psychopathology of a given patient. However,
proper implementation of the PANSS requires highly trained
personnel to conduct the assessment and to interpret the results,
and there is potential for site to site variability, especially
outside the research setting.
[0277] Each of the PANSS composite scales and subscales can be
considered a clinical endophenotype. The ability to link genetic
profiles to these clinical endophenotypes changes as response to
psychotic treatments, or severity of the diseases, will enable
clinicians to refine a patient's diagnosis and develop a
personalized therapeutic strategy for each patient. By identifying
the genetic contributions to specific endophenotypes, the physician
can create a personalized diagnosis and treatment regime for the
patient.
[0278] Additionally, changes in PANSS or the Brief Psychiatric
Rating Scale (BPRS), which is derived from PANSS, are often the
primary measures of efficacy in clinical trials. Moreover, certain
subscales and composite scores are also evaluated for change. For
example, positive symptoms and negative symptoms are two composite
scores that have clinical relevance.
V. TREATMENT OF PSYCHOTIC DISORDERS
[0279] As described herein, the presence of a OPRP genetic
signature described herein has been correlated with an altered
response to a treatment, e.g., a pharmacological treatment. An
altered response can be, for example, a positive response (i.e., an
improvement in one or more symptoms of the disease), negative
response (worsening of one or more symptoms of the disease), no
response, or the presence or absence of side effects). Thus, the
new methods can also include selecting or developing a treatment
regimen for a subject determined to or suspected to have a
psychotic disorder such as a psychotic disorder, based upon the
absence or presence of a OPRP genetic signature.
[0280] For example, the inventors identified a OPRP genetic
signature and developed its use in determining the optimal use of
antipsychotic medications: i) Patients who are OPRP genetic
signature negative have a higher probability of clinically
significant improvement when treated with olanzapine when compared
to patients who are OPRP genetic signature positive or untested.
ii) Patients who are OPRP genetic signature negative may have a
higher probability of clinically significant improvement when
treated with olanzapine compared to other antipsychotic drugs. For
example, this group responds better to olanzapine than to
perphenazine, quetiapine, risperidone, or ziprasidone. iii)
Patients who are OPRP genetic signature positive have a lower
probability of clinically significant improvement when treated with
olanzapine compared to similar patients who are OPRP genetic
signature negative. Since olanzapine has a significant metabolic
side effect burden compared to alternative first-line
antipsychotics that demonstrate non-inferiority to olanzapine, it
may be appropriate to recommend that first-line antipsychotics with
lower metabolic side-effect burdens than olanzapine be used
preferentially for OPRP genetic signature positive patients.
[0281] The methods can also include administering a selected
treatment regimen to a subject having, or suspected to have a
psychotic disorder such as a psychotic disorder, to thereby treat,
prevent or delay further progression of the disease. A treatment
regimen can include the administration of a selected antipsychotic
medications to a subject identified as at risk of developing a
psychotic disorder, before the onset of any psychotic episodes. The
medications can be selected based on the absence of a OPRP genetic
signature that is associated with, for example, good response, or
the absence of significant side effects.
[0282] As used herein, the term "treat" or "treatment" is defined
as the prescription, application or administration of a treatment
regimen, e.g., a therapeutic agent or modality, to a subject, e.g.,
a patient. The subject can be a patient having a symptom of a
psychotic disorder, or at risk of developing (i.e., a
predisposition toward) such a disorder. The treatment can be to
cure, heal, alleviate, relieve, alter, remedy, ameliorate,
palliate, improve or affect a psychotic disorder, the symptoms of a
psychotic disorder, or the predisposition toward a psychotic
disorder.
[0283] The methods described herein, e.g., methods of determining a
treatment regimen and methods of treatment or prevention of a
psychotic disorder, can further include the step of monitoring the
subject, e.g., for a change (e.g., an increase or decrease) in one
or more of the diagnostic criteria for a psychotic disorder, listed
herein, or any other parameter related to clinical outcome. The
subject can be monitored in one or more of the following periods:
prior to beginning of treatment; during the treatment; or after one
or more elements of the treatment have been administered.
Monitoring can be used to evaluate the need for further treatment
with the same or a different therapeutic agent or modality.
Generally, a decrease in one or more of the parameters described
above is indicative of the improved condition of the subject,
although with red blood cell and platelet levels, an increase can
be associated with the improved condition of the subject.
[0284] The methods can be used, e.g., to evaluate the suitability
of, or to choose between alternative treatments, e.g., a particular
dosage, mode of delivery, time of delivery, inclusion of adjunctive
therapy, e.g., administration in combination with a second agent,
or generally to determine the subject's probable drug response
genotype. The effects of the treatment or combination of treatments
on each of these subjects can be used to determine if a treatment
or combination of treatments is particularly effective on a
sub-group of subjects having a psychotic disorder. In other
embodiments, various treatments or combinations of treatments can
be evaluated by administering two different treatments or
combinations of treatments to at least two different subjects
having a psychotic disorder, and a determined OPRP genetic
signature status as described herein. Such methods can be used to
determine if a particular treatment or combination of treatments is
more effective than others in treating this subset of patients.
[0285] A. Current Treatments for Psychotic Disorders
[0286] Atypical antipsychotic drugs listed in order of current
prescribing frequency for these disorders include: risperidone,
quetiapine, olanzapine, aripiprazole, ziprasidone, clozapine,
paliperidone, and iloperidone. Typical antipsychotic drugs include
haloperidol, fluphenazine, perphenazine, and others (Meltzer and
Bobo, 2009). Atypical antipsychotics are favored because of lower
parkinsonian side effects and perceived greater efficacy. There are
several long acting formulations of typical antipsychotic drugs,
which are seldom used in the US. Among the atypical agents, only
long acting, injectable risperidone, paliperidone and olanzapine
are currently available; and others, e.g., long acting
aripiprazole, are in development. These formulations are highly
effective since they provide great help with regard to compliance,
an enormous problem with both bipolar and schizophrenia patients.
However, they are underutilized in the marketplace.
[0287] All of the antipsychotic medications have some degree of
side-effects and other limitations. Metabolic side effects with
some atypical antipsychotic drugs (weight gain, increased lipids,
and problems with glucose regulation, including diabetes)
exacerbate the discontinuation rates and limit overall
effectiveness the implicated drugs. Olanzapine and clozapine, two
of the most efficacious drugs for treating psychosis, have the
greatest incidence of metabolic side-effects (Nasrallah, 2007).
[0288] Subjects with SZ typically require acute treatment for
psychotic exacerbations, and long-term treatment including
maintenance and prophylactic strategies to sustain symptom
improvement and prevent recurrence of psychosis. Subjects with
schizoaffective disorder experience the symptoms of both SZ and
affective disorder (manic and/or depressive), thus require the
specific treatments for each disorder. Subjects with SPD sometimes
require medication for acute psychotic episodes but are often
treated using psychosocial methods. The methods described herein
can include the administration of one or more accepted or
experimental treatment modalities to a person identified as having,
suspected to have, or at risk of developing a psychotic disorder
such as SZ, SPD, or a SD, based on the presence of a OPRP genetic
signature status. Currently accepted treatments presently include
both pharmacologic and psychosocial management, and occasionally
electroconvulsive therapy (ECT).
[0289] Standard pharmacologic therapies for SZ and SD include the
administration of one or more antipsychotic medications, which are
typically antagonists acting at postsynaptic D.sub.2 dopamine
receptors in the brain. Antipsychotic medications include
conventional, or first generation, antipsychotic agents, which are
sometimes referred to as neuroleptics because of their neurologic
side effects, and second generation antipsychotic agents, which are
less likely to exhibit neuroleptic effects and have been termed
atypical antipsychotics.
[0290] Standard pharmacologic therapies for SD also include the
administration of a combination of antidepressant, and anti-anxiety
medication. Suitable antidepressants include serotonergic
antidepressants, e.g., fluoxetine or trazodone. Suitable
anxiolytics include benzodiazepines, e.g., lorazepam, clonazepam.
Lithium can also be administered. Thus, in some embodiments, the
methods can include the administration of one or more
antidepressant and/or anti-anxiety medications to a person
identified as having or suspected to have SD in combination with a
treatment plan based on OPRP genetic signature status.
[0291] The methods can also include psychosocial and rehabilitation
interventions, e.g., interventions that are generally accepted as
therapeutically beneficial, e.g., cognitive-behavioral therapy for
treatment-resistant positive psychotic symptoms; supportive,
problem-solving, educationally oriented psychotherapy; family
therapy and education programs aimed at helping patients and their
families understand the patient's illness, reduce stress, and
enhance coping capabilities; social and living skills training;
supported employment programs; and/or the provision of supervised
residential living arrangements.
[0292] Currently accepted treatments for SZ are described in
greater detail in the Practice Guideline for the Treatment of
Patients With Schizophrenia, 2004, which is incorporated herein by
reference in its entirety.
[0293] Currently accepted treatments for BD are described in
greater detail in the Treatment of Patients With Bipolar Disorder,
2006, which is incorporated herein by reference in its
entirety.
[0294] There are seven commonly prescribed atypical antipsychotic
medications for bipolar disorder:
[0295] Abilify (aripiprazole)
[0296] Risperdal (risperidone)
[0297] Zyprexa (olanzapine)
[0298] Seroquel (quetiapine)
[0299] Geodon (ziprasidone)
[0300] Cloazril (clozapine)
[0301] Symbyax (olanzapine/fluoxetine)
[0302] The atypical antipsychotics have several significant
side-effects, including weight gain, metabolic and hormonal
disregulation, and sexual dysfunction. Weight gain, in particular,
can be a significant issue as many people treated with atypical
antipsychotics expect to gain weight, sometimes significantly so.
Because weight gain is also associated with an increased risk for
Type II diabetes, individuals taking an atyptical antipsychotic
should be carefully monitored by their physician. Other metabolic
disturbances include elevated prolactin levels and altered steroid
metabolism. Additionally, both men and women report significant
levels of sexual dysfunction.
[0303] Drugs approved for the treatment of Bipolar disorder can
have one or more indications, e.g., U.S. FDA (or other regulatory
body) approved uses. Some of these indications include: Treatment
of Acute Mania episodes; Bipolar Mania maintenance; Bipolar
depression; Treatment of mixed mania and depression episodes.
[0304] Clinicians most commonly initiate treatment with oral
risperidone, especially now that it is generic. Often, however,
clinicians will switch patients to another drug after less than 1
to 6 months treatment. This common practice occurs based on what is
perceived by patients and clinicians as both insufficient efficacy
and unacceptable side effects, such as Parkinsonism, prolactin
elevations or weight gain. Olanzapine, which was found to be the
most effective treatment in the CATIE study and is closest in
pharmacology to clozapine (the drug generally accepted to have the
highest efficacy, particularly in treatment resistant subjects), is
considered to be a highly effective agent (Meltzer and Bobo, 2009).
Indeed, olanzapine became the most prescribed treatment and initial
drug of choice after its introduction until concerns about
metabolic side effects became evident (Meltzer, 2005). Metabolic
side effects (weight gain, glucose dysregulation, lipid
dysregulation and risk of diabetes) have greatly reduced the
utilization of olanzapine despite its high efficacy.
[0305] B. Pharmacogenetic Testing
[0306] Clinicians currently have no way of knowing which drug is
best for a specific patient other than from previous successful or
unsuccessful trials. They make decisions based on their overall
experience with a given drug as well as the influence of
advertising and recommendations from clinic supervisors. Also
options may be limited because, without a medical rationale, many
states limit access to highly efficacious medications (primarily
olanzapine) for Medicaid recipients due to cost concerns.
[0307] Payers would welcome a diagnostic test that enhances
compliance and response rates for their clients. Compliance with
oral antipsychotic drugs is a major problem, with 50% of patients
ceasing to take them within 6 months of prescription, leading to
relapse (return of psychosis) and hospitalization. While U.S.
consumers and government agencies spend a considerable amount of
money on atypical drugs, relapse and hospitalization represent the
largest costs associated with schizophrenia and BP. Thus, reducing
the rate of hospitalizations and relapse can lead to very
significant cost savings and improved patient care.
[0308] It is consensus opinion among experts in the treatment of
schizophrenia that a pharmacogenetic test which could deliver
information that led to a more rapid and extensive control of
psychosis would become the dominant driver of choice of medication
options. Physicians could engage patients in a rational dialogue
regarding treatment choice based on genetic profile. With this
additional information, physicians and patients could make
calculated risk-benefit analysis regarding potential efficacy and
side-effect concerns of the various antipsychotic medications.
There is also a published cost-effectiveness analysis which
supports the value of pharmacogenetic testing (Perlis et al.,
2005).
[0309] With regards to both prophylactic and therapeutic methods of
treatment of psychotic disorders such as a psychotic disorder, such
treatments may be specifically tailored or modified, based on
knowledge obtained from the field of pharmacogenomics.
"Pharmacogenomics," as used herein, refers to the application of
genomics technologies such as structural chromosomal analysis, to
drugs in clinical development and on the market. See, for example,
Eichelbaum et al. (1996) and Linder et al. (1997). Specifically, as
used herein, the term refers the study of how a patient's genes
determine his or her response to a drug (e.g., a patient's "drug
response phenotype," or "drug response genotype"). Thus, another
aspect of the invention provides methods for tailoring an
individual's prophylactic or therapeutic treatment according to
that individual's drug response genotype, especially, a OPRP
genetic signature status.
[0310] Information generated from pharmacogenomic research using a
method described herein can be used to determine appropriate dosage
and treatment regimens for prophylactic or therapeutic treatment of
an individual. This knowledge, when applied to dosing or drug
selection, can avoid adverse reactions or therapeutic failure and
thus enhance therapeutic or prophylactic efficiency when
administering a therapeutic composition, e.g., a cytotoxic agent or
combination of cytotoxic agents, to a patient, as a means of
treating or preventing psychotic disorders such as a psychotic
disorder.
[0311] In one embodiment, a physician or clinician may consider
applying knowledge obtained in relevant pharmacogenomics studies,
e.g., using a method described herein, when determining whether to
administer a pharmaceutical composition, e.g., an antipsychotic
agent or a combination of antipsychotic agents, to a subject. In
another embodiment, a physician or clinician may consider applying
such knowledge when determining the dosage, e.g., amount per
treatment or frequency of treatments, of a treatment, e.g., a
antipsychotic agent or combination of antipsychotic agents,
administered to a patient.
[0312] As one example, information regarding a genetic signature
associated with an altered pharmacogenomic response for psychotic
disorders as described herein, can be used to stratify or select a
subject population for a clinical trial. The information can, in
some embodiments, be used to stratify individuals that may exhibit
a toxic response to a treatment from those that will not. In other
cases, the information can be used to separate those that are more
likely to be non-responders from those who will be responders. The
OPRP genetic signature described herein can be used in
pharmacogenomics-based design and to manage the conduct of a
clinical trial, e.g., as described in U.S. Pat. Pub. No.
2003/0108938.
[0313] As another example, information regarding a OPRP genetic
signature associated with an increased severity of psychotic
disorders, or with altered pharmacogenomic response for psychotic
disorders, as described herein, can be used to stratify or select
human cells or cell lines for drug testing purposes. Human cells
are useful for studying the effect of a polymorphism on
physiological function, and for identifying and/or evaluating
potential therapeutic agents for the treatment of psychotic
disorders, e.g., anti-psychotics. Thus the methods can include
performing the present methods on genetic material from a cell
line. The information can, in some embodiments, be used to separate
cells that respond particular drugs from those that do not respond,
e.g. which cells show altered second messenger signaling.
[0314] C. Theranostics
[0315] As used herein, the word theranostic is a combination of a
specific therapy and diagnostic. The combination represents the use
of a diagnostic test to identify a specific patient subtype(s) of
psychotic disorders such as a psychotic disorder that have common
genetic, clinical, metabolic, and/or prognostic features. By
performing a diagnostic test, e.g. a genetic test to determine OPRP
genetic signature, the physician or clinician can place the patient
into a specific disease sub-type or category, for example, an OPRP
genetic signature positive or negative subgroup. Moreover, patients
in this sub-type respond to a given therapy in a particular
manner.
[0316] Also included herein are compositions and methods for the
identification and treatment of subjects who have an increased
severity of a psychotic disorder, or altered clinical presentation
of a psychotic disorder, such that a theranostic approach can be
taken to test such individuals to determine the effectiveness of a
particular therapeutic intervention (e.g., a pharmaceutical or
non-pharmaceutical intervention as described herein) and/or to
alter the intervention to enhance the effectiveness. Thus, the
methods and compositions described herein provide a means of
optimizing the treatment of a subject having or suspected to have a
psychotic disorder such as SZ. Provided herein is a theranostic
approach to treating and preventing a psychotic disorder such as
SZ, by integrating diagnostics and therapeutics to improve the
real-time treatment of a subject. Practically, this means creating
tests that can identify which patients are most suited to a
particular therapy, and providing feedback on how well a drug is
working to optimize treatment regimens.
[0317] Within the clinical trial setting, a theranostic method or
composition of the invention can provide key information to
optimize trial design, monitor efficacy, and enhance drug safety.
For instance, "trial design" theranostics can be used for patient
stratification, determination of patient eligibility
(inclusion/exclusion), creation of homogeneous treatment groups,
and selection of patient samples that are representative of the
general population. Such theranostic tests can therefore provide
the means for patient efficacy enrichment, thereby minimizing the
number of individuals needed for trial recruitment. "Efficacy"
theranostics are useful for monitoring therapy and assessing
efficacy criteria. Finally, "safety" theranostics can be used to
prevent adverse drug reactions or avoid medication error.
[0318] The methods described herein can include retrospective
analysis of clinical trial data as well, both at the subject level
and for the entire trial, to detect correlations between a genetic
signature as described herein and any measurable or quantifiable
parameter relating to the outcome of the treatment, e.g., efficacy
(the results of which may be binary (i.e., yes and no) as well as
along a continuum), side-effect profile (e.g., weight gain,
metabolic dysfunction, lipid dysfunction, movement disorders, or
extrapyramidal symptoms), treatment maintenance and discontinuation
rates, return to work status, hospitalizations, suicidality, total
healthcare cost, social functioning scales, response to
non-pharmacological treatments, and/or dose response curves. The
results of these correlations can then be used to influence
decision-making, e.g., regarding treatment or therapeutic
strategies, provision of services, and/or payment. For example, a
correlation between a positive outcome parameter (e.g., high
efficacy, low side effect profile, high treatment maintenance/low
discontinuation rates, good return to work status, low
hospitalizations, low suicidality, low total healthcare cost, high
social function scale, favorable response to non-pharmacological
treatments, and/or acceptable dose response curves) and a OPRP
genetic signature can influence treatment such that the treatment
is recommended or selected based on the presence or absence of the
OPRP genetic signature.
VI. KITS
[0319] Certain aspects of the present invention provides kits, such
as diagnostic and therapeutic kits. Kits may comprise a container
with a label. Suitable containers include, for example, bottles,
vials, and test tubes. The containers may be formed from a variety
of materials such as glass or plastic. The container may hold a
composition which includes a probe or an array that could be used
to determine a OPRP genetic signature, which could be effective for
diagnostic or pharmacogenomic applications. The label on the
container may indicate that the composition is used for a specific
diagnostic or pharmacogenomic application, and may also indicate
directions for either in vivo or in vitro use, such as those
described above. The kit of the invention will typically comprise
the container described above and one or more other containers
comprising materials desirable from a commercial and user
standpoint, including buffers, diluents, filters, needles,
syringes, and package inserts with instructions for use.
[0320] Within the scope of the invention are kits comprising a
probe that hybridizes with a region of human chromosome as
described herein and can be used to detect a polymorphism related
to a OPRP genetic signature. The kit can include one or more other
elements including: instructions for use; and other reagents, e.g.,
a label, or an agent useful for attaching a label to the probe.
Instructions for use can include instructions for diagnostic
applications of the probe for assessing severity of a psychotic
disorder such as SZ in a method described herein. Other
instructions can include instructions for attaching a label to the
probe, instructions for performing in situ analysis with the probe,
and/or instructions for obtaining a sample to be analyzed from a
subject. As discussed above, the kit can include a label, e.g., any
of the labels described herein. In some embodiments, the kit
includes a labeled probe that hybridizes to a region of human
chromosome as described herein, e.g., a labeled probe as described
herein.
[0321] The kit can also include one or more additional probes that
hybridize to the same chromosome, e.g., chromosome 2 or 5, or
another chromosome or portion thereof that can have an abnormality
associated with diagnostic applications. For example, the
additional probe or probes can be: a probe that hybridizes to human
chromosome 22q11-12 or a portion thereof, (e.g., a probe that
detects a sequence associated with a psychotic disorder in this
region of chromosome 22), or probes that hybridize to all or a
portion of 22q12.3 (e.g., near D22S283), 22q11.2, 22q11.2,
22q11-q13, 1q42.1, 1q42.1, 1q21-q22, 2p, 2q, 3p25, 4p, 4q,
5q11.2-q13.3, 6p22.3, 6p23, 6q13-q26, 7q, 8p12-21, 8q, 9p,
10p15-p13 (e.g., near D10S189), 10q22.3, 11q14-q21, 12q24, 13q34,
13q32, 14q32.3, 15q15, 16p, 17q, 18p, 18q, 19p. 20p, 21q, Xq,
and/or the X/Y pseudoautosomal region. A kit that includes
additional probes can further include labels, e.g., one or more of
the same or different labels for the probes. In other embodiments,
the additional probe or probes provided with the kit can be a
labeled probe or probes. When the kit further includes one or more
additional probe or probes, the kit can further provide
instructions for the use of the additional probe or probes.
[0322] Kits for use in self-testing can also be provided. For
example, such test kits can include devices and instructions that a
subject can use to obtain a sample, e.g., of buccal cells or blood,
without the aid of a health care provider. For example, buccal
cells can be obtained using a buccal swab or brush, or using
mouthwash.
[0323] Kits as provided herein can also include a mailer, e.g., a
postage paid envelope or mailing pack, that can be used to return
the sample for analysis, e.g., to a laboratory. The kit can include
one or more containers for the sample, or the sample can be in a
standard blood collection vial. The kit can also include one or
more of an informed consent form, a test requisition form, and
instructions on how to use the kit in a method described herein.
Methods for using such kits are also included herein. One or more
of the forms, e.g., the test requisition form, and the container
holding the sample, can be coded, e.g., with a bar code, for
identifying the subject who provided the sample.
[0324] Kits may also comprise or be coupled to a system which can
make recommendations and/or analysis of efficacy, risk or side
effects for treatment of a psychotic disorder based on a determined
OPRP genetic signature status. The system may comprise a server, a
processor, or a tangible computer readable program product. For
example, if the kit determines the presence or absence of an OPRP
genetic signature, the system may perform an analysis and generate
an efficacy and risk profile for treatment with a psychotic
treatment, such as treating with olanzapine.
VII. PROBES
[0325] Nucleic acid probes can be used to detect and/or quantify
the presence of a particular target nucleic acid sequence within a
sample of nucleic acid sequences, e.g., as hybridization probes, or
to amplify a particular target sequence within a sample, e.g., as a
primer. Probes have a complimentary nucleic acid sequence that
selectively hybridizes to the target nucleic acid sequence. In
order for a probe to hybridize to a target sequence, the
hybridization probe must have sufficient identity with the target
sequence, i.e., at least 70%, e.g., 80%, 90%, 95%, 98% or more
identity to the target sequence, or any range derivable therein.
The probe sequence must also be sufficiently long so that the probe
exhibits selectivity for the target sequence over non-target
sequences. For example, the probe will be at least 10, e.g., 15,
20, 25, 30, 35, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or
more nucleotides in length, or any range derivable therein. In some
embodiments, the probes are not more than 30, 50, 100, 200, 300,
500, 750, or 1000 nucleotides in length, or any range derivable
therein. Specifically, probes may be about 20 to about
1.times.10.sup.6 nucleotides in length. Probes include primers,
which generally refers to a single-stranded oligonucleotide probe
that can act as a point of initiation of template-directed DNA
synthesis using methods such as PCR (polymerase chain reaction),
LCR (ligase chain reaction), etc., for amplification of a target
sequence.
[0326] In some embodiments, the probe is a test probe, e.g., a
probe that can be used to detect polymorphisms in a region
described herein, e.g., SV2C or MGAT4C polymorphisms as described
herein. In some embodiments, the probe can hybridize to a target
sequence in complete linkage disequilibrium with one of the SNPs
described herein for determination of an OPRP genetic
signature.
[0327] In some embodiments, the probe can bind to another marker
sequence associated with a psychotic disorder such as SZ as
described herein.
[0328] Control probes can also be used. For example, a probe that
binds a less variable sequence, e.g., repetitive DNA associated
with a centromere of a chromosome, can be used as a control. Probes
that hybridize with various centromeric DNA and locus-specific DNA
are available commercially, for example, from Vysis, Inc. (Downers
Grove, Ill.), Molecular Probes, Inc. (Eugene, Oreg.), or from
Cytocell (Oxfordshire, UK). Probe sets are available commercially,
e.g., from Applied Biosystems, e.g., the Assays-on-Demand SNP kits.
Alternatively, probes can be synthesized, e.g., chemically or in
vitro, or made from chromosomal or genomic DNA through standard
techniques. For example, sources of DNA that can be used include
genomic DNA, cloned DNA sequences, somatic cell hybrids that
contain one, or a part of one, human chromosome along with the
normal chromosome complement of the host, and chromosomes purified
by flow cytometry or microdissection. The region of interest can be
isolated through cloning, or by site-specific amplification via the
polymerase chain reaction (PCR). See, for example, Nath and Johnson
(1998); Wheeless et al. (1994); U.S. Pat. No. 5,491,224.
[0329] In some embodiments, the probes are labeled, e.g., by direct
labeling, with a fluorophore, an organic molecule that fluoresces
after absorbing light of lower wavelength/higher energy. A directly
labeled fluorophore allows the probe to be visualized without a
secondary detection molecule. After covalently attaching a
fluorophore to a nucleotide, the nucleotide can be directly
incorporated into the probe with standard techniques such as nick
translation, random priming, and PCR labeling. Alternatively,
deoxycytidine nucleotides within the probe can be transaminated
with a linker. The fluorophore then is covalently attached to the
transaminated deoxycytidine nucleotides. See, e.g., U.S. Pat. No.
5,491,224.
[0330] Fluorophores of different colors can be chosen such that
each probe in a set can be distinctly visualized. For example, a
combination of the following fluorophores can be used:
7-amino-4-methylcoumarin-3-acetic acid (AMCA), Texas Red.TM.
(Molecular Probes, Inc., Eugene, Oreg.),
5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B,
5-(and-6)-carboxyfluorescein, fluorescein-5-isothiocyanate (FITC),
7-diethylaminocoumarin-3-carboxylic acid,
tetramethylrhodamine-5-(and-6)-isothiocyanate,
5-(and-6)-carboxytetramethylrhodamine,
7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein
5-(and-6)-carboxamido]hexanoic acid,
N-(4,4-difluoro-5,7-dimethyl-4-bora-3 a,4a
diaza-3-indacenepropionic acid, eosin-5-isothiocyanate,
erythrosin-5-isothiocyanate, and Cascade.TM. blue acetylazide
(Molecular Probes, Inc., Eugene, Oreg.). Fluorescently labeled
probes can be viewed with a fluorescence microscope and an
appropriate filter for each fluorophore, or by using dual or triple
band-pass filter sets to observe multiple fluorophores. See, for
example, U.S. Pat. No. 5,776,688. Alternatively, techniques such as
flow cytometry can be used to examine the hybridization pattern of
the probes. Fluorescence-based arrays are also known in the
art.
[0331] In other embodiments, the probes can be indirectly labeled
with, e.g., biotin or digoxygenin, or labeled with radioactive
isotopes such as .sup.32P and .sup.3H. For example, a probe
indirectly labeled with biotin can be detected by avidin conjugated
to a detectable marker. For example, avidin can be conjugated to an
enzymatic marker such as alkaline phosphatase or horseradish
peroxidase. Enzymatic markers can be detected in standard
colorimetric reactions using a substrate and/or a catalyst for the
enzyme. Catalysts for alkaline phosphatase include
5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium.
Diaminobenzoate can be used as a catalyst for horseradish
peroxidase.
[0332] Oligonucleotide probes that exhibit differential or
selective binding to polymorphic sites may readily be designed by
one of ordinary skill in the art. For example, an oligonucleotide
that is perfectly complementary to a sequence that encompasses a
polymorphic site (i.e., a sequence that includes the polymorphic
site, within it or at one end), such as rs2285162, rs2285166, or
rs2285167, will generally hybridize preferentially to a nucleic
acid comprising that sequence, as opposed to a nucleic acid
comprising an alternate polymorphic variant.
VIII. ARRAYS AND USES THEREOF
[0333] In another aspect, the invention features methods of
determining the absence or presence of an OPRP genetic signature
using an array described above. In a further aspect, the invention
features arrays that include a substrate having a plurality of
addressable areas, and methods of using them. At least one area of
the plurality includes a nucleic acid probe that binds specifically
to a sequence comprising a polymorphism such rs11960832 or
rs7975477 and can be used to detect the absence or presence of said
polymorphism, e.g., one or more SNPs, microsatellites,
minisatellites, or indels, to determine an OPRP genetic signature.
For example, the array can include one or more nucleic acid probes
that can be used to detect a polymorphism such as rs11960832 or
rs7975477. In some embodiments, the array further includes at least
one area that includes a nucleic acid probe that can be used to
specifically detect another marker associated with a psychotic
disorder such as SZ as described herein. The substrate can be,
e.g., a two-dimensional substrate known in the art such as a glass
slide, a wafer (e.g., silica or plastic), a mass spectroscopy
plate, or a three-dimensional substrate such as a gel pad. In some
embodiments, the probes are nucleic acid capture probes.
[0334] Methods for generating arrays are known in the art and
include, e.g., photolithographic methods (see, e.g., U.S. Pat. Nos.
5,143,854; 5,510,270; and 5,527,681), mechanical methods (e.g.,
directed-flow methods as described in U.S. Pat. No. 5,384,261),
pin-based methods (e.g., as described in U.S. Pat. No. 5,288,514),
and bead-based techniques (e.g., as described in PCT US/93/04145).
The array typically includes oligonucleotide probes capable of
specifically hybridizing to different polymorphic variants.
According to the method, a nucleic acid of interest, e.g., a
nucleic acid encompassing a polymorphic site, (which is typically
amplified) is hybridized with the array and scanned. Hybridization
and scanning are generally carried out according to standard
methods. See, e.g., Published PCT Application Nos. WO 92/10092 and
WO 95/11995, and U.S. Pat. No. 5,424,186. After hybridization and
washing, the array is scanned to determine the position on the
array to which the nucleic acid hybridizes. The hybridization data
obtained from the scan is typically in the form of fluorescence
intensities as a function of location on the array.
[0335] Arrays can include multiple detection blocks (i.e., multiple
groups of probes designed for detection of particular
polymorphisms). Such arrays can be used to analyze multiple
different polymorphisms. Detection blocks may be grouped within a
single array or in multiple, separate arrays so that varying
conditions (e.g., conditions optimized for particular
polymorphisms) may be used during the hybridization. For example,
it may be desirable to provide for the detection of those
polymorphisms that fall within G-C rich stretches of a genomic
sequence, separately from those falling in A-T rich segments.
[0336] Additional description of use of oligonucleotide arrays for
detection of polymorphisms can be found, for example, in U.S. Pat.
Nos. 5,858,659 and 5,837,832. In addition to oligonucleotide
arrays, cDNA arrays may be used similarly in certain embodiments of
the invention.
[0337] The methods described herein can include providing an array
as described herein; contacting the array with a sample, e.g., a
portion of genomic DNA that includes at least a portion of human
chromosome 22, e.g., a region between and/or including SNPs for a
SULT4A gene, and/or optionally, a different portion of genomic DNA,
e.g., a portion that includes a different portion of human
chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21 and/or 22, or another chromosome, e.g.,
including another region associated with a psychotic disorder,
pharmacological response, and/or psychiatric endophenotypes, and
detecting binding of a nucleic acid from the sample to the array.
Optionally, the method includes amplifying nucleic acid from the
sample, e.g., genomic DNA that includes a portion of a human
chromosome described herein, and, optionally, a region that
includes another region associated with a psychotic disorder,
pharmacological response, and/or psychiatric endophenotypes, prior
to or during contact with the array.
[0338] In some aspects, the methods described herein can include
using an array that can ascertain differential expression patterns
or copy numbers of one or more genes in samples from normal and
affected individuals (see, e.g., Redon et al., 2006). For example,
arrays of probes to a marker described herein can be used to
measure polymorphisms between DNA from a subject having a psychotic
disorder and control DNA, e.g., DNA obtained from an individual
that does not have a psychotic disorder and has no familial risk
factors for a psychotic disorder. Since the clones on the array
contain sequence tags, their positions on the array are accurately
known relative to the genomic sequence. Different hybridization
patterns between DNA from an individual afflicted with a psychotic
disorder such as SZ and DNA from a normal individual at areas in
the array corresponding to markers in human chromosome 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
and/or 22 as described herein, and, optionally, one or more other
regions associated with a psychotic disorder are indicative of a
risk of SZ-spectrum disorders. Methods for array production,
hybridization, and analysis are described, e.g., in Snijders et al.
(2001); Klein et al. (1999); Albertson et al. (2003); and Snijders
et al. (2002). Real time quantitative PCR can also be used to
determine copy number.
IX. EXAMPLES
[0339] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
Example 1
Assigning OPRP Genetic Signature Status
[0340] Finished genotypes provided by others were used to establish
OPRP genetic signature status using a simple and intuitive scoring
method based on the genotypes of SNPs rs11960832 and rs7975477. A
positive OPRP genetic signature comprises a homozygous genotype for
the T allele at SNP marker rs11960832 [i.e.,
rs11960832(T)/rs11960832(T) homozygosity] in combination with
either a homozygous or heterozygous genotype for the T allele at
marker rs7975477 [i.e., rs7975477(T)/rs7975477(T) homozygosity or
rs7975477(T)/rs7975477(C) heterozygosity].
A. Genotyping Methodology
[0341] The inventors seek only to document the well established
quality of the genotyping methodologies used for the Examples. Both
the Affymetrix and Illumina platforms are widely used commercially
available platforms. The technology behind both platforms has been
included in CLIA-approved genotyping tests at the manufactures' own
facilities and at third party providers.
[0342] The data from the inventors derived from a large scale
genotyping project that used microarray-based whole genome SNP
genotyping approaches. The project was performed by the CATIE study
group using Affymetrix and Perlegen microarray platforms (Sullivan
et al., 2008).
[0343] The inventors were provided finished genotype data and do
not have access to raw data files such as .cel files. As described
in the previous and present examples, genotypes provided by others
were used to establish OPRP genetic signature status using a simple
and intuitive scoring method for the presence of this genetic
signature.
B. Genotype Determination in the CATIE Study
[0344] Details of the genotyping performed by the CATIE consortium,
including their rigorous quality control procedures, are described
elsewhere (Sullivan et al., 2008). Briefly, peripheral venous blood
was collected, and genomic DNA was extracted from lymphocytes.
Analyses were performed at Perlegen Sciences in its CLIA, GLP
facility using two microarray genotyping systems. The first was the
Affymetrix 500K "A" chipset (Nsp I and Sty I chips, Santa Clara,
Calif.) used as specified by the manufacturer. Detailed description
of the SNP detection methodology can be found in Affymetrix product
documentation (available on the world wide web at
www.affymetrix.com/products_services/arrays/specific/500k.affx).
Secondly, Perlegen used a custom 164K chip. The genotype calling
methodology and extensive quality control measures used by the
CATIE study group are reported by Sullivan and coworkers (Sullivan
et al., 2008) and further described in detail in the supplemental
technical material provided by the CATIE consortium (Sullivan et
al., 2009).
[0345] As an example of the level of quality control used, the
CATIE group performed duplicate analysis on 36 samples. The
proportion of SNPs with non-missing genotype calls that disagreed
in these duplicated samples was 0.00291. As an additional control,
277 individuals were genotyped at a second facility using a
different SNP-calling algorithm to investigate potential site bias.
Only 0.73% of called genotypes differed between the two sites.
C. Frequency of the OPRP Genetic Signature
[0346] Table 1 summarizes the observed frequencies for the OPRP
Genetic Signature in Caucasians and African Americans.
TABLE-US-00001 TABLE 1 OPRP Genetic Signature Frequency Population
Approximate Frequency % Caucasian 6.5 African American 23.5
D. Using SNP Genotypes to Determine OPRP Genetic Signature
Status
[0347] For the SNPS available in the CATIE study, OPRP genetic
signature status is determined based on the genotype of the SNPs,
SNPs rs11960832(T or C) and rs7975477(T or C). Patients are
designated as OPRP genetic signature positive or negative using the
simple scoring method illustrated in Table 2. As can be seen, only
two of the nine possible genotype combinations result in a positive
OPRP genetic signature status for an individual. Note that, OPRP
genetic signature status can be assigned unambiguously in each case
and that OPRP positive and negative statuses are mutually exclusive
for any given individual who will carry a total of two and only two
alleles for each of the two SNPs.
TABLE-US-00002 TABLE 2 Assignment OPRP Genetic Signature Based on
SNP Genotypes rs11960832 rs7975477 OPRP Status T/T T/T Positive T/T
T/C Positive T/T C/C Negative T/C T/T Negative T/C T/C Negative T/C
C/C Negative C/C T/T Negative C/C T/C Negative C/C C/C Negative
[0348] The genetic signature scoring can be automated in Microsoft
Excel by combining a series of logical arguments. For purposes of
illustration, samples of the scoring by the Excel spreadsheet are
reproduced below (Table 3). The example is not intended to be
exhaustive. Failed genotypes, which are rare, are coded as question
marks and result in "NO" designation in column "D". Column "G"
provides the genetic signature status with a blank cell indicating
genotyping failure that requires retesting.
TABLE-US-00003 TABLE 3 Sample Output for OPRP Genetic Signature
calling Excel Spreadsheet F Positive G A B C D E status call OPRP
Sample ID rs11960832 rs7975477 Callable? Genotype possible? Status
1 T_T T_T YES T_T T_T Yes Positive 2 T_T T_C YES T_T T_C Yes
Positive 3 T_T C_C YES T_T C_C Yes Negative 4 T_C T_T YES T_C T_T
Yes Negative 5 T_C T_C YES T_C T_C Yes Negative 6 T_C C_C YES T_C
C_C Yes Negative 7 C_C T_T YES C_C T_T Yes Negative 8 C_C T_C YES
C-C T_C Yes Negative 9 C_C C_C YES C_C C-C Yes Negative 10 ? ? NO ?
No 11 T_T ? NO T_T ? No 12 ? T_T NO ? T_T No
[0349] In summary, once genotyping has been performed for
rs11960832 and rs7975477 (or markers in complete linkage
disequilibrium with each of these), OPRP genetic signature status
can be assigned using a simple and intuitive scoring method. This
method is easily automated using logical functions in programs such
as Microsoft Excel.
Example 2
The OPRP Genetic Signature Predicts Poor Response to Olanzapine
[0350] The CATIE study, a large federally funded clinical trial
designed to assess the efficacy of antipsychotics in a real world
setting, is a valuable resource for determining the role of genes
in baseline psychopathology and drug response (Lieberman et al.,
2005; Stroup et al., 2003). As part of the CATIE trial, detailed
clinical evaluations were conducted, including Positive and
Negative Syndrome Scale (PANSS) measurements at multiple time
points, cognitive evaluation, vital signs, blood chemistry results,
and drug response data. Additionally, whole genome SNP genotyping
was performed for roughly half of the trial participants (Sullivan
et al., 2008).
[0351] The inventors used samples collected in the course of the
CATIE trial to study genetic signatures to determine if a genetic
signature might contribute to the clinical differences in response
to olanzapine. The inventors contemplated that a combination of one
or more commonly occurring genetic variants (SNPs) might account
for the poor response to olanzapine displayed by some patients.
A. Data and Methods Relating to the CATIE Sample
[0352] Genotype and phenotype data for the CATIE trial were
recently made available to qualified researchers through the NIMH
Center for Collaborative Genetic Studies on Mental Disorders. The
sample consisted of a total of 738 patients. For the present study,
the inventors assigned OPRP status to 628 subjects, including 411
subjects of self-reported European ancestry and 217 subjects of
self-reported African ancestry. Further details on the patient
population are described in the study by Sullivan and coworkers
(Sullivan et al., 2008). The CATIE SNP genotype data evaluated
included a total of 492,900 SNPs located throughout the genome.
[0353] The design of the CATIE study has been described in detail
by others (Lieberman et al., 2005; Stroup et al., 2003). Briefly,
1460 subjects were randomly assigned one of several antipsychotics
and those who did not respond or who chose to quit their current
medication were re-randomized to another drug. Subjects that failed
Phase 1 treatment with the typical antipsychotic perphenazine were
treated differently than those subjects that failed phase I
treatment with an atypical antipsychotic. Instead of entering into
Phase II of the trial, subjects who switched from perphenazine
entered Phase IB. For Phase IB, subjects were randomly assigned to
an atypical antipsychotic--olanzapine, quetiapine or risperidone.
Subjects who failed Phase IB then entered Phase II.
[0354] A total of 738 subjects consented to provide DNA for genetic
study. Details regarding SNP genotyping and quality control have
been recently published (Sullivan et al., 2008). Only retrospective
genetic analyses, judged to be exempt from human studies
requirements by an IRB, were conducted in the current study. For
the genetic analyses presented herein, the inventors combined and
evaluated drug response data for both Phase I and Phase IB of the
CATIE study. All tested patients were studied using well
established clinical endpoints comparing baseline, intermediate,
and last observation carried forward (LOCF) for the PANSS scores
using CATIE data. LOCF analysis is a commonly used clinical
endpoint for clinical trials for neuropsychiatric drugs, with
particular changes in PANSS scores being used to indicate
clinically significant response (Leucht et al., 2009).
[0355] Using the clinical data from the CAIE trial, the inventors
derived several different metrics used for quantifying response in
clinical trials of antipsychotic medications. The most commonly
used psychometric instrument is the Positive and Negative Syndrome
Scale (PANSS), a 30-item semi-quantitative instrument scored by
clinical professionals (Kay et al., 1987). The greater the decrease
in PANSS score, the better the clinical response. The most direct
measure of clinical response is absolute change in PANSS score. In
addition to absolute change, the improvement is often reported as a
percentage change from baseline PANSS score.
[0356] For example, many drug trials for antipsychotic medications
report response as quantitative changes in PANSS score (Leucht et
al., 2009). This approach is particularly useful for trials with
active comparators or in cases where claims of drug superiority or
non-inferiority are important (i.e. where relative improvement in
symptoms is a key factor).
[0357] Alternatively the percentage change in PANSS may be used to
derive a categorical definition of response, wherein subjects who
meet a certain critical threshold of change are classified as
responders and those that do not meet that criterion are classified
as non-responders. For example, a decrease of at least 10% in total
PANSS may be used as a threshold for response (Leucht et al.,
2009).
[0358] Both approaches shed light on the clinical utility of the
OPRP Genetic Signature as a biomarker, so the inventors presented
results for both categorical definitions of response and for
quantitative changes in percent PANSS.
B. Methods for Initial Genetic Signature Discovery and
Characterization
[0359] To examine the relationship of genotypes to drug response
the inventors used the publically available PLINK software (Purcell
et al., 2007; available on the world wide web at
pngu.mgh.harvard.edu/purcell/plink/) and Helix tree (Version 6.4.1;
Golden Helix, Bozeman, Mont.). The inventors used Last observation
Carry Forward (LOCF) delta PANSS values as a measure of response to
antipsychotic treatment. The inventors identified the TT genotype
of SNP marker rs11960832 as a predictor of poor olanzapine
response. The inventors refined the test further by conducting
association analysis on using only those subjects that comprised
the TT genotype of rs11960832. This further analysis enabled the
authors to refine the test to include genotypes at SNP marker
rs7975477. Presence of the TT or TC genotypes of rs7975477 in
individuals that comprised the TT genotype at rs11960832 indicates
OPRP positive status. The addition of the second SNP improved the
utility of the test by enabling the test to work on all
ethnicities.
C. The OPRP Genetic Signature Predicts Response to Antipsychotics
Based on Quantitative Change in PANSS Score
[0360] As mentioned previously, the mean change in absolute or
percent PANSS provides an important measure of efficacy in patients
undergoing antipsychotic treatments. Indeed, many pivotal trials in
the psychosis field used absolute and/or percentage change in PANSS
Score as the primary endpoint (Leucht et al., 2009). The
performance of the investigational drug is then compared with
placebo and/or an active comparator. Therefore, in addition to
examining a categorical definition of clinically significant
response, the inventors determined the impact of segmentation by
OPRP genetic signature status on the quantitative measure of
clinical improvement--delta PANSS for LOCF.
[0361] Table 4 shows the means and standard deviations (SD) for the
percent change in PANSS for each of the drug arms segmented by OPRP
Genetic Signature status for the CATIE study. A more negative
number represents a greater degree of improvement. As can be seen
from Table 4, the OPRP positive group responded significantly worse
to olanzapine than did the OPRP negative group (+4.3% worse vs.
-11.6% better, P=0.000001). OPRP positive patients responded more
poorly to olanzapine than to any of the other antipsychotics
individually or as a group. In contrast, OPRP negative patients
responded well to olanzapine, with the response to olanzapine for
this group of patients being statistically superior to response to
perphenazine (P<0.001), to quetiapine (P<0.00001), to
ziprasidone (P<0.00001), and to risperidone (P<0.05), as well
as to all other drugs combined (.sup.++++P<0.00001).
TABLE-US-00004 TABLE 4 Change in PANSS Values for the CATIE Study
OPRP Positive OPRP Negative DELTA DELTA Drug N PANSS %.sup.a
SD.sup.b N PANSS %.sup.a SD.sup.b Olanzapine 26 4.3 10.5 139 -11.6
15.3* Perphenazine 12 -7.7{circumflex over ( )} 20.1 110
-4.2.sup.+++ 17.8 Quetiapine 18 -1.2 20.7 147 -3.2.sup.++++ 16.8
Risperidone 20 -4.2{circumflex over ( )} 16.1 146 -6.4.sup.+ 18.2
Ziprasidone 11 -0.5 9.5 69 -1.5.sup.++++ 14.4 All Drugs 87 -1 15.9
611 -5.9 17.4 All Drugs - 61 -3{circumflex over ( )}.sup. 17 472
-4.2.sup.++++ 17.6 except olanzapine .sup.aMean change in PANSS
score from baseline to LOCF .sup.bStandard deviation of the mean *P
= 0.000001 olanzapine OPRP positive performed worse than OPRP
negative {circumflex over ( )}P < 0.05 olanzapine treated OPRP
positive subjects responded significantly worse than OPRP positive
subjects treated with other drugs .sup.+P < 0.05, and .sup.++P
< 0.01 .sup.+++P < 0.001, and .sup.++++P < 0.00001
olanzapine treated OPRP negative subjects responded significantly
better than OPRP negative subjects treated with other drugs
[0362] Another way to consider the response of the various groups
is to analyze the difference in the mean PANSS changes. Table 5
compares various olanzapine treated OPRP positive subjects to
various drug-OPRP groups. The positive mean differences between the
groups indicate poorer response for the olanzapine treated OPRP
positive patients. Additionally, the effect size (mean
difference/standard deviation of pooled sample) is included in this
table. The importance of the effect size will be discussed in the
next section. For now, however, take note that the some effect
sizes are greater than or equal to 0.5 suggesting the biomarker is
identifying important differences in treatment response.
TABLE-US-00005 TABLE 5 Relative Response of Olanzapine-Treated OPRP
Positive Subjects Compared to Other Groups in CATIE Comparison -
Mean difference.sup.1 Effect Olanzapine OPRP + (95% CI) size.sup.2
P-Value.sup.3 Vs risperidone OPRP + 8.4 (0.6 to 16.4) 0.6 0.03 Vs
perphenazine OPRP + 12 (2.0 to 22.0) 0.7 0.02 Vs quetiapine OPRP +
5.5 (-4.1 to 15.0) 0.3 0.25 Vs ziprasidone OPRP + 4.8 (-2.7 to
12.3) 0.2 0.19 Vs OPRP + except olanzapine 7.3 (0.1 to 14.5) 0.5
0.03 Vs olanzapine OPRP - 15.9 (9.7 to 22.1) 1.0 0.000001
.sup.1Mean difference calculated by subtracting the mean delta
PANSS of the comparator group from the mean DELTA PANSS of the
olanzapine treated OPRP positive (+) group .sup.2Effect size is
calculated by dividing the mean difference by the standard
deviation .sup.3P-value calculated using the T-test for comparison
of 2 means
D. Categorical Responder/Nonresponder Statistics Based on OPRP
Genetic Signature
[0363] As described above CATIE patients were studied using well
established clinical endpoints comparing baseline, intermediate,
and last observation carried forward (LOCF) for the PANSS scores.
LOCF analysis is a commonly used clinical endpoint for clinical
trials for neuropsychiatric drugs, with changes in PANSS scores of
negative 10% being used as a possible endpoint to indicate
clinically significant response (Leucht et al., 2009).
[0364] As summarized in Table 6, when patients are segmented by
OPRP genetic signature status and treatment arm, olanzapine-treated
OPRP positive subjects demonstrated a lesser likelihood of
achieving a 10% PANSS decrease than any other group in CATIE.
TABLE-US-00006 TABLE 6 Relationship of OPRP Status to Drug Response
in CATIE OPRP Positive.sup.a OPRP Negative.sup.a Drug .ltoreq.-10%
.gtoreq.-10% Responders .ltoreq.-10% .gtoreq.-10% Responders
Olanzapine 1 25 4% 73 66 53%* Risperidone 7 12 35%{circumflex over
( )} 55 91 38%.sup.+ Quetiapine 4 14 22% 48 99 33%.sup.+++
Perphenazine 5 7 42%{circumflex over ( )}{circumflex over ( )} 39
71 35%.sup.+ Ziprasidone 2 9 18% 16 53 23%.sup.++++ All Drugs 19 68
22% 231 380 38% All Except 18 42 30%{circumflex over (
)}{circumflex over ( )} 158 314 33%.sup.++++ Olanzapine
.sup.aNumbers of individuals showing the specified percent change
in total PANSS (LOCF). A greater response corresponds to a more
negative change in PANSS score, with individuals showing a change
in PANSS of .ltoreq.-10% being categorized as responders *P =
0.000002 olanzapine OPRP positive performed worse than OPRP
negative {circumflex over ( )}P < 0.05, {circumflex over (
)}{circumflex over ( )}P < 0.01 olanzapine treated OPRP positive
subjects responded significantly worse than OPRP positive subjects
treated with other drugs .sup.+P < 0.05, and .sup.++P < 0.01
.sup.+++P < 0.001, and .sup.++++P < 0.0001 olanzapine treated
OPRP negative subjects responded significantly better than OPRP
negative subjects treated with other drugs.
[0365] Several points may be made regarding the data it Table 6.
First, OPRP positive patients have a statistically lower
probability of experiencing a clinical response using olanzapine
therapy when compared to patients who are OPRP negative
(P=0.000002). Second, OPRP positive patients have a lower
probability of experiencing a clinically significant response using
olanzapine when compared to all other antipsychotic drugs combined
(P<0.01) or when compared specifically to risperidone
(P<0.05) or to perphenazine (P<0.01). Third, OPRP negative
patients respond better to olanzapine than to any of the other
antipsychotics individually or as a group. Therefore, based on
clinical improvement, OPRP positive patients are a subset of
patients who are particularly poor candidates for olanzapine
treatment, while OPRP negative are a subset of patients who respond
particularly well to olanzapine.
[0366] The inventors also examined the impact of the OPRP status on
whether patients' symptoms actually got worse when treated with
olanzapine. This is an important safety consideration for
antipsychotic drugs response, and failure of a drug to display the
desired clinical response on a specific subset of patients could
impact the drug label, being contraindicated for a particular
subset of patients (see Example 5: "Risk Management Involving the
OPRP Genetic Test). As summarized in Table 7, when patients are
segmented by OPRP status and treatment arm, olanzapine-treated OPRP
positive subjects demonstrated a greater likelihood of displaying a
worsening of symptoms (LOCF delta PANSS .gtoreq.0%) than any other
group in CATIE.
TABLE-US-00007 TABLE 7 Relationship of OPRP Status to Worsening
Symptoms in CATIE OPRP Positive.sup.a OPRP Negative.sup.a Drug
.gtoreq.0% .ltoreq.0% Worsening .gtoreq.0% .ltoreq.0% Worsening
Olanzapine 18 8 69% 26 113 19%* .sup. Risperidone 7 13
35%{circumflex over ( )} 55 91 38%.sup.+++ Quetiapine 9 9 50% 62 95
42%.sup.+++ Perphenazine 3 9 25%{circumflex over ( )} 45 65
41%.sup.+++ Ziprasidone 4 7 36% 34 35 .sup. 49%.sup.++++ All Drugs
41 46 47% 222 389 36% .sup. All Except 23 38 38%{circumflex over (
)}{circumflex over ( )} 196 286 .sup. 41%.sup.++++ Olanzapine
.sup.aNumbers of individuals showing the specified percent change
in total PANSS (LOCF). Worsening of symptoms corresponds to an
increase in PANSS score, with individuals showing a delta PANSS
.gtoreq.0% being categorized as having worsening symptoms. *P =
0.0000007 olanzapine OPRP positive performed worse than OPRP
negative {circumflex over ( )}P < 0.05, {circumflex over (
)}{circumflex over ( )}P < 0.01 significantly more olanzapine
treated OPRP positive subjects displayed worsening of symptoms than
OPRP positive subjects treated with other drugs. .sup.+P < 0.05,
and .sup.++P < 0.01 .sup.+++P < 0.001, and .sup.++++P <
0.0001 significantly fewer olanzapine treated OPRP negative
subjects displayed worsening of symptoms than OPRP negative
subjects treated with other drugs.
[0367] Several points may be made regarding the data it Table 7.
First, OPRP positive patients have a statistically higher
probability of experiencing a worsening of symptoms using
olanzapine therapy when compared to patients who are OPRP negative
(P=0.0000007). Second, OPRP positive patients have a higher
probability of experiencing a worsening symptoms using olanzapine
when compared to all other antipsychotic drugs combined (P<0.01)
or when compared specifically to risperidone (P<0.05) or to
perphenazine (P<0.05). Third, OPRP negative patients have a
significantly lower probability of displaying worsening symptoms
when treated with olanzapine than when treated with any of the
other antipsychotics individually or as a group. Therefore, based
on worsening symptoms, OPRP positive patients are a subset of
patients who are particularly poor candidates for olanzapine
treatment, while OPRP negative are a subset of patients who respond
particularly well to olanzapine.
[0368] In summary, the results for the CATIE study show that the
ORRP genetic signature can be used to define subsets of patients
that respond differently to antipsychotic medications. OPRP
positive subjects, when treated with olanzapine, respond poorly and
are at elevated risk of experiencing a worsening of symptoms as
compared to either OPRP negative subjects treated with olanzapine
or to OPRP positive subjects treated with other antipsychotics. In
contrast OPRP negative patients respond particularly well to
olanzapine and are at decreased risk of experiencing a worsening of
symptoms as compared to either OPRP positive subjects treated with
olanzapine or to OPRP negative subjects treated with other
antipsychotics.
Example 3
Clinical Utility of the Biomarker
[0369] The primary rationale for determining the OPRP status of a
patient is to alter medical practice in some manner. Currently in
the psychiatric space, physicians lack useful tools to help them
select the most efficacious antipsychotic medication for individual
patients. All of the currently approved antipsychotics demonstrated
superiority to placebo for treating psychotic symptoms as part of
their approval process at the FDA. Examples of comparative
effectiveness can be found in any New Drug Approval, e.g. the
olanzapine approval package (Zyprexa (olanzapine) Approval Package
NDA 20-592. FDA, Center for Drug Evaluation and Research 1996
Available from: world wide web via
accessdata.fda.gov/drugsatfda_docs/nda/96/020592_Original_Approval_Pkg
%20.pdf). However, a recently published meta-analysis of
registration quality clinical trials showed only modest
improvements over placebo.
[0370] Table 8 shows the results for the atypical antipsychotics
used in the CATIE study. These drugs had effect sizes ranging from
-0.42 to -0.59. The effect size is defined as the difference in the
mean response for each drug minus the change in the placebo arm,
divided by the standard deviation. In this case, a negative number
means a greater improvement in psychopathology, i.e. a greater
reduction in PANSS. For comparison, the same metrics are provided
for olanzapine-treated OPRP positive patients compared to various
other OPRP-drug combinations from the CATIE study. The effect size
of the latter ranged from 0.2 to 1.0. To place this in context, the
effect size for olanzapine treated OPRP positive vs. negative
patients in CATIE was roughly 60% larger and in the opposite
direction (1.0 vs. -0.59) than the effect size seen when comparing
olanzapine to placebo for a population not segment by OPRP
status.
TABLE-US-00008 TABLE 8 Comparative Effect Sizes of Atypical
Antipsychotics vs. Placebo and First Generation Antipsychotics
Number of Effect Size vs. Effect Size CATIE Drug Studies
Placebo.sup.c vs. FGA.sup.d Effect Size Olanzapine 6 -0.59 -0.21
1.0.sup.a Quetiapine 5 -0.42 0.01 0.3.sup.b Risperidone 7 -0.59
-0.25 0.6.sup.b Ziprasidone 4 -0.48 -0.04 0.2.sup.b
.sup.aOlanzapine OPRP positive versus olanzapine OPRP negative
.sup.bOlanzapme OPRP positive versus drug OPRP positive
.sup.cLeucht et al. (2009) .sup.dTGA = first generation
antipsychotics. Results from Davis et al. (2003).
[0371] Currently, clinical practice emphasizes the increased
efficacy of atypical antipsychotics over typical antipsychotics.
Another meta-analysis examined the efficacy advantage of atypical
antipsychotics compared to first generation, or typical,
antipsychotics. This analysis revealed a very minor advantage for
some of the atypical antipsychotics over typical antipsychotics,
with effect sizes ranging from -0.25 to 0.01. Only olanzapine and
risperidone showed a significant advantage in the meta-analysis.
The effect sizes due to OPRP status for olanzapine (OPRP+vs. OPRP-)
or for olanzapine vs. other drugs after segmentation by OPRP status
are up to four times as large as those seen when comparing
olanzapine or risperidone to first generation antipsychotics in the
meta-analysis. Based on these findings, a pharmacogenetic test for
OPRP status could offer physicians a tool to identify a
sub-population, OPRP positive subjects, for which there is a
treatment option(s) that provides twice, or more, the efficacy
advantage over olanzapine than the advantage currently observed by
atypical over typical antipsychotics.
[0372] Another recent meta-analysis compared the effectiveness of
the various atypical antipsychotics to each other. This study used
the weighted mean difference in PANSS score (absolute not percent
difference). Olanzapine consistently showed modest superiority to
quetiapine, risperidone, and Ziprasidone, as shown in Table 9.
However, this modest increase in efficacy in the unsegmented
population is much smaller than the efficacy improvement observed
for OPRP negative subjects treated with olanzapine in the CATIE
sample. Conversely, the OPRP positive subjects treated with
olanzapine displayed inferior response compared to other
antipsychotics, in contrast to the results in the unsegemented
population. Thus the a positive OPRP genetic signature identifies a
special population for which the currently accepted paradigm of
olanzapine having superior efficacy is inaccurate.
TABLE-US-00009 TABLE 9 Mean Difference Between Olanzapine and Other
Atypical Antipsychotics.sup.a CATIE CATIE CATIE Olanzapine vs.
Meta-analysis.sup.b unsegemented OPRP.sup.b + OPRP - Risperidone
-1.9 -3.5 8.4 -5.2 (-3.3 to -0.6) Quetiapine -3.7 -6.2 5.5 -8.4
(-5.4 to -1.9) Ziprasidone -8.3 -4.9 4.8 -10.1 (-11.0 to -5.6)
.sup.aNegative values indicate that olanzapine displayed superior
efficacy, and positive values indicate that olanzapine displayed
inferior efficacy (measured in delta PANSS). .sup.bMean (95% CI)
see Leucht et al. (2009)
[0373] In conclusion, segmentation by OPRP status identifies a
sub-population, OPRP positive patients, that demonstrates inferior
response to olanzapine. Conversely, OPRP negative patients show
more improvement when treated with olanzapine than do OPRP positive
subjects. Finally, for the OPRP negative patients, olanzapine
demonstrates enhanced superiority over other medications based on
meta-analysis for patient populations not segmented by OPRP
status.
Example 4
Diagnostic Performance Using Categorical Definitions of
Response
[0374] Several different measures of diagnostic performance can be
used for comparing dichotomous outcomes. Two important metrics
include percent positive agreement (PPA), a substitute for
sensitivity, and percent negative agreement (PNA), a substitute for
specificity. Tables 10 presents these measures of diagnostic
performance along with the diagnostic odds ratio (DOR) for
prediction of worsening of symptoms in CATIE for olanzapine
treatment of OPRP positive patients compared to other groups.
TABLE-US-00010 TABLE 10 Diagnostic Performance of the OPRP Test in
the CATIE Study For Worsening Symptoms (Delta PANSS .gtoreq. 0)
PNA.sup.c DOR.sup.d Comparison.sup.a Worsen Non-Worsen PPA.sup.b
(95% CI) (95% CI) (95% CI) Olanzapine + 18 8 0.41 0.93 9.85
Olanzapine - 26 113 (0.28 to 0.56) (0.87 to 0.97) (3.8 to 25)
Olanzapine + 18 8 0.86 0.53 6.75 Perphenazine + 3 9 (0.65 to 0.95)
(0.31 to 0.74) (1.4 to 32) Olanzapine + 18 8 0.67 0.53 2.25
Quetiapine + 9 9 (0.48 to 0.81) (0.31 to 0.74) (0.65 to 7.8)
Olanzapine + 18 8 0.72 0.62 4.17 Risperidone + 7 13 (0.52 to 0.86)
(0.541 to 0.79) (1.20 to 14.4) Olanzapine + 18 8 0.782 0.57 3.94
Ziprasidone + 4 7 (0.61 to 0.93) (0.25 to 0.70) (0.89 to 17.4)
.sup.aA plus sign indicates OPRP positive and a negative sign
indicates OPRP negative .sup.bPercent Positive Agreement = (true
positive)/(true positive + false negative) = OPRP positive
olanzapine worsen/all worsen. .sup.cPercent Negative Agreement =
(true negative)/(true negative + false positive) = OPRP negative
non-worsen for comparator/all non-worsen .sup.dDiagnostic Odds
Ratio - (True positive * true negative)/(False positive * false
negative)
Example 5
Risk Management Involving OPRP Test
[0375] The OPRP test, as well as any test including an OPRP
determination, will be used in the risk-benefit analysis for
prescribing atypical antipsychotics--olanzapine in particular. The
highly variable efficacy of olanzapine and moderate to large side
effect burden create an opportunity to greatly enhance patient care
and usefulness of olanzapine when combined with the OPRP test.
[0376] The risk management program (exemplified in FIG. 1) has the
potential of becoming an FDA-mandated safety program for
prescribing olanzapine vs. other antipsychotics. By incorporating
the OPRP genetic signature determination into an electronic data
exchange that interfaces with physicians, pharmacies labs and
patients, this invention may be applied to guide all of the four
groups involved in selection of and dispensing of olanzapine
utilizing information that will optimize potential therapeutic
benefits (such as optimal efficacy and improvement of symptoms) and
minimize potential risks (such as lack of drug effect and risks
associated with lack of drug effect like hospitalization and
worsening of symptoms).
[0377] All of the methods disclosed and claimed herein can be made
and executed without undue experimentation in light of the present
disclosure. While the compositions and methods of this invention
have been described in terms of preferred embodiments, it will be
apparent to those of skill in the art that variations may be
applied to the methods and in the steps or in the sequence of steps
of the method described herein without departing from the concept,
spirit and scope of the invention. More specifically, it will be
apparent that certain agents which are both chemically and
physiologically related may be substituted for the agents described
herein while the same or similar results would be achieved. All
such similar substitutes and modifications apparent to those
skilled in the art are deemed to be within the spirit, scope and
concept of the invention as defined by the appended claims.
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