WO2015127557A1 - Compositions and methods for the treatment and prevention of antipsychotic medication-induced weight gain - Google Patents
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Definitions
- the present invention relates to the field of psychiatry.
- the invention relates to methods and compositions for the treatment and prevention of antipsychotic medication-induced weight gain based upon one or more genetic polymorphisms associated with such weight gain in human subjects.
- Antipsychotics are widely used for treating psychiatric disorders including schizophrenia, mood, bipolar disorders and autism. Most second generation antipsychotic medications have been associated with substantial weight gain and metabolic disturbances, increasing the risk for premature death (Lencz and Malhotra, 2009; Muller and Kennedy, 2006). The high prevalence of over 30% of treated individuals experiencing significant weight gain makes these side effects one of the leading causes of patient non-compliance leading to increased treatment costs.
- AIWG antipsychotic-induced weight gain
- Twin and family studies have consistently pointed to high heritability suggesting a possible role of genetic factors in AIWG (Gebhardt et al., 2010).
- GLP-1 Glucagon-like peptide 1
- GLP-1 R G-protein coupled GLP-1 receptors
- GLP-1 Besides augmenting insulin secretion, GLP-1 inhibits glucagon secretion and delays gastric emptying (Phillips and Prins 2011). The insulinotropic effect depends on blood glucose levels (Fu et al. 2013), and impaired GLP-1 induced insulin secretion has been found in type 2 diabetes patients (Herzberg-Schafer et al. 2012). Interestingly, an antipsychotic-like effect of a GLP-1 receptor agonist has recently been described in a mouse model (Dixit et al. 2013).
- Antipsychotics with high or medium-high risk for antipsychotic-induced weight gain such as olanzapine (Smith et al. 2011), clozapine or quetiapine (Smith et al. 2009) have been shown to decrease GLP-1 levels in rat models. These effects seem to occur after a longer treatment period, since studies with short-term treatment did not show an impact of olanzapine on GLP-1 levels (Vidarsdottir et al. 2010; van der Zwaal et al. 2012). Recent research has indicated a beneficial effect of GLP-1 analogs for treatment of AIWG in animal models (Lykkegaard et al. 2008).
- GLP-1 analogs were effective to induce weight loss not only in subjects with type 2 diabetes (Flint et al. 2013), but also in non-diabetic patients (Astrup et al. 2012; Vilsboll et al. 2012).
- the gene encoding GLP-1, GCG is located on chromosome 2q36-37.
- GCG encodes a preproprotein which is cleaved into four different proteins involved in glucose homeostasis (glucagon, GLP-1, GLP-2, oxyntomodulin). Genetic variation in GCG has previously been associated with weight, insulin, GLP-1 and glucagon levels (Torekov et al. 2011).
- the human GLP-1 receptor gene GLPIR is located on chromosome 6p21. Variation in this gene has been associated with morning Cortisol levels (Sheikh et al. 2010) and altered insulin secretion following GLP-1 infusion (Sathananthan et al. 2010). In animal models, genetic variation in GLPIR influenced food intake (Kumar et al. 2007) and gastric emptying (Kumar et al. 2008). On the other hand, glplr-deficient mice showed normal feeding behavior in an earlier study (Scrocchi et al. 1996). Despite these preliminary findings, GCG and GLPIR are interesting candidate genes for AIWG due to their implication in food intake and glucose metabolism.
- the orexin system includes the orexin gene coding for pre-pro-orexin which is cleaved into two polypeptides, Orexin A (OXA, hypocretin 1, 33 amino acids) and Orexin B (OXB, hypocretin 2, 28 amino acids).
- Orexin A OXA, hypocretin 1, 33 amino acids
- Orexin B OXB, hypocretin 2, 28 amino acids.
- the biological action of the orexin peptides is mediated through two G-protein coupled receptors orexin receptor 1 (OX1R or HCRTR1) and orexin receptor 2 (OX2R or HCRTR2; (Sakurai and Mieda 2011; Kukkonen 2013; Perez- Leighton et al. 2013)).
- OXA has higher affinity for OX1R whereas OXA and OXB have equal affinity for OX2R.
- Orexins are primarily expressed in the lateral hypothalamic area, a region associated with feeding behavior and arousal. Decreased extracellular glucose levels activate orexin neurons whereas increased glucose concentrations have the opposite effect (Yamanaka et al. 2003; Burdakov et al. 2005). Similarly, the orexigenic peptide ghrelin activates 60% of orexin neurons, whereas the anorexigenic peptide leptin inhibits most orexin neurons (Yamanaka et al. 2003). Increased level of orexin mRNA is observed in fasting conditions and intracerebro vascular (ICV) injection of orexin during light period induces feeding behavior in rats and mice.
- ICV intracerebro vascular
- mice lacking orexin neurons exhibit hypophagia, lower levels of spontaneous physical activity (SPA) and develop late-onset obesity on a regular diet (Hara et al. 2001; Akiyama et al. 2004).
- SPA spontaneous physical activity
- Orexin receptors are expressed in several regions in the brain.
- OX1R compared to OX2R, are predominant in the locus coeruleous, paraventricular thalamic nucleus and bed nucleus of the stria terminalis.
- OX2R are mainly expressed in the arcuate nucleus (ARC), paraventricular nucleus and lateral hypothalamic area (Marcus et al. 2001; Funato et al. 2009).
- the OX2R has been shown to play a major role in preventing high fat diet induced obesity and insulin insensitivity in mice (Funato et al. 2009).
- OX2R agonist administration to wildtype-mice on a high fat diet suppressed food intake and led to significantly less fat mass.
- mice with OX1R deletion showed improved glucose tolerance and insulin sensitivity on a high fat diet suggesting that OX1R may also have a role in mediating the effect of high fat diet on glucose metabolism (Funato et al. 2009).
- Overall OX2R appears to have a major role in adverse dietary conditions with OX1R making minor contribution.
- the orexin gene and its receptors have also been associated to narcolepsy in mice, dogs and humans (Kukkonen 2013).
- individuals with narcolepsy have decreased caloric intake but have a higher body mass index and increased incidence of metabolic syndrome (Schuld et al. 2000; Nishino 2007).
- the orexin system is modulated by leptin via its receptors, especially OX2R (Funato et al. 2009), and sends excitatory signals to neuropeptide Y (NPY) expressing neurons in the ARC (Muroya et al. 2004).
- NPY neuropeptide Y
- ARC neuropeptide Y
- CB1 cannabinoid receptor type 1
- Antipsychotics associated with weight gain increase activity in orexin neurons compared to antipsychotics with no weight gain liability (Fadel et al. 2002).
- antipsychotics associated with higher risk of weight gain e.g. clozapine and olanzapine
- activated orexin neurons significantly more than antipsychotics with relatively less AIWG risk e.g. risperidone.
- AIWG risk e.g. risperidone
- the NDUFS1 gene ( ADH dehydrogenase (ubiquinone) Fe-S protein 1, 75KDa) is part of the complex I of OXPHOS. This gene encodes the largest and one of the "core subunits" of this complex and the protein is located in the iron-sulfur fragment of the enzyme complex (Smeitink et al., 1998). NDUFS1 is part of the hydrophilic arm of the complex which is responsible for the transfer of electrons (Finel, 1998, Scola et al., 2013). Reduced levels of NDUFS1 mRNA and down-regulation of the protein in postmortem brain from schizophrenia patients have been reported (Maurer et al., 2001; Prabakaran et al., 2004).
- NDUFS1 Mutations in NDUFS1 have been associated with isolated complex I deficiency (Hoefs et al., 2010), and dysfunction in the cellular oxidative metabolism with increased mitochondrial Reactive Oxygen Species (mROS) production (luso et al., 2006).
- mROS mitochondrial Reactive Oxygen Species
- mROS are involved in the regulation of the ATP-dependent potassium channel in POMC neurons, an important step to neuronal depolarization and downstream events that will lead to decreased food intake.
- the buffering of mROS appears to be crucial to keep active the ghrelin- dependent gene expression and downstream events to stimulate food intake.
- the translocator protein-18 kDa (TSPO, chr22:43547520-43559248 Genome Reference Consortium Build 37) is a housekeeping gene. While the precise functions of TSPO are an active area of research, it is known to play a key role in steroid biosynthesis. TSPO is expressed by many tissues throughout the body, and at particularly high levels in steroidogenic tissues such as the adrenal glands and gonads. In the brain, TSPO is expressed selectively by activated microglia and reactive astrocytes, mediators of the brain's inflammatory response, which has led to the use of TSPO as an in vivo marker of neuroinflammation in PET imaging studies (reviewed by Venneti et al., 2013).
- TSPO is localized primarily to the outer mitochondrial membrane, where it forms a multimeric complex with voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) (McEnery et al., 1992).
- VDAC voltage-dependent anion channel
- ANT adenine nucleotide transporter
- TSPO plays a role in weight regulation, possibly through its effect on mitochondrial metabolism.
- ob/ob mouse an established animal model of obesity, increased TSPO binding capacity was observed in the hippocampus and hypothalamus (Giannaccini et al., 2011).
- TSPO ligands PK1195 and Ro5- 4864 were recently identified as key regulators of whole-body energy control in zebra fish and mice (Gut et al., 2013).
- PK1195 treatment significantly lowered lipid accumulation in the liver, free and LDL cholesterol, and blood glucose levels (Gut et al., 2013).
- antipsychotic-induced weight gain that provide physicians and other health care professionals with the opportunity to provide educated decisions for prescribing medications in treatment regimens.
- personalized medicine approaches that lower the risk of developing antipsychotic induced weight gain and related ailments such as diabetes and cardiovascular disease.
- the present invention provides methods, including computer implemented methods, and compositions, including computer program products and computer systems, for improving therapeutic outcomes for patients being treated or in need of treatment with one or more medications to alleviate one or more symptoms of a psychiatric disease or disorder, also referred to herein as "psychiatric patients".
- the invention provides improvements in therapeutic outcomes by preventing or reducing weight gain in a psychiatric patient being treated with one or more antipsychotic medications.
- the invention provides methods for selecting an antipsychotic medication for a psychiatric patient that minimizes the psychiatric patient's risk of clinically significant weight gain induced by the medication.
- a patient is at high risk of clinically significant weight gain if they are likely to experience a weight gain of 7% or greater from their baseline weight (before taking the medication).
- a patient is at intermediate risk if they are likely to experience a weight gain of between 2% and 7%, and a patient is at low risk if they are likely to experience a weight gain of less than 2%, or even lose weight.
- Patients characterized as being in the high risk group according to the methods described herein should use medications such as olanzapine and clozapine very cautiously, or avoid their use in favor of, for example, other medications that are not associated with weigh gain.
- use very cautiously means that the medication should be given initially at a dose lower than recommended, if it is used at all, and the patients should be closely monitored for weight gain.
- medications such as olanzapine and clozapine should be avoided in patients characterized as at high risk of weight gain.
- Such patients should also use medications such as quetiapine, risperidone, and paliperidone with caution.
- use with caution means that medication can initially be given at the recommended dose and the patient should be monitored for weight gain.
- the patient is first categorized as being at risk or not at risk for weigh gain using an algorithm that incorporates data attributes characterizing the patient's genotype at a set of SNPs as described herein.
- the invention also provides methods of reducing a psychiatric patient's risk of clinically significant weight gain induced by an antipsychotic medication as well as methods for determining a psychiatric patient's susceptibility to such weight gain by identifying at- risk patients and providing an assessment of that risk, as described herein. Also provided are methods for designing a therapeutic regimen for a patient that minimizes the risk of weight gain by identifying at-risk patients, providing an assessment of that risk, and further categorizing a set of medications according to the relative risk of weight gain presented by each for that patient. The methods may also include generating and outputting a report identifying a patient according to risk of clinically significant weight gain induced by an antipsychotic medication, assessment of that risk, and medications categorized according to the relative risk of weight gain presented by each for the patient.
- the invention provides a method of selecting an antipyschotic medication or administering an antipyschotic medication to a subject in need thereof comprising: (1) determining or receiving the subject's genotype for at least one SNP selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2); (2) assigning an AIWG risk assessment to the subject, and (3) selecting or administering an antipsychotic medication to the subject based on the subject's AIWG risk assessment such that antipsychotic medications having a tendency to induce weight gain are avoided in favor of those having little tendency to induce weight gain where the AIWG risk
- step (2) the subject is assigned an AIWG risk assessment of "high”, “intermediate”, or “low” based on the subject's total genetic risk score, defined as the sum of the individual risk scores of each genotype determined or received in step (1).
- the antipsychotic medication is administered to the subject based on the subject's AIWG risk assessment as follows: (i) if the risk assessment is high, administer one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or administer risperidone, paliperidone, or quetiapine in combination with weight monitoring, and avoid administering clozapine and olanzapine; (ii) if the risk assessment is intermediate, administer one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripi
- step (1) comprises determining or receiving the subject's genotype for rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3)
- step (1) comprises or consists of determining or receiving the subject's genotype for at least two SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- step (1) comprises or consists of determining or receiving the subject's genotype for at least two SNPs, one or both of which is selected from rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and the remaining SNP is selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- step (1) comprises or consists of determining or receiving the subject's genotype for a set of two SNPs, one or both of which is selected from rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and the remaining SNP is selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- the set of two SNPs is selected from among the following: rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3)
- rs3134701 SEQ ID NO: 2) (HCRTR2) and rs6435326 (SEQ ID NO: 6) (NDUFS1); rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2) and rs6435326 (SEQ ID NO: 6)
- rs3134701 SEQ ID NO: 2) (HCRTR2) and rsl3429709 (SEQ ID NO: 1) (GCG); and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2) and rsl3429709 (SEQ ID NO: 1) (GCG).
- step (1) comprises or consists of determining or receiving the subject's genotype for a set of two SNPs
- the subject is assigned an AIWG risk assessment of "high” if the subject has a total genetic risk score of at least 2
- the subject is assigned an AIWG risk assessment of "intermediate” if the subject has a total genetic risk score of 1
- the subject is assigned an AIWG risk assessment of "low” if the subject has a total genetic risk score of 0.
- step (1) comprises or consists of determining or receiving the subject's genotype for at least three SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for at least three SNPs, one or two of which is selected from rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and the remaining SNP is selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for a set of three SNPs, one or two of which is selected from rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and the remaining selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- the set of three SNPs is selected from the following: rs3134701 (SEQ ID NO: 2) (HCRTR2), rsl3429709 (SEQ ID NO: 1) (GCG), and rs6435326 (SEQ ID NO: 6) (NDUFS1); rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rsl3429709 (SEQ ID NO: 1) (GCG), and rs6435326 (SEQ ID NO: 6) (NDUFSl);
- rs3134701 SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and rs6435326 (SEQ ID NO: 6) (NDUFSl); and
- rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for a set of three SNPs
- the subject is assigned an AIWG risk assessment of "high” if the subject has a total genetic risk score of at least 3, an AIWG risk assessment of "intermediate” if the subject has a total genetic risk score of at least 2 but less than 3, and an AIWG risk assessment of "low” if the subject has a total genetic risk score of less than 2.
- step (1) comprises or consists of determining or receiving the subject's genotype for at least four SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for at least four SNPs, one or two of which is selected from rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and the remaining SNP is selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFSl), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for a set of four or five SNPs, one or two of which is selected from rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and the remaining SNP is selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFSl), and rs6971 (SEQ ID NO: 9) (TSPO).
- the set of SNPs is selected from one of the following: rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rsl3429709 (SEQ ID NO: 1) (GCG), and rs6971 (SEQ ID NO: 9) (TSPO); rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rsl3429709 (SEQ ID NO: 1) (GCG), and rs6435326 (SEQ ID NO: 6) (NDUFS1);
- rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO);
- rs3134701 SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO);
- rs3134701 SEQ ID NO: 2) (HCRTR2), rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO); and
- rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for a set of four or five SNPs
- the subject is assigned an AIWG risk assessment of "high” if the subject has a total genetic risk score of at least 4, an AIWG risk assessment of "intermediate” if the subject has a total genetic risk score of at least 2 but less than 4, and an AIWG risk assessment of "low” if the subject has a total genetic risk score of less than 2.
- step (1) comprises or consists of determining or receiving the subject's genotype for at least five SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- step (1) comprises or consists of determining or receiving the subject's genotype for at least six SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- step (1) further comprises or consists of determining or receiving the subject's genotype for one or more additional SNP's selected from rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNRl), and rsl6147 (SEQ ID NO: 13) (NPY).
- the subject is assigned an AIWG risk assessment of "high” if the subject has a total genetic risk score of at least 6, an AIWG risk assessment of "intermediate” if the subject has a total genetic risk score less than 6 but greater than 3, and an AIWG risk assessment of "low” if the subject has a total genetic risk score of 3 or less.
- step (1) comprises or consists of determining or receiving the subject's genotype for at least seven SNPs, the at least seven SNPs comprising at least four SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2) and three SNPs selected from rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNR1), and rsl6147 (SEQ ID NO: 13) (NPY).
- SEQ ID NO: 1 GCG
- rs3134701 SEQ ID NO:
- the seven SNPs are selected from rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNR1), and rsl6147 (SEQ ID NO: 13) (NPY).
- the subject is assigned an AIWG risk assessment of "high” if the subject has a total genetic risk score of at least 5, an AIWG risk assessment of "intermediate” if the subject has a total genetic risk score less than 5 but at least 2, and an AIWG risk assessment of "low” if the subject has a total genetic risk score of less than 2.
- the method may further comprise weight monitoring in combination with one or more of (i) the administration of an appetite suppressant or hypoglycemic medication selected from the group consisting of a sulfonylurea, thiazolidinedione, alpha glucosidase inhibitor, and metformin; (ii) a diet plan; and (iii) an exercise regimen.
- an appetite suppressant or hypoglycemic medication selected from the group consisting of a sulfonylurea, thiazolidinedione, alpha glucosidase inhibitor, and metformin
- a diet plan a diet plan
- an exercise regimen selected from the group consisting of a sulfonylurea, thiazolidinedione, alpha glucosidase inhibitor, and metformin
- the step of determining the subject's genotype for at least one SNP comprises a step of contacting a set of SNP-specific primers with DNA extracted from a sample from the subject, allowing the primers to bind to the DNA, and amplifying the SNP containing regions of the DNA using a polymerase chain reaction.
- the set of SNP-specific primers comprises primers for amplifying two or more SNPs selected from the group consisting of rs 13429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- At least one of the set of SNP- specific primers comprises primers for amplifying rs3134701 (SEQ ID NO: 2) (HCRTR2) or rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2).
- the set of SNP-specific primers comprises primers for amplifying at least the SNPs defined by rsl 3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3)
- the set of SNP-specific primers comprises primers for amplifying the set of SNPs defined by rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), and rs6435326 (SEQ ID NO: 6) (NDUFSl) and one or more additional SNPs defined by rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNR1), and rsl6147 (SEQ ID NO: 13) (NPY).
- the step of receiving the subject's genotype for at least one SNP comprises receiving, in a computer system, the patient's genotype for the at least one SNP, the computer system comprising a database which comprises a plurality of antipsychotic medication profiles, each medication profile comprising information about the medication's side effects, including its tendency to induce weight gain, and optionally including additional information about the medication such as interactions and adverse events.
- step 2 is also performed using said computer system and the method further comprises the step of outputting the identity of an antipsychotic medication for administering to the patient.
- a user enters the patient's genotype in the computer system.
- the patient's genotype is received directly from equipment used in determining the patient's genotype.
- the invention also provides a non-transitory computer readable medium containing executable instructions that when executed cause a processor to perform operations comprising assigning an AIWG risk assessment to a subject based on a subject's genotype at one or more SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- the one or more SNPs comprises rs3134701 (SEQ ID NO: 2) (HCRTR2) and/or rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2).
- the one or more SNPs is at least seven SNPs, the at least seven SNPs comprising at least four SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2) and three SNPs defined by rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO:
- the seven SNPs are defined by rsl 3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNR1), and rsl6147 (SEQ ID NO: 13) (NPY).
- the invention also provides a kit of parts comprising a set of nucleotides suitable for amplifying at least two SNPs selected from the group consisting of rsl3429709 (SEQ ID NO:
- the set of nucleotides includes nucleotides suitable for amplifying at least one of rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2).
- the set of nucleotides includes nucleotides suitable for amplifying at least seven SNPs, the at least seven SNPs comprising at least four SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3)
- HTR2 A 2 HCTR2 A 2
- rs6435326 SEQ ID NO: 6
- NDUFS1 rs6971
- TSPO rs279858
- GABRA2 GABRA2
- the seven SNPs are defined by rsl 3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNR1), and rsl6147 (SEQ ID NO: 13) (NPY).
- the invention provides a method for selecting an antipsychotic medication for a subject in need of treatment for a psychiatric disease or disorder, the methods comprising selecting an antipsychotic medication based on the subject's AIWG risk assessment such that antipsychotic medications having a high tendency to induce weight gain are avoided in favor of those having a low or intermediate tendency to induce weight gain.
- the method comprises selecting one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapine in combination with weight monitoring, and avoiding clozapine and olanzapine.
- antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapin
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or selecting clozapine or olanzapine in combination with weight monitoring.
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine
- the invention provides a method for determining a subject's susceptibility to antipsychotic medication induced weight gain based on the subject's AIWG risk assessment.
- the subject's susceptibility is determined to be high and the method comprises recommending for the subject one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or recommending risperidone, paliperidone, or quetiapine in combination with weight monitoring, and recommending that the subject avoid clozapine and olanzapine.
- the subject's susceptibility is determined to be intermediate and the methods comprise recommending for the subject one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole,
- chlorpromazine is amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or recommending clozapine or olanzapine in combination with weight monitoring.
- the subject's susceptibility is determined to be low and the methods comprise recommending for the subject one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, as
- the invention provides a method for designing a therapeutic regimen for a subject in need of treatment with an antipsychotic medication, the methods comprising selecting an antipsychotic medication based on the subject's AIWG risk assessment such that antipsychotic medications having a high tendency to induce weight gain are avoided in favor of those having a low or intermediate tendency to induce weight gain.
- the method comprises selecting one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapine in combination with weight monitoring, and avoiding clozapine and olanzapine.
- antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapin
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or selecting clozapine or olanzapine in combination with weight monitoring.
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- additional elements such as diet and exercise may be added to the regimen to mitigate weight gain.
- FIG. 1 is a block diagram of a system in accordance with some embodiments of the present subject matter. DETAILED DESCRIPTION
- the present subject matter relates in part to the discovery of certain genetic markers that are informative regarding a subject's risk of experiencing a clinically significant weight gain during treatment with an antipsychotic medication.
- the genetic markers are in the form of single nucleotide polymorphisms (SNPs) determined by the inventors to be associated with clinically significant weight gain in human subjects treated with antipsychotic medications, also referred to herein as "psychiatric patients”.
- SNPs single nucleotide polymorphisms
- Clinically significant weight gain associated with antipsychotic medication treatment is referred to herein as "anti-psychotic-induced weight gain" or "AIWG”.
- the methods of the invention provide an output indicating a subject's risk of AIWG based upon the subject's genotype at one or more SNPs, as described herein, and optionally one or more additional subject specific factors as described below.
- the subject is a psychiatric patient.
- the term "psychiatric patient” refers to a human subject having a diagnosis indicating that the subject is in need of treatment with one or more medications to alleviate one or more symptoms of a psychiatric disease or disorder.
- the one or more medications is an antipsychotic medication.
- the output of risk provided by the methods of the invention is referred to herein as the "AIWG risk assessment".
- the AIWG risk assessment incorporates information about the subject's genotype at one or more SNPs.
- the AIWG risk assessment may also incorporate other information about the subject, as discussed below.
- the methods of the invention provide a model which incorporates information about the subject's genotype for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 SNPs as described herein.
- the model incorporates information about 1, 2, 3, 4, 5, 6, 7 or 8 SNPs.
- the model incorporates information about 4 or 5 SNPs or information about 6, 7, or 8 SNPs.
- the model incorporates information about at least 6 or at least 7 SNPs.
- the methods of the invention further comprise an output indicating the set of antipsychotic medications that is administered or should be administered to the subject and the set of antipsychotic medications that should be avoided based upon the subject's AIWG risk assessment as determined by the methods of the present invention.
- the invention provides methods that comprise administering or selecting one or more antipsychotic medications based upon a subject's AIWG risk assessment. In one embodiment, where the subject's AIWG risk assessment is "high” the methods comprise administering or selecting a medication having a low risk of inducing weight gain, or administering or selecting a medication having an intermediate risk of inducing weight gain in combination with weight monitoring. In another embodiment, where the subject's AIWG risk assessment is "intermediate” the methods comprise administering or selecting a medication having a low or intermediate risk of inducing weight gain.
- a subject's weight gain is considered to be clinically significant if it increases by 7% or more after the subject has been treated with one or more antipsychotic medications for a period of time, compared to the subject's baseline weight.
- the subject's baseline weight is the subject's weight before treatment with the one or more antipsychotic medications.
- the clinically significant weight gain is between 7 and 10% of the subject's baseline weight.
- the clinically significant weight gain is between 10 and 15% of the subject's baseline weight.
- the clinically significant weight gain is greater than 15% of the subject's baseline weight.
- the period of antipsychotic medication treatment comprises a period of months, for example, 2, 3, 4, 5, or 6 months, or more, for example 12 or 24 months.
- the subject is a human subject, and more specifically an adult subject, a pediatric subject, or an elderly subject, as those terms are understood in the medical arts.
- the subject is further defined according to the subject's ethnicity.
- the subject self-identifies or is genetically determined to be a member of an ethnic group selected from African, North African, Southern African, European, Western European, Northern European, Asian, Japanese, Han Chinese, and Korean.
- the subject's ethnicity is determined by genetic analysis according to routine methods.
- the subject is of European ethnicity.
- the subject is of African ethnicity.
- the subject is of Asian ethnicity.
- the subject is of non- European ethnicity.
- ethnicity and ancestry are used
- the methods of the invention are directed to subjects in need of treatment with one or more antipsychotic medications.
- the subject in need of treatment is one who does not present with any symptoms, or does not present with sufficient symptoms of a psychiatric disease or disorder to have a diagnosis but is at increased risk of developing a psychiatric disease or disorder because of a family history of such disease or disorder.
- the subject in need of treatment is one who presents with sufficient symptoms of a psychiatric disease or disorder to be diagnosed with a psychiatric disease or disorder.
- a subject being treated or in need of treatment with one or more medications to alleviate one or more symptoms of a psychiatric disease or disorder is also referred to herein as a "psychiatric patient".
- the subject is a psychiatric patient diagnosed with a psychiatric disease or disorder.
- the subject is a psychiatric patient already undergoing treatment for a psychiatric disease or disorder which comprises administering one or more antipsychotic medications and the treatment is revised according to the methods of the present invention.
- the subject has not yet begun treatment for a psychiatric disease or disorder and the subject is treated with one or more antipsychotic medications according to the methods of the present invention.
- the psychiatric disease or disorder is selected from the group consisting of schizophrenia and schizoaffective disorders.
- the psychiatric disease or disorder is bipolar disorder.
- the psychiatric disease or disorder is selected from a conduct disorder.
- the psychiatric disease or disorder is autism or an autism spectrum disorder.
- the psychiatric disease or disorder is attention deficient hyperactivity disorder (ADHD).
- the psychiatric disease or disorder is depression.
- the invention provides methods for altering an existing treatment regimen or designing an initial treatment regimen for a subject in need of treatment with one or more antipsychotic medications, the method comprising determining the set of antipsychotic medications to be administered to the subject as well as the set of antipsychotic medications that should not be administered to the subject based upon the subject's AIWG risk assessment. In one embodiment, the methods further comprise the step of administering one or more antipsychotic medications to the subject.
- the methods of the invention comprise determining a subject's genotype at one or more SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6922310 (SEQ ID NO: 4) (HCRTR2 A 3), rs2653350 (SEQ ID NO: 5) (HCRTR2 A 4), rs6435326 (SEQ ID NO: 6) (NDUFS1), rsl053517 (SEQ ID NO: 7)
- NUFS1 A 1 rs 1801318 (SEQ ID NO: 8) (NDUFS1 A 2), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- the methods of the invention comprise determining or receiving a subject's genotype for at least one SNP selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- the GABRA2 polymorphism is described in Applicant's U.S. Provisional Application Serial No. 61/892,094, filed on October 17, 2013, the contents of which are hereby incorporated by reference.
- the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs comprising at least two SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs comprising at least three SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6)
- NUFS1 NUFS1
- TSPO rs6971
- the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs comprising at least four SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs comprising at least five SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs comprising at least six SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs that includes at least one of rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2). In one embodiment, the methods of the invention comprise determining or receiving a subject's genotype for a panel of SNPs that includes at least rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2).
- the panel of SNPs also includes one, two, or three, additional SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- the methods of the invention further comprise determining or receiving the subject's genotype at one or more additional SNPs selected from the group consisting of rs489693 (MC4R, see e.g., Malhotra et al, Arch Gen Psychiatry 69:904-912, 2012), rsl6147 (NPY, see e.g., Tiwari et al, J Clin Psychopharmacology 33:11-17, 2013 ), and rs806378 (CNR1, see e.g., Tiwari et al, Neuropsychopharmacology 35:1315-1324, 2010).
- M4R Malhotra et al, Arch Gen Psychiatry 69:904-912, 2012
- NPY see e.g., Tiwari et al, J Clin Psychopharmacology 33:11-17, 2013
- rs806378 CNR1, see e.g., Tiwari et al, Neuropsychopharmacology 35:1315
- the methods of the invention further comprise determining or receiving a subject's genotype for at least one additional SNP selected from the group consisting of rs2268639 (SEQ ID NO: 10) (GLPR1), rs489693 (SEQ ID NO: 11) (MC4R), rs806378 (SEQ ID NO: 12) (CNR1), and rsl6147 (SEQ ID NO: 13) (NPY).
- the at least one additional SNP is rs489693 (SEQ ID NO: 11) (MC4R).
- the methods of the invention further comprise identifying the number of risk genotypes the subject carries and, optionally, assigning a risk score to each genotype.
- a risk genotype includes information about whether, and in certain embodiments, how ⁇ e.g., dominant or recessive) each allele of the genotype is significantly associated with an increased risk of AIWG.
- the term "risk allele” refers to an allele of an SNP identified as being associated with an increased risk of clinically significant weight gain in a subject being treated with one or more antipsychotic medications.
- a particular allele is further classified as a dominant or recessive allele with respect to AIWG.
- Each "risk genotype" of an SNP is further assigned a risk score based upon whether or not the genotype contains a risk allele and further based upon whether or not the risk allele is dominant or recessive. Risk alleles and associated genotypes for particular SNPs are indicated in Table 1.
- SNPs are referred to by their "rs" number as well as a reference sequence (see Table 3 for SNP reference sequences and their sequence identifiers as used herein).
- the reference sequence shows the single nucleotide polymorphism in bold.
- the "rs" number for a given SNP is a reference number provided by the HapMap consortium. The rs number is sufficient to obtain much of the known information regarding a particular SNP, for example by querying the rs number in the HapMap database or similar databases including the UCSC Genome Bioinformatics Web Page and similar databases maintained by the US National Center for Biotechnology Information.
- the AIWG risk model of the invention incorporates information about a subject's genotype at one or more SNPs, preferably a subject's genotype for at least 5, at least 6, or at least 7 SNPs, and provides an output in the form of an AIWG risk assessment indicating the likelihood that the subject will experience a clinically significant weight gain while undergoing treatment with an antipsychotic agent, in particular an antipsychotic agent having a tendency to induce weight gain.
- Antipsychotic agents having a tendency to induce weight gain include medications such as risperidone, paliperidone and quetiapine, which have an intermediate risk of inducing weight gain, as well as clozapine and olanzapine, which have a high risk of inducing weight gain.
- Antipsychotic agents having a low risk of inducing weight gain include haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole,
- the AIWG risk assessment is qualitative, e.g., high, intermediate, low. In another embodiment, the AIWG risk assessment is a numerical value.
- the AIWG risk assessment incorporates the subject's total genetic risk score for one or more SNP's included in the model. The total genetic risk score is the sum of the individual risk scores for each genotype of each SNPs included in the model. The individual risk score for each genotype incorporates information regarding the contribution of each allele in the genotype to AIWG, as determined by the present invention.
- the individual risk score includes information regarding the mode of inheritance (dominant or recessive) of the allele.
- the numerical value for a genotype's risk score ranges from 0 (no risk of clinically significant weight gain) to 1 (highest risk of clinically significant weight gain).
- Table 1 lists the genotypes and risk scores for a set of SNPs that the inventors have determined are significantly associated with antipsychotic medication-induced weight gain and which may be incorporated individually or in panels of two or more into the risk model of the invention.
- Table 2 shows exemplary, but non-limiting, panels of SNPs for incorporation into a risk model as described herein.
- the model includes 2 SNPs and the AIWG risk assessment is high if the subject has a total genetic risk score of at least 2, intermediate if the subject has a total genetic risk score of 1 or more, but less than 2, and low if the subject has a total genetic risk score of less than 1 , for example, 0.
- the model includes 3 SNPs and the AIWG risk assessment is high if the subject has a total genetic risk score of at least 3, intermediate if the total genetic risk score is between 1 and 3, for example, 2, and low if the subject has a total genetic risk score of less than 2, for example, 0 or 1.
- the model includes 4 or 5 SNPs and the AIWG risk assessment is high if the subject has a total genetic risk score of at least 4, intermediate if the total genetic risk score is less than 4 but greater than 1, for example, 2 or 3, and low if the subject has a total genetic risk score of less than 2, for example, 0 or 1.
- the model includes 6, 7, or 8 SNPs and the AIWG risk assessment is high if the subject has a total genetic risk score of at least 6, intermediate if the total genetic risk score is less than 6 but greater than 3, and low if the subject has a total genetic risk score of 3 or less.
- the model includes 6, 7, or 8 SNPs and the AIWG risk assessment is high if the subject has a total genetic risk score of at least 5, intermediate if the total genetic risk score is less than 5 but at least 2, and low if the subject has a total genetic risk score of less than 2.
- the model may incorporate other relevant information into the AIWG risk assessment.
- the model may incorporate information regarding the subject's ethnicity, duration of disease, baseline severity of disease, duration of treatment, medication dose, baseline weight, age, and gender.
- the AIWG risk assessment incorporates information regarding the subject's ethnicity.
- the model determines the risk assessment cutoffs for the total genetic risk score based upon the panel of SNPs included in the model and the expected percentage weight change for the panel.
- a total genetic risk score associated with an expected percentage weight change of less than 4% represents a low risk
- a total genetic risk score associated with an expected percentage weight change of between 4% and 7% represents an intermediate risk
- a total genetic risk score associated with an expected percentage weight change of more than 7% represents a high risk.
- an expected percentage weight change of 7% to 10% represents a high risk and more than 10% represents a very high risk.
- the AIWG risk assessment is used in methods to improve therapeutic outcomes by preventing or reducing weight gain in a psychiatric patient being treated with one or more antipsychotic medications; for selecting an antipsychotic medication for a psychiatric patient that minimizes the patient's risk of clinically significant weight gain induced by the medication; reduce a psychiatric patient's risk of clinically significant weight gain induced by an antipsychotic medication; and for determining a psychiatric patient's susceptibility to weight gain by identifying at-risk patients and providing an assessment of that risk.
- the AIWG risk assessment is also used in methods for designing a therapeutic regimen for a patient that minimizes the risk of weight gain.
- the methods may also include generating and outputting a patient-specific report identifying the patient according to the patient's particular risk of clinically significant weight gain induced by an antipsychotic medication, providing an assessment of that risk, and including a list of medications categorized according to the relative risk of weight gain presented by each for the patient.
- Risk Markers and Alleles for AIWG are generated and outputting a patient-specific report identifying the patient according to the patient's particular risk of clinically significant weight gain induced by an antipsychotic medication, providing an assessment of that risk, and including a list of medications categorized according to the relative risk of weight gain presented by each for the patient.
- the present invention provides a number of risk alleles for AIWG, as shown 1 below.
- Table 2 Exemplary Panels of Genetic Markers Associated with Antipsychotic Medication-Induced Weight Gain
- rs6435326 NDUFS1 GGAATAACTCCTTTTGTAAT AAAGA [ A/T] AGATTT A SEQ ID NO: 6 AATGAAGTTAAAAGTGCA
- the methods of the invention provide for the treatment of a subject having a psychiatric disease or disorder based upon the subject's AIWG risk assessment as determined according to the invention.
- the AIWG risk assessment incorporates information about the subject's genotype at one or more SNPs, as provided herein.
- the AIWG risk assessment incorporates the subject's total genetic risk score, as provided herein, and optionally one or more additional patient-specific data attributes selected from the subject's ethnicity, duration of disease, baseline severity of disease, duration of treatment, medication dose, baseline weight, age, and gender.
- the methods of the invention also provide for different treatments, or different treatment regimens, for the subject depending on the subject's AIWG risk assessment.
- the methods of the invention include methods for designing a treatment regimen, methods for selecting an antipsychotic medication for administration to a subject, and methods for determining a subject's susceptibility to AIWG, all using the subject's AIWG risk assessment, as provided herein.
- the methods of the invention are applicable to a subject regardless of the subject's ethnicity because risk alleles identified by the invention occur with similar frequencies among the major ethnic groups, as shown in the table below.
- Table 4 Genotypic and allelic frequencies of the SNPs in different populations. CEU- European ancestry; HCB &JPT: Asian Ancestry and YRI: Sub-Sa African ancestr .
- the methods of the invention provide for the treatment of a subject in need of treatment for a psychiatric disease or disorder, the methods comprising administering an antipsychotic medication to the subject based on the subject's AIWG risk assessment such that antipsychotic medications having a high tendency to induce weight gain are avoided in favor of those having a low or intermediate tendency to induce weight gain.
- the method comprises administering one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or administering risperidone or quetiapine in combination with weight monitoring, and avoiding clozapine and olanzapine.
- antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or administering risperidone or quetia
- weight monitoring means the periodic determination of the subject's weight during treatment.
- the weight monitoring may include determining the subject's weight every two weeks for the first three to six months of treatment, then on a monthly basis.
- Weight monitoring is used to monitor any weight gain by the subject during treatment. For example, if the subject gains weight initially, and continues to gain weight such that the subject is on a course to gain 7% or more relative to the subject's baseline weight (the subject's weight at the start of treatment), the clinician should consider changing the subject's treatment regimen either to substitute the subject's antipsychotic medication for one having a lower tendency to induce weight gain, and/or adding to the regimen additional elements to mitigate weight gain, such as diet and exercise.
- the methods comprise administering one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or administering clozapine or olanzapine in combination with weight monitoring.
- antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or administering
- the methods comprise administering one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpnde, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- the methods of the invention provide for selecting an
- the methods comprising selecting an antipsychotic medication based on the subject's AIWG risk assessment such that antipsychotic medications having a high tendency to induce weight gain are avoided in favor of those having a low or intermediate tendency to induce weight gain.
- the method comprises selecting one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapine in combination with weight monitoring, and avoiding clozapine and olanzapine.
- antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapin
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or selecting clozapine or olanzapine in combination with weight monitoring.
- antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or selecting cloza
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine
- the methods of the invention provide for determining a subject's susceptibility to antipsychotic medication induced weight gain based on the subject's AIWG risk assessment.
- the subject's susceptibility is determined to be high and the method comprises recommending for the subject one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or recommending risperidone, paliperidone, or quetiapine in combination with weight monitoring, and recommending that the subject avoid clozapine and olanzapine.
- the subject's susceptibility is determined to be intermediate and the methods comprise recommending for the subject one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole,
- chlorpromazine is amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or recommending clozapine or olanzapine in combination with weight monitoring.
- the subject's susceptibility is determined to be low and the methods comprise recommending for the subject one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, as
- the methods of the invention provide for designing a therapeutic regimen for a subject in need of treatment with an antipsychotic medication, the methods comprising selecting an antipsychotic medication based on the subject's AIWG risk assessment such that antipsychotic medications having a high tendency to induce weight gain are avoided in favor of those having a low or intermediate tendency to induce weight gain.
- the method comprises selecting one or more antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapine in combination with weight monitoring, and avoiding clozapine and olanzapine.
- antipsychotic medications selected from the group consisting of haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, iloperidone, asenapine, and lurasidone, or selecting risperidone, paliperidone, or quetiapin
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, and lurasidone, or selecting clozapine or olanzapine in combination with weight monitoring.
- the methods comprise selecting one or more antipsychotic medications selected from the group consisting of risperidone, quetiapine, haloperidol, perphenazine, thioridazine, ziprasidone, aripiprazole, chlorpromazine, amisulpride, fluphenazine, molindone, loxapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine, olanzapine, and any other weight neutral antipsychotic.
- additional elements such as diet and exercise may be added to the regimen to mitigate weight gain.
- the methods of the invention further comprise one or more additional steps selected from the group consisting of (1) testing the subject for one or more additional genetic markers, (2) advising and/or counseling the subject with respect to the results of an AIWG risk assessment, (3) transmitting, advising and/or conveying the results of an AIWG risk assessment to a physician, medical service provider or other third party, (4) altering the subject's treatment regimen based on the results of an AIWG risk assessment in order to lower the subjects risk of weight gain, (5) treating the subject prior to, concurrently with or after antipsychotic treatment with one or more therapies to control weight gain, for example, administering to the subject an appetite suppressant or hypoglycemic medication selected from the group consisting of a sulfonylurea, thiazolidinedione, alpha glucosidase inhibitor, and metformin, (6) monitoring the subject's weight over a period of time, (7) monitoring the subject for metabolic syndrome or the development of metabolic syndrome which may include measuring one or more of blood lipid profiles,
- the subject presents with one or more psychotic symptoms, schizophrenia symptoms, schizoaffective disorder symptoms or a combination thereof.
- the psychotic symptoms may comprise positive symptoms such as, but not limited to distortions or exaggerations of inferential thinking (i.e. delusions), perception (i.e. hallucinations), language and communication (disorganized speech) and behavioral monitoring (grossly disorganized or catatonic behavior) or any combination thereof.
- the positive symptoms may comprise distinct dimensions, for example, psychotic dimensions including, but not limited to delusions and hallucinations and disorganization dimensions including, but not limited to disorganized speech and behavior.
- the symptoms may also comprise one or more negative symptoms, for example, but not limited to symptoms that reflect a diminution or loss of normal function (including but not limited to, loss of motivation, loss of social interest, loss of communication, or a combination thereof). Further, the subject may exhibit a combination of both positive and negative symptoms.
- the subject has been diagnosed or is suspected of having schizophrenia or schizoaffective disorder on the basis of the subject's having presented with one or more of the foregoing positive and negative psychotic symptoms.
- the subject presents with one or more symptoms selected from the group consisting of catatonia, depressed mood, severe obsessions and/or compulsions or psychomotor agitation.
- the subject presents with one or more symptoms of mania, including but not limited to elevated, expansive or irritable mood, exaggerated goal-directed activity, inflated self-esteem or grandiosity and decreased need for sleep.
- the subject presents with one or more symptoms of impulse-control, conduct or disruptive disorders including failure to control aggressive impulses, aggression to people/animals/property and serious violations of widely accepted rules. Further symptoms include disruptive behavior in neurodevelopmental disorders including but not limited to intellectual disability, autism and attention-deficit/hyperactivity disorder.
- the subject presents with one or more symptoms of severe tic disorders including Tourette syndrome or with severe stereotypic movement disorders.
- the genotype of the subject is determined by techniques known in the art, for example, PCR analysis, DNA sequencing, 5'exonuclease fluorescence assay, sequencing by probe hybridization, dot blotting, and oligonucleotide array (DNA Chip) hybridization analysis, or combinations thereof.
- Such techniques are described, for example, in Ausubel, et al. (eds), 1989, Current Protocols in Molecular Biology, Green Publishing Associates, Inc., and John Wiley & Sons, Inc., New York, at p. 2.10.3, and in Maniatis et al., in Molecular Cloning (A Laboratory Manual), Cold Spring Harbor Laboratory, 1982, p. 387 389).
- Realtime PCR methods that can be used to detect SNPs, include, e.g., Taqman or molecular beacon-based assays (U.S. Pat. Nos. 5,210,015; 5,487,972; and PCT WO 95/13399) are useful to monitor for the presence or absence of a SNP.
- Genotyping technology is commercially available, for example from companies such as Applied Biosystems, Inc (Foster City, CA). Any suitable biological sample from the subject can be used as the source of the DNA for genotyping. Kits
- kits for practicing the methods of the present invention.
- a kit provided by the invention comprises a set of primers adapted to amplify, in a polymerase chain reaction, at least one nucleotide sequence comprising a single nucleotide polymorphism (SNP) as defined in the SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- SNP single nucleotide polymorphism
- the kit comprises a set of primers adapted to amplify, in a polymerase chain reaction, at least one nucleotide sequence comprising a single nucleotide polymorphism (SNP) as defined in the SNPs selected from the group consisting of rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2).
- SNP single nucleotide polymorphism
- the kit comprises a set of primers adapted to amplify at least one nucleotide sequence comprising a single nucleotide polymorphism (SNP) as defined in the SNPs selected from the group consisting of rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2) and at least one additional set of primers adapted to amplify at least one nucleotide sequence comprising a single nucleotide polymorphism (SNP) as defined in the SNPs selected from the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFSl), and rs6971 (SEQ ID NO: 9) (TSPO).
- SNP single nucleotide polymorphism
- a kit provided by the invention comprises one or more polynucleotide probes adapted to hybridize with at least one SNP defined in the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2).
- SNP SNP defined in the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6) (NDUFSl),
- the kit comprises one or more polynucleotide probes adapted to hybridize with at least one SNP defined in the group consisting of rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2).
- the kit comprises one or more polynucleotide probes adapted to hybridize with at least one SNP defined in the group consisting of rs3134701 (SEQ ID NO: 2) (HCRTR2) and rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2) and the kit further comprises one or more additional polynucleotide probes adapted to hybridize with at least one SNP defined in the group consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFSl), and rs6971 (SEQ ID NO: 9) (TSPO).
- hybridize refers to specific hybridization such as occurs between the probe and its complementary nucleotide sequence under high stringency hybridization conditions, as those conditions are understood in the art.
- the probe is labeled with a detectable label, such as a radionuclide, a fluorescent molecule, a magnetic bead, or chemical entity, or any other suitable label that can be attached to or incorporated within a polynucleotide sequence.
- the probe is attached covalently or physically associated with a support for example, but not limited to a biochip, array, slide, multiwell plate, bead or the like.
- the probe comprises an array of nucleic acids attached or associated with a solid support.
- kits of the present invention may also optionally comprise one or more reagents and/or products including, but not limited to, one or more buffers for performing PCR or probe hybridization, or any step in such a process as would be known to a person of skill in the art, one or more DNA amplifying enzymes, or any combination thereof; one or more reagents, components and products for genotyping the polymorphisms as described herein, including, but not limited to those used in exonuclease assays, nucleotide sequencing, or any combination thereof; one or more reagents, components or products for performing a DNA sequencing reaction that determines the sequence of a nucleotide sequence of an SNP defined herein; a gene chip or array comprising one or a plurality of nucleotide sequences comprising or consisting of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (
- kits for example, but not limited to any product, composition described in the kit or elsewhere in the application.
- the present invention provides one or more nucleic acid primers or probes.
- the nucleic acid primers and probes may be of any suitable length for use in the method of the present invention. Without wishing to be limiting in any manner, it is generally preferred that the primers and probes be between about 9 and about 100 nucleotides, for example, but not limited to about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 25, 27, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, about 100 nucleotides or any amount therein between.
- the length of the primers and probes may also be defined by a range of any two of the values provided above or any two values therein between.
- the probe comprise at least one, more preferably 3 or more nucleotides on each side of the polymorphic site. It is also contemplated that one or more of the primers or nucleic acid probes may be labeled as is known in the art, for example, but not limited to, with a radioactive element or tag, fluorophore, or the like.
- a microarray, gene chip or the like which comprises the nucleotide sequence defined by any one or more of rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3)
- HCTR2 A 2 rs6435326 (SEQ ID NO: 6) (NDUFS1), rs6971 (SEQ ID NO: 9) (TSPO), and rs279858 (SEQ ID NO: 14) (GABRA2), or a fragment thereof which comprises the polymorphic site.
- the microarray or gene chip comprises nucleotide sequences defined by at least rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2) and optionally further comprising nucleotide sequences defined by one or more of rsl3429709 (SEQ ID NO: 1) (GCG), rs6435326 (SEQ ID NO: 6) (NDUFS1), and rs6971 (SEQ ID NO: 9) (TSPO).
- the microarray also may comprise the complement of the nucleotide sequences or a fragment thereof which comprises the polymorphic site.
- the nucleotide sequences are of a length such as, but not limited to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more continuous nucleotides to permit strong hybridization under stringent hybridization conditions.
- the microarray comprises or consists of one or more nucleotide sequences comprising the polymorphic sites in rsl3429709 (SEQ ID NO: 1) (GCG), rs3134701 (SEQ ID NO: 2) (HCRTR2), rs4142972 (SEQ ID NO: 3) (HCRTR2 A 2), rs6435326 (SEQ ID NO: 6)
- microarray may comprise additional nucleotide sequences for other genes, for example, but not limited to those involved or implicated in the diagnosis or development of schizophrenia, schizoaffective disorder or the like.
- FIG. 1 illustrates an example of a system that can implement one or more features described herein.
- system 100 includes a processor 110 and a memory 120.
- memory 120 can include executable instructions that when executed by processor 110, cause the processor 110 to perform one or more operations discussed herein.
- System 100 also includes a user interface 160 which permits the system to interact with a user through, for example, one or more input devices 170 and one or more displays 175.
- System 100 can also include one or more modules and/or engines that implement one or more features described herein.
- system 100 can include Genetic Risk Score Generator 130, which can, for example, generate a total genetic risk score for a subject representing the risk of weight gain associated with the subject's genotype.
- System 100 can also include AIWG Risk Assessment Generator 140 which can, for example, generate an AIWG risk assessment for the subject using one or more data attributes including the subject's total genetic risk score.
- system 110 can include Antipsychotic
- Medication Selection Engine 150 which can, for example, select an antipsychotic medication for the subject based on the subject's AIWG risk assessment.
- system 100 can be configured to receive a patient's data from a genotype determining equipment 180.
- one or more patient data can be stored in a data storage or database 190 which is connected to the system via a data connection.
- One or more aspects or features of the subject matter described herein can be realized in digital electronic circuitry, integrated circuitry, specially designed application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs) computer hardware, firmware, software, and/or combinations thereof.
- ASICs application specific integrated circuits
- FPGAs field programmable gate arrays
- These various aspects or features can include implementation in one or more computer programs that are executable and/or interpretable on a programmable system including at least one programmable processor, which can be special or general purpose, coupled to receive data and instructions from, and to transmit data and instructions to, a storage system, at least one input device, and at least one output device.
- the programmable system or computing system may include clients and servers.
- a client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.
- machine-readable signal refers to any signal used to provide machine instructions and/or data to a programmable processor.
- the machine-readable medium can store such machine instructions non- transitorily, such as for example as would a non-transient solid-state memory or a magnetic hard drive or any equivalent storage medium.
- the machine-readable medium can alternatively or additionally store such machine instructions in a transient manner, such as for example as would a processor cache or other random access memory associated with one or more physical processor cores.
- one or more aspects or features of the subject matter described herein can be implemented on a computer having a display device, such as for example a cathode ray tube (CRT) or a liquid crystal display (LCD) or a light emitting diode (LED) monitor for displaying information to the user and a keyboard and a pointing device, such as for example a mouse or a trackball, by which the user may provide input to the computer.
- a display device such as for example a cathode ray tube (CRT) or a liquid crystal display (LCD) or a light emitting diode (LED) monitor for displaying information to the user
- LCD liquid crystal display
- LED light emitting diode
- a keyboard and a pointing device such as for example a mouse or a trackball
- feedback provided to the user can be any form of sensory feedback, such as for example visual feedback, auditory feedback, or tactile feedback; and input from the user may be received in any form, including, but not limited to, acoustic, speech, or tactile input.
- Other possible input devices include, but are not limited to, touch screens or other touch-sensitive devices such as single or multi-point resistive or capacitive trackpads, voice recognition hardware and software, optical scanners, optical pointers, digital image capture devices and associated interpretation software, and the like.
- SNPs Single nucleotide polymorphisms in or near GCG and GLPIR were selected using the hapmap database (http://hapmap.ncbi.nlm.nih.gov/) based on linkage
- LD disequilibrium
- region 10 kb upstream and 2 kb downstream of the genes.
- SNPs in the GCG region rsl990761, rs41368446, rsl3429709, rs3761656) were selected. All SNPs were located near the gene due to very low minor allele frequency of variants in the gene.
- Haplotype analysis for categorical variables was performed in haploview (>7% weight gain from baseline vs. ⁇ 7% weight gain) and for quantitative variable (weight gain %) in U PHASED version 3.1.4.
- Gene-gene interaction was tested using the R-package mbmdr. To correct for multiple testing, we applied gene-wide Nyholt-correction.
- Exclusion criteria for these studies included pregnancy, organic brain disorder, severe head injuries, previous medical conditions which required treatment and were not stable (Hepatitis C, HIV, Thyroid disorder or diabetes mellitus), substance dependence, clinically relevant mental retardation and severe personality disorder.
- Genomic DNA was extracted from blood samples using the high-salt method (Lahiri and Nurnberger 1991).
- TagSNPs were selected from the CEU population in HapMap (Haploview 4.2(Barrett et al. 2005)) using a region ⁇ 10Kb upstream and 2Kb downstream of the HCRTR1 and HCRTR2 genes (minor allele frequency>0.05, r2> 0.8).
- a total of 5 tagSNPs covering a 20kb region including HCRTR1 ( ⁇ 9.6kb) and 28 tagSNPs covering 120kb including HCRTR2 ( ⁇ 108kb) were included in this study. All genotyping was carried out using customised GoldenGate Genotyping Assays (Illumina, Inc. San Diego, CA, USA). As a quality control ⁇ 5% of the total sample was re-genotyped and 100% concordance rate was observed in this study.
- HCRTPvl was associated with AIWG (p>0.05).
- Table 6 SNPs in orexin receptor 2 (HCRTR2) associated with antipsychotic induced weight gain at genotypic and/or allelic level.
- Mitochondria are the main source of energy for neurons and play a role in many of the neuronal functions. Altered gene expression of mitochondrial genes has been described for schizophrenia and there is increasing evidence that antipsychotics such as clozapine and olanzapine may modulate mitochondrial function.
- antipsychotics such as clozapine and olanzapine may modulate mitochondrial function.
- nuclear-encoded mitochondrial genes particularly those with altered gene expression or involved in oxidative phosphorylation, mitochondrial biogenesis, inflammation and apoptosis, are more likely to be associated with AIWG. To the best our knowledge, this is the first study to explore genetic variation in the mitochondrial genes in the context of AIWG. In total, 60 SNPs were genotyped in 77 individuals.
- Table 7 Demographic and clinical characteristics of samples.
- SNPs were selected based on evidence of regulatory function. All SNPs with scores of If or greater in RegulomeDB (Dunham et ah, 2012) within lOkb upstream or downstream of TSPO were selected for genotyping
- Marker rs6973 located in the 3 ' UTR of TSPO, was also selected based on miRNA binding and regulatory potential from SNPinfo (Xu and Taylor, 2009). Selected SNPs captured 77% of common alleles across the TSPO gene region.
- Genotyping was done using Assays-on-Demand for all SNPS with the TaqMan allele specific assay method, using the Viia7 Sequence Detection System (Applied Biosystems, Foster City, CA, USA). PCR was performed in a final reaction volume of ⁇ , consisting of 20ng of genomic DNA, 2X TaqMan Universal Master Mix, and 40X SNP Genotyping Assay Mix (Applied Biosystems, Foster City, CA, USA), and amplification under the following conditions: 95°C for lOmin, followed by 50 cycles of 92°C for 15s and 60°C for lmin.
- Genotypes were determined with the Applied Biosystems allelic discrimination software, and confirmed independently by two experienced researchers. Genotype call rates were >95% for all eight markers. Replication was performed for a random sample of 10% of study subjects for quality control, with 100% concordant genotypes observed.
- rs6971 is a functional polymorphism and shows robust association with TSPO binding affinity, both in vitro (Owen et al., 2012) and in vivo (Mizrahi et al., 2012, Kreisl et al., 2013).
- the 'Thr' allele is associated with much lower TSPO binding affinity than the 'Ala' allele, and individuals homozygous for 'Thr' have little to no binding of TSPO-specific PET radioligands.
- previous studies have found no association between TSPO polymorphisms and schizophrenia diagnosis (Kurumaji et al., 2000, Fallin et al., 2005), this is the first study to investigate TSPO polymorphisms in association with AIWG.
- Genomic DNA was extracted from blood samples using the high-salt method (Lahiri and Nurnberger 1991). Single nucleotide polymorphisms (SNPs) were genotyped using TaqMan® SNP Genotyping Assays (rs806378, rsl6147 and rs489693; Applied Biosystems Inc, Foster City, CA) or using customized GoldenGate Genotyping Assays (rs 13429709, rs3134701 and rs4142972, Illumina, Inc. San Diego, CA, USA).
- SNPs Single nucleotide polymorphisms
- the total genetic risk score for each individual was then determined by adding genotypes at all the four loci leading to a score ranging from 0 (no-risk) to 8 (highest risk). This score was then entered as a factor in ANCOVA to determine the cumulative effect of these variants on AIWG.
- the above comparison was corrected for the effect of baseline weight and duration of treatment by using them as covariates.
- the risk model predicts weight gain only when subjects are treated with high weight gain risk medications (e.g. clozapine and olanzapine). These individuals should be treated with alternative antipsychotics having a low propensity for inducing weight gain in order to prevent unwanted weight gain.
- high weight gain risk medications e.g. clozapine and olanzapine.
- Table 14 Distribution of weight change (%) across risk score categories using three SNP combinations.
- Table 15 Distribution of weight change (%) across risk score categories using four or five SNP combinations
- Table 16 Distribution of weight change (%) across risk score categories using six, seven or eight SNP combinations
- Table 17 Analysis of the risk models associated with antipsychotic induced weight gain in subjects treated with antipsychotics with low weight gain risk.
- Table 18 Distribution of weight change (%) across risk score categories using pairwise combination between rs279858 in GABRA2 and SNPs in the AIWG model.
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WO2017059106A1 (en) * | 2015-09-30 | 2017-04-06 | Indivior Uk Limited | Psychiatric treatment for patients with gene polymorphisms |
US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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