EMPIRICAL QUANTITATIVE APPROACHES FOR PSYCHIATRIC DISORDERS PHENOTYPES

20090006001

12/164090

June 29, 2008

Psychiatric phenotypes as currently defined are primarily the result of clinical consensus criteria rather than empirical research. A novel approach to characterizing psychiatric phenotypes is presented herein, termed PhenoChipping. A massive parallel profiling of cognitive and affective state is done with a PhenoChip composed of a battery of existing and new quantitative psychiatric rating scales, as well as hand neuromotor measures. Phenotypic overlap among, as well as phenotypic heterogeneity within, the three major psychotic disorders studied were demonstrated. Empirically derived clusterings of (endo)phenotypes and of patients serve genetic, pharmacological, and imaging research, as well as clinical practice.

Niculescu, III, Alexander B. (Indianapolis, IN, US); Lohr, James B. (San Diego, CA, US)

INDIANA UNIVERSITY RESEARCH AND TECHNOLOGY CORPORATION (Indianapolis, IN, US), THE REGENTS OF THE UNIVERSITY OF CALIFORNIA (Oakland, CA, US)

1. A method of systematic phenotypic profiling of one or more individuals with psychiatric disorders to identify empirical relationships between phenotypic items (phenes) and the disorders, the method comprising: (a) identifying a plurality of psychiatric phenotypic items (phenes), wherein the phenes are quantitatively measured; (b) assigning a numerical value for one or more of the phenes; and (c) generating a phenotypic profile for the one or more individuals with psychiatric disorders based on a statistical analysis of the association of the phenes, wherein the phenotypic profile comprises empirical relationships between phenotypic items and the disorders.

2. The method of claim 1, wherein the psychiatric phenotypic items (phenes) are selected from the group consisting of psychiatric rating scales, biomarkers, brain imaging, electroencephalography (EEG), and other neurophysiological data.

3. The method of claim 1, wherein the plurality of phenes are FIL, FIR, LVS, RVS, SFGEN, SF-36, Simplified Mood Scale (SMS), Mood, Motivdo, Mvmtactv, Thnkactv, Selfestm, Interest, Appetite, TotMood, Simplified Anxiety Scale(SAS), Anxiety, Uncertnt, Fear, Anger, TotAnxty, TOTAFFECT, SMS+SAS, PANSS Items, PANSSPOS, PANSSNEG, PANSSGEN, Depression Scales, HAM-D17, HAM-D28, Mania Rating Scale, and YMRS.

4. The method of claim 1, wherein the phenes are derived from measuring Positive and Negative Symptoms Scale (PANSS) (with a positive symptom subscale-PANSSPOS, a negative symptom subscale-PANSSNEG, and a disorganization subscale-PANSSGEN); Hamilton Rating Scale for Depression (HAM-D 17 and HAM-D 28); Young Mania Rating Scale (YMRS); Medical Outcomes Study Short Form-36 (SF-36); Total Affective State Scale (TASS); and neurophysiological motor measures (VS-velocity scaling, and FI-force instability).

5. The method of claim 1, wherein the psychiatric disorders are selected from the group consisting of affective and psychotic disorders.

6. The method of claim 5, wherein the affective disorder is selected from the group consisting of bipolar, depression and anxiety and the psychotic disorder is selected from the group consisting of schizophrenia and schizoaffective disorders.

7. The method of claim 1, wherein the empirical relationships are obtained from a hierarchical clustering analysis.

8. The method of claim 1, wherein the numerial values are normalized using z-scoring.

9. A method of personalizing a psychiatric treatment plan of a subject based on phenotypic profiling, the method comprising: (a) obtaining a quantitiative psychiatric phenotypic profile of the subject comprising a plurality of psychiatric phenotypic items (phenes); (b) comparing the phenotypic profile of the subject to one or more reference psychiatric phenotypic profiles of one or more psychiatric disorders; and (c) selecting a psychiatric treatment plan based on the outcome of the comparison of the phenotypic profile of the patient with the reference psychiatric phenotypic profiles.

10. The method of claim 9, wherein the reference psychiatric phenotypic profiles are obtained from successful psychiatric treatments for psychiatric disorders.

11. The method of claim 9, wherein the plurality of psychiatric phenotypic items (phenes) is selected from the group consisting of psychiatric rating scales, biomarkers, brain imaging, electroencephalography (EEG), and other neurophysiological data.

12. The method of claim 10, wherein the the plurality of psychiatric phenotypic items (phenes) is selected from the group consisting of phenes listed in Table II.

13. The method of claim 9, wherein the reference psychiatric phenotypic profiles comprise psychiatric phenotypic profiles of a plurality of subjects and clinicopathological data selected from the group consisting of age, previous personal and/or familial history of psychiatric disorder, clinical response to psychiatric disorder, and any genetic or biochemical predisposition to psychiatric illness.

14. The method of claim 9, wherein the association between the phenotypic profile of the subject and the reference psychiatric phenotypic profiles is statistically significant.

15. A method of optimizing psychiatric drug discovery or clinical trials, the method comprising: (a) obtaining quantitative psychiatric phenotypic data for a first set of plurality of subjects in a first clinical trial, wherein the phenotypic data comprises a plurality of psychiatric phenotypic items (phenes); (b) obtaining clinical trial criteria data from the plurality of the subjects for a psychiatric drug; (c) generating quantitative psychiatric phenotypic profiles comprising one or more of the psychiatric phenotypic items for one or more of the clinical trial criteria, thereby identifying one or more phenes as surrogate markers for a clinical outcome; (d) obtaining quantitative psychiatric phenotypic data for a second set of plurality of subjects in a second clinical trial; and (e) selecting subjects from the second set if the quantitative psychiatric phenotypic data comprises one or more phenes from the first set such that the subjects from the second set are more likely to respond to the psychiatric drug in the second clinical trial.

16. The method of claim 15, wherein the clinical trials criteria are selected from the group consisting of responders/non-responders and side-effects/no side-effects to a psychiatric drug of interest.

17. The method of claim 15, wherein the phenotypic profiles comprise similarity assessed using a hierarchical clustering approach.

18. The method of claim 15, wherein the plurality of psychiatric phenotypic items (phenes) is selected from the group consisting of psychiatric rating scales, biomarkers, brain imaging, and neurophysiological data.

19. The method of claim 15, further comprising sequential enriching of subjects that are more likely to respond to the psychiatric drug based on one or more of phenes or one or more of the clinical trial criteria.

20. The method of claim 15, wherein the quantitative psychiatric phenotypic profiles identify subgroups of subjects associated with a category selected from the group consisting of clinical trial outcome to a new drug, response to a certain existing clinical treatment, and associated with a biomarker or groups of biomarkers.

21. A method of diagnosing a psychiatric disorder in an individual, the method comprising: (a) performing a systematic phenotypic profiling of the individual, wherein the phenotypic profiling is based on a plurality of quantitative psychiatric phenotypes; (b) comparing the phenotypic profiling of the individual to one or more reference phenotypic profiles for one or more psychiatric disorders; and (c) diagnosing the psychiatric disorder if the phenotypic profiling of the individual is statistically similar to one of the reference phenotypic profiles.

22. The method of claim 21, wherein the phenotypic profiling comprises one or more phenes selected from Table II and one or more scoring system selected from the group consisting of Positive and Negative Symptoms Scale (PANSS); a positive symptom subscale (PANSSPOS); a negative symptom subscale (PANSSNEG); a disorganization subscale (PANSSGEN); Hamilton Rating Scale for Depression (HAM-D 17 and HAM-D 28); Young Mania Rating Scale (YMRS); Medical Outcomes Study Short Form-36 (SF-36); Total Affective State Scale (TASS); VS-velocity scaling, and FI-force instability.

23. The method of claim 21, wherein the psychiatric disorder is selected from the group consisting of mood and psychotic disorders.

24. The method of claim 21, wherein the phenotypic profiling is selected from the group consisting of psychiatric rating scales, biomarkers, brain imaging, electroencephalography (EEG), fMRI, PET scans, and other neurophysiological data.

25. The method of claim 21, wherein the phenotypic profiling is based on quantitative measurements obtained through a questionnaire.

26. The method of claim 21, wherein the phenotypic profiling is based on quantitative measurements obtained through a clinical examination.

27. The method of claim 21, wherein the phenotypic profiling is based on quantitative measurements obtained through measurements of biomarkers in bodily fluids.

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