METHODS AND SYSTEMS FOR DETECTING PSYCHOTIC DISORDERS ASSOCIATED WITH SEROTONIN RECEPTOR DEFICIENCIES

Abstract

Methods for detecting psychotic disorders such as but not limited to schizophrenia or bipolar I disorder featuring administering to a patient a dose of an antipsychotic medication; and subjecting the patient to an evaluation at a time point following administration of the dose of the antipsychotic medication. The evaluation is adapted to determine responsiveness or sleepiness (or amount of sleep) resulting from the dose of the antipsychotic medication.

Claims

1. A method for detecting a psychotic disorder in a human patient, said method comprising: a. administering to the patient a dose of an antipsychotic medication; and b. subjecting the patient to an evaluation at a time point following administration of the dose of the antipsychotic medication, wherein if the patient is asleep for at least 30 minutes after administration then the patient does not have a psychotic disorder, wherein if the patient is asleep for less than 30 minutes, then the patient does have a psychotic disorder; and c. administering an anti-schizophrenia medication to the patient if the patient has a psychotic disorder.

2. The method of claim 1, wherein the antipsychotic medication is a first generation antipsychotic medication.

3. The method of claim 2, wherein the first generation antipsychotic medication is haloperidol, chlorpromazine, or a combination thereof.

4. The method of claim 1, wherein the antipsychotic medication is a second generation antipsychotic medication.

5. The method of claim 4, wherein the second-generation antipsychotic medication is ziprasidone or olanzapine.

6. The method of claim 1, wherein the antipsychotic medication comprises a selective 5-HT2AR antagonist.

7. The method of claim 1, wherein the time point following administration of the medication is from 5 to 10 minutes, from 10 to 30 minutes, from 15 to 60 minutes, from 5 to 120 minutes, from 10 to 180 minutes, or more than 180 minutes.

8. The method of claim 1, wherein if the patient is asleep for at least 1 hour after administration then the patient does not have a psychotic disorder.

9. The method of claim 1, wherein if the patient is asleep for at least 2 hours after administration then the patient does not have a psychotic disorder.

10. A method for detecting altered serotonin receptor levels or activity in a human patient, said method comprising: a. administering to the patient a dose of an antipsychotic medication; and b. subjecting the patient to an evaluation at a time point following administration of the dose of the antipsychotic medication, the evaluation is for determining a level of sedation resulting from the dose of the antipsychotic medication; wherein if the level of sedation is a score of 6, 7 or X according to Stanford Sleepiness Scale (SSS), a score of 15 or greater according to Chalder Fatigue Scale (CFM), or a score of 3 or 4 according to Pasero Opioid-Induced Sedation Scale (POSS), a score of less than 15 on the Glasgow Coma Scale (GCS), or a combination thereof, then the patient does not have altered serotonin receptor levels or activity, whereas if the level of sedation is a score of 1, 2, 3, or 4 according to Stanford Sleepiness Scale (SSS), a score of 0-12 according to Chalder Fatigue Scale (CFM), a score of 1 or 2 according to Pasero Opioid-Induced Sedation Scale (POSS), or a combination thereof, then the patient does have altered serotonin receptor levels or activity; and c. administering an anti-schizophrenia medication to the patient if the patient has altered serotonin receptor levels or activity.

11. The method of claim 10, wherein altered serotonin receptor levels or activity is: a deficiency in serotonin 2A receptor activity, a deficiency in serotonin 2A receptor levels, an elevation in serotonin 1A receptor activity, or an elevation in serotonin 1A receptor levels.

12. The method of claim 11, wherein a deficiency in serotonin 2A receptor activity is associated with schizophrenia or bipolar I disorder.

13. The method of claim 10, wherein the antipsychotic medication is a first generation antipsychotic medication.

14. The method of claim 13, wherein the first generation antipsychotic medication is haloperidol, chlorpromazine, or a combination thereof.

15. The method of claim 10, wherein the antipsychotic medication is a second generation antipsychotic medication.

16. The method of claim 15, wherein the second-generation antipsychotic medication is ziprasidone or olanzapine.

17. The method of claim 10, wherein the antipsychotic medication is a selective 5-HT2AR antagonist or a 5-HT2AR inverse agonist.

18. The method of claim 10, wherein the time point following administration of the medication is from 5 to 10 minutes, from 10 to 30 minutes, from 15 to 60 minutes, from 5 to 120 minutes, from 10 to 180 minutes, or more than 180 minutes.

19. The method of claim 10, wherein if the patient is asleep for at least 30 minutes after administration then the patient does not have a psychotic disorder.

20. The method of claim 10, wherein if the patient is asleep for at least 1 hour after administration then the patient does not have a psychotic disorder.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:

[0045] FIG. 1 shows EEG recordings of early growth response 3 knockout (Egr3KO, e.g., Egr3−/−) mice vs. wild type (WT) mice in response to clozapine (4 hour recording after high dose clozapine; EEG channels are upper two traces, EMG lower traces).

[0046] FIG. 2A shows representative sample EEG traces (20-min) from a wild type mouse (left) and an Egr3−/− mouse (right). Mice were spontaneously awake in undisturbed home cage conditions throughout the 20-minute interval. During dark phase.

[0047] FIG. 2B shows EEG state instability in Egr3-deficient mice. EEG beta (15-35 Hz) activity measured by FFT (in 10 sec epochs) of 20-min EEG recordings from a wild type mouse (red) and an Egr3−/− mouse (orange).

[0048] FIG. 2C shows averaged epoch-by-epoch change in beta activity across consecutive epochs of wake, and the active and quiet substates of wake, in wild type (red, n=12) and Egr3−/− (blue, n=13) mice. Values are normalized as a percent of absolute beta activity.

[0049] FIG. 3A shows the effect of Egr3 disruption on the electroencephalographic (EEG) power profiles of the wake state. Mean values+/−standard error of the mean in the 1 to 20 Hz and beta (15-35 Hz) range across the 24 h baseline recording are shown. Asterisks indicate significant differences between Egr3-deficient mice (n=15) and wild type mice (n=16). Sex differences were not detected.

[0050] FIG. 3B shows the effect of Egr3 disruption on the electroencephalographic (EEG) power profiles of the active wakefulness (AW) state. Mean values+/−standard error of the mean in the 1 to 20 Hz and beta (15-35 Hz) range across the 24 h baseline recording are shown. Asterisks indicate significant differences between Egr3-deficient mice (n=15) and wild type mice (n=16). Sex differences were not detected.

[0051] FIG. 3C shows the effect of Egr3 disruption on the electroencephalographic (EEG) power profiles of the quiet wakefulness (QW) state. Mean values+/−standard error of the mean in the 1 to 20 Hz and beta (15-35 Hz) range across the 24 h baseline recording are shown. Asterisks indicate significant differences between Egr3-deficient mice (n=15) and wild type mice (n=16). Sex differences were not detected.

[0052] FIG. 3D shows the effect of Egr3 disruption on the electroencephalographic (EEG) power profiles of the slow wave sleep (SWS) state. Mean values+/−standard error of the mean in the 1 to 20 Hz and beta (15-35 Hz) range across the 24 h baseline recording are shown. Asterisks indicate significant differences between Egr3-deficient mice (n=15) and wild type mice (n=16). Sex differences were not detected.

[0053] FIG. 3E shows the effect of Egr3 disruption on the electroencephalographic (EEG) power profiles of the rapid eye movement sleep (REMS) state. Mean values+/−standard error of the mean in the 1 to 20 Hz and beta (15-35 Hz) range across the 24 h baseline recording are shown. Asterisks indicate significant differences between Egr3-deficient mice (n=15) and wild type mice (n=16). Sex differences were not detected.

[0054] FIG. 4A shows latency to 2 minutes accumulated active wakefulness (AW) and quiet wakefulness (QW) in response to 6 hrs sleep disruption.

[0055] FIG. 4B shows time spent in AW and QW during session of 6 hrs sleep disruption (SD).

[0056] FIG. 4C shows progressive increase in slow wave activity (SWA; 1-4 Hz), theta (5-8 Hz), and beta (15-35 Hz) activity during quiet wakefulness over the time course of 6 hrs sleep disruption. The insets show the absolute EEG power.

[0057] FIG. 4D shows sleep intensity (SWA) during recovery sleep and time matched baseline condition. Asterisks indicate significant differences between Egr3-deficient mice (n=15) and wild type mice (n=16). Data are shown as mean values+/−standard error of the mean. Squares indicate significant differences compared to baseline level. P values indicate main effect of time (repeated-measures analysis of variance). Sex differences were not detected.

[0058] FIG. 5A shows latency to 2 minutes accumulated active wakefulness (AW) after vehicle or clozapine administration (in wild type mice+1+ and Egr3-deficient mice −/−).

[0059] FIG. 5B shows time spent in wakefulness and sleep after vehicle or clozapine administration (in wild type mice+1+ and Egr3-deficient mice −/−).

[0060] FIG. 5C shows slowing of the waking EEG (SWA; 1-4 Hz) during the 2 hr interval after clozapine administration. Data are shown as mean values+/−standard error of the mean. Asterisks indicate significant differences compared to vehicle treatment. Sex differences were not detected.

[0061] FIG. 6A shows latency to 2 minutes accumulated active wakefulness (AW) after 5-HT2 antagonists treatment (5 mg/kg) in Egr3-deficient mice (n=7) and wild type mice (n=8).

[0062] FIG. 6B shows time spent in active wakefulness after vehicle or 5-HT2 antagonist(s). Asterisks indicate significant differences compared to vehicle treatment.

[0063] FIG. 6C shows time spent in quiet wakefulness after vehicle or 5-HT2 antagonist(s). Asterisks indicate significant differences compared to vehicle treatment.

[0064] FIG. 6D shows waking EEG spectral power. “a” and “b” and asterisks indicate significant differences compared to vehicle treatment, 5-HT2A, 5-HT2BC or both antagonist, respectively. Sex differences were not detected.

DETAILED DESCRIPTION OF THE INVENTION

[0065] The present invention features methods for detecting or diagnosing psychotic disorders, e.g., psychotic disorders associated with deficiencies in serotonin 2A receptors/receptor activity (and/or increases in serotonin 1A receptors/receptor activity), e.g., schizophrenia, bipolar I disorder, etc. The present invention also features methods of distinguishing psychotic disorders, e.g., psychotic disorders associated with deficiencies in serotonin 2A receptors/receptor activity (and/or increases in serotonin 1A receptors/receptor activity) such as but not limited to schizophrenia, bipolar I disorder, etc., from other causes of psychosis. The present invention also features detecting resistance to sedative effects of particular drugs such as antipsychotic drugs.

[0066] As previously discussed, the methods may comprise administering a dose of an antipsychotic medication to an individual displaying signs or symptoms of a psychotic disorder associated with a deficiency in serotonin 2A receptors/receptor activity and/or increases in serotonin 1A receptors/receptor activity (e.g., schizophrenia, bipolar I disorder, etc.) and subjecting the individual to an evaluation adapted to determine the degree of sleepiness or sedation resulting from the dose of the antipsychotic medication. Without wishing to limit the present invention to any theory or mechanism, it is believed that the degree of sleepiness or sedation resulting from the dose of the antipsychotic medication may be able to be correlated with the presence of the psychotic disorder associated with a deficiency in serotonin 2A receptors/receptor activity and/or increases in serotonin 1A receptors/receptor activity (e.g., schizophrenia, bipolar I disorder, etc.). For example, a high resistance to the sedative/sleepiness side effects that are typically caused by the antipsychotic medication (e.g., lack of sedation) may be considered indicative of schizophrenia or indicative of a high probability of schizophrenia. Or, in some embodiments, a low resistance to the sedative/sleepiness side effects that are typically caused by the antipsychotic medication (e.g., complete sedation) may be considered indicative that the individual does not have schizophrenia (or bipolar I, etc.) or indicative of a high probability that the individual does not have schizophrenia (or bipolar I, etc.).

[0067] In some embodiments, the antipsychotic medication comprises: clozapine, an appropriate derivative of clozapine, a second-generation antipsychotic, a selective 5-HT2AR antagonist (e.g., M100907 (Volinanserin)), an appropriate derivative of the selective 5-HT2AR antagonist, a 5-HT2AR inverse agonist (e.g., pimavanserin (APC-103), a derivative thereof, ziprasidone, olanzapine, or the like. The present invention is not limited to the aforementioned medications.

[0068] In some embodiments, the evaluation comprises a physical examination (or a physical stimulation). In some embodiments, the evaluation comprises a questionnaire. The present invention is not limited to the aforementioned types of evaluations and may include any other appropriate types of evaluations or combinations of types of evaluations. A physical examination may include measuring pulse, respiratory rate, blood pressure, oxygen saturation, the like, or a combination thereof. In some embodiments, the physical examination comprises subjecting the patient to a stimulus and measuring the response to the stimulus, e.g., to determine arousability, responsiveness, alertness, etc. For example, in some embodiments, the patient is subjected to a sternal rub. In some embodiments, the patient is subjected to nail bed pressure. In some embodiments, the patient is subjected to smelling salts. In some embodiments, failure to arouse after a sternal rub is indicative of complete sedation (or significant sedation, etc.). In some embodiments, failure to arouse after nail bed pressure is indicative of complete sedation (or significant sedation, etc.). In some embodiments, failure to arouse after smelling salts is indicative of complete sedation (or significant sedation, etc.).

[0069] In some embodiments, the examination comprises asking the patient to open his/her eyes for a period of time (e.g., 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, more than 60 seconds, 0 to 5 seconds, 5 to 10 seconds, 5 to 15 seconds, 10 to 30 seconds, 10 to 60 seconds, the like, etc.). In some embodiments, failure to keep the eyes open for that period of time is indicative of complete sedation (or significant sedation, etc.).

[0070] In some embodiments, complete sedation (or significant sedation) is indicative of a lack of schizophrenia or indicative of a high probability of lack of the psychotic disorder associated with a deficiency in serotonin 2A receptors/receptor activity and/or increases in serotonin 1A receptors/receptor activity (e.g., schizophrenia, bipolar I disorder, etc.). In some embodiments, lack of complete sedation or lack of significant sedation (e.g., resistance to sedative effects of the medication) is indicative of the psychotic disorder associated with a deficiency in serotonin 2A receptors/receptor activity and/or increases in serotonin 1A receptors/receptor activity (e.g., schizophrenia, bipolar I disorder, etc.) or indicative of a high probability of the psychotic disorder associated with a deficiency in serotonin 2A receptors/receptor activity and/or increases in serotonin 1A receptors/receptor activity (e.g., schizophrenia, bipolar I disorder, etc.).

[0071] In some embodiments, the patient is evaluated using a questionnaire. In some embodiments, the questions are used to help determine sleepiness or sedation levels. In some embodiments, the time needed for the patient to respond to various questions is used to help determine sleepiness or sedation levels. In some embodiments, the overall level of attention of the patient is assessed to help determine sleepiness or sedation levels.

[0072] The present invention is not limited to the aforementioned means of measuring sleepiness or sedation. For example, in some embodiments, the Stanford Sleepiness Scale (SSS), the psychomotor vigilance task (PVT), the Epworth Sleepiness Scale (ESS), the Chalder Fatigue Scale (CFM), the Fatigue Severity Scale (FSS), the Pasero Opioid-Induced Sedation Scale (POSS), Pasero Opioid-Induced Sedation Scale (POSS), Glasgow Coma Scale (GCS), the like, or a combination thereof used to help assess sleepiness or sedation.

[0073] In some embodiments, the method comprises evaluating a biological sample (e.g., blood or other appropriate biological sample) of the individual. For example, in some embodiments, the method comprises assessing peripheral levels of the serotonin 2A receptor. In some embodiments, the method comprises assessing peripheral levels of the serotonin 1A receptor. The results of the biological sample evaluation may be correlated with a diagnosis of schizophrenia as appropriate.

[0074] In some embodiments, the method comprises subjecting the patient to a positron emission tomography (PET) scan, e.g., to evaluation levels of brain serotonin 2A receptor (5-HT2AR) and/or serotonin 1A receptor (5-HT1AR). In some embodiments, the method comprises subjecting the patient to an electroencephalogram (EEG) (e.g., waking and sleep, at baseline, following antipsychotic administration, etc.). Data from these tests may be used to help determine a diagnosis of schizophrenia.

[0075] The present invention also features a kit comprising the dose of the medication. In some embodiments, the kit further comprises a questionnaire. In some embodiments, the kit further comprises a set of instructions for evaluating the patient.

[0076] For reference, FIG. 1, FIG. 2A, FIG. 2B, FIG. 2C, FIG. 3A, FIG. 3B, FIG. 3C, FIG. 3D, FIG. 3E, FIG. 4A, FIG. 4B, FIG. 4C, FIG. 4D, FIG. 5A, FIG. 5B, FIG. 5C, FIG. 6A, FIG. 6B, FIG. 6C, and FIG. 6D together show data showing differences between Egr3 deficient mice (knock out (KO) mice) and wild type mice (WT), e.g., differences in EEG recordings between Egr3 KO mice compared to WT mice in response to clozapine administration (and show differences in epoch-by-epoch beta activity of the two types of mice). For example, FIG. 1 shows that there can be a marked difference in the pattern of response to clozapine in Egr3 KO mice. Without wishing to limit the present invention to any theory or mechanism, it is believed that there is a correlation between susceptibility to sedation in schizophrenic patients (or in animal models that may attempt to simulate schizophrenia or schizophrenia-like conditions). This may be used to help distinguish schizophrenia from other causes of psychosis, e.g., psychiatric illnesses (e.g., bipolar II disorder, major depression with psychotic features, delusional disorder, PTSD), medical illnesses (e.g., delirium, toxicity of a drug, imbalance of electrolytes, hormones, other metabolic disturbances, infection, etc.), effects of drugs or alcohol, etc.

[0077] FIG. 3A, FIG. 3B, FIG. 3C, FIG. 3D, FIG. 3E, FIG. 4A, FIG. 4B, FIG. 4C, FIG. 4D, FIG. 5A, FIG. 5B, FIG. 5C, FIG. 6A, FIG. 6B, FIG. 6C, and FIG. 6D investigate sleep and waking behavioral phenotypes in Egr3-deficient mice associated with serotonin receptor 5-HT2 deficits. FIG. 3A-3E shows the effect of Egr3 disruption on the EEG power profiles of different wake and sleep states. FIG. 4A-4D show responses to sleep disruption. FIG. 5A-5O show clozapine-induced changes in waking and sleep in Egr3-deficient mice and wild type mice. FIG. 6A-6D show changes in waking after 5-HT2 antagonists treatment in Egr3-deficient mice.

[0078] In some embodiments, the evaluation for determining the level of sedation comprises using a Bispectral Index (derived from an EEG-related algorithm). For example, the Bispectral Index (BIS) is a scale of sedation from 0 to 100, wherein 100 is awake and 0 is a flatline EEG. In some embodiments, a high level of sedation is a BIS of 80 or less. In some embodiments, a high level of sedation is a BIS of 70 or less. In some embodiments, a high level of sedation is a BIS of 60 or less. In some embodiments, a high level of sedation is a BIS of 50 or less. In some embodiments, a low level of sedation (e.g., a level of sedation towards no sedation) is a BIS of 70 or more or 80 or more. In some embodiments, a low level of sedation is a BIS of 90 or more. Other sleepiness scales or methods for determining levels of sedation may be correlated with the BIS scale.

[0079] High levels and low levels of sedation are well known to one of ordinary skill in the art and recognized by presentation, e.g., a high level of sedation is that when a patient does not respond to verbal stimulus and/or physical stimulus or the patient is in a deep hypnotic state. A low level of sedation may be that when a patient is awake and can respond to verbal stimuli. The present invention is not limited to the aforementioned examples of sedation levels.

Example 1

[0080] Example 1 describes an example of research used to help determine parameters for determining the level of sleepiness or sedation (or lack thereof) that is associated with schizophrenia or a lack of schizophrenia. EEG patterns in patients recently diagnosed with schizophrenia or schizophrenia-like disorders will be compared at baseline and after a typical dose of clozapine (or other antipsychotic medication). Subjects will undergo one to 5 hours of continuous videotaped EEG monitoring. Before and after drug administration, patients' somnolence will be rated using the Stanford Sleepiness Scale (SSS) and the Psychomotor Vigilance Task (PVT) (or other scale, e.g., ESS, CFM, FSS, POSS, etc.). Baseline and post-antipsychotic administration EEG and EMG recordings during both sleep and awake states will be read. Statistical analyses will be conducted to identify correlations between EEG response, scores on sedation assessments, and clinical diagnosis.

Example 2

[0081] Example 2 describes an example of research used to help determine parameters for determining the level of sleepiness or sedation (or lack thereof) that is associated with schizophrenia or a lack of schizophrenia. EEG patterns in patients recently diagnosed with schizophrenia or schizophrenia-like disorders will be compared at baseline and after a typical dose of medication (e.g., ziprasidone, olanzapine, the like, combinations thereof, e.g., antipsychotics with receptor binding profiles designed to mimic the serotonin 2A receptor and dopamine D2 receptor binding profile of clozapine, etc.). Subjects will undergo 1 hour of continuous EEG monitoring (e.g., including continuous observation by at least one individual) before medication administration and 4 hours of continuous EEG monitoring (e.g., including continuous observation by at least one individual) after medication administration. Before and after drug administration, patients' somnolence or sedation may be rated using the a scale, e.g., the Stanford Sleepiness Scale (SSS), the Psychomotor Vigilance Task (PVT), the ESS, the CFM, the FSS, the POSS, the like, combinations thereof, etc. Baseline and post-medication recordings during both sleep and awake states will be read. Statistical analyses will be conducted to identify correlations between EEG response, scores on sedation assessments, and clinical diagnosis.

Example 3

[0082] A 35-year-old male presents to the emergency department complaining of hallucinations. The attending physician requests a psychiatry consult. The psychiatrist orders a test according to the present invention: the patient is administered a dose of olanzapine at time zero; one hour following the administration of the medication, the nurse evaluates the patient. The evaluation comprises the following tests: (a) respiratory rate measurement; (b) oxygen saturation measurement; and (c) pulse measurement. Since the patient appears relatively alert, the evaluation also comprises an eye test wherein the patient is asked to keep his eyes open for 10 seconds. The patient's respiratory rate, oxygen saturation, and pulse are not significantly altered by the administration of the medication. The patient has no difficulty keeping his eyes open for more than 10 seconds. Based on the results of the evaluation, the psychiatrist diagnoses the patient with a high probability of having schizophrenia. The psychiatrist makes medication decisions based upon the results of this test.

Example 4

[0083] A 27-year-old female presents to the emergency department complaining of disorganized speech and abnormal motor behavior. The attending physician requests a psychiatry consult. The psychiatrist orders a test according to the present invention: the patient is administered a dose of olanzapine at time zero; one hour following the administration of the medication, the nurse evaluates the patient. The evaluation comprises the following tests: (a) respiratory rate measurement; (b) oxygen saturation measurement; and (c) pulse measurement. Since the patient appears sedated, the evaluation also comprises a sternal rub and an eye test wherein the patient is asked to keep her eyes open for 10 seconds. Respiratory depression is observed, as is a decrease in pulse. The patient is barely aroused by a sternal rub. She is unable to keep her eyes open for more than 3 seconds. Based on the results of the evaluation, the psychiatrist diagnoses the patient with a high probability of not having schizophrenia.

Example 5

[0084] Twenty patients enroll in a study to assess levels of sleepiness after taking certain antipsychotic drugs.

[0085] Two patients receive 20 mg ziprasidone, two patients receive 40 mg ziprasidone, and two patients receive 60 mg zipradisone. Two patients receive 2.5 mg olanzapine, two patients receive 5 mg olanzapine, two patients receive 7.5 mg olanzapine, and two patients receive 10 mg olanzapine. Six patients receive placebo.

[0086] The patients remain in the clinic for at least four hours while research assistants assess the level of sleepiness of the patients. A questionnaire is given every hour for four hours.

Example 6

[0087] A 45-year-old female presents to the emergency department complaining of disorganized speech and abnormal motor behavior. The attending physician requests a psychiatry consult. The psychiatrist orders a test according to the present invention: the patient is administered a dose of olanzapine at time zero; one hour following the administration of the medication, and the patient is evaluated. One hour after administration of the drug, she is unable to keep her eyes open and falls asleep for 1 hour. Based on the results of the evaluation, the psychiatrist diagnoses the patient with a high probability of not having schizophrenia.

Example 7

[0088] A 35-year-old female presents to the emergency department complaining of disorganized speech and abnormal motor behavior. The attending physician requests a psychiatry consult. The psychiatrist orders a test according to the present invention: the patient is administered a dose of a first generation antipsychotic at time zero; one hour following the administration of the medication the patient is evaluated. One hour after administration of the drug, she is unable to keep her eyes open and falls asleep for 30 minutes. Based on the results of the evaluation, the psychiatrist diagnoses the patient with a high probability of not having schizophrenia.

[0089] The disclosures of the following documents are incorporated in their entirety by reference herein: Williams et al., 2012, Neuropsychopharmacology 37:2285-2298; Gallitano-Mendel et al., 2008, Neuropsychopharmacology 33:1266-1275; McOmish et al, 2012, Neuropsychopharmacology 37:2747-2755; Maple et al., 2015, ACS Chem Neurosci (7):1137-42; Gronli et al., 2016, Sleep 39(12):1-11.

[0090] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety.

[0091] Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims. Therefore, the scope of the invention is only to be limited by the following claims. Reference numbers recited in the claims are exemplary and for ease of review by the patent office only, and are not limiting in any way. In some embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some embodiments, descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting of”, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting of” is met.