WO2004014429A1 - Regulator for mental disease risk fragility - Google Patents

Abstract

Paying attention to the risk fragility mechanism of the brain, it is intended to provide a remedy for mental diseases which covers deficiencies in the existing psychotropics and exhibits a novel function mechanism. More specifically speaking, there is found out a novel remedy for mental diseases having a novel mechanism which comprises regulating progressive disturbance in brain function corresponding to the risk fragility in a mental disease showing an undulatory appearance and progress pattern, thus continuously stabilizing stress responses in the remission stage and inhibiting the reoccurrence of symptoms. Then it is found out that this remedy is useful in treating integration disorder syndrome (schizophrenia), amphetamine-induced mental disease, manic-depression and so on. Namely, a remedy for mental diseases showing an undulatory appearance and progress pattern which comprises as the main ingredient a compound exhibiting an effect of regulating progressive disturbance in brain function corresponding to the risk fragility.

Description

Description ^j Mental illness onset vulnerability control agent

Technical field

 The present invention relates to a drug for treating mental disorders having a novel mechanism of action. More specifically, the present invention relates to a therapeutic agent for a mental disease in which symptoms show a wavy appearance progression pattern with the progression of cerebral dysfunction corresponding to the mental disease onset vulnerability. Another aspect of the present invention is to provide a method for screening a therapeutic drug for a mental disease in which symptoms are accompanied by a progression of cerebral dysfunction corresponding to psychiatric disease onset vulnerability, and the symptoms show a wavy appearance pattern. The present invention relates to a novel compound or a therapeutic agent for a psychiatric disorder, which is used as a marker for the control of progressive cerebral dysfunction corresponding to onset vulnerability, and to a novel compound or a therapeutic agent for a mental disorder that is screened.

Background art

 Conventionally, the main development index of therapeutic drugs for schizophrenia (schizophrenia, schizophrenia, Schizophrenia) has been the inhibitory effect on so-called positive symptoms expressed as hallucinations and delusional states. Emphasis has been placed on the antagonism of behavioral changes elicited by the acute pharmacological effects of dopamine-based direct or indirect agonists, such as amphetamines. Indeed, while antipsychotics developed with these indices show good improvement in positive symptoms, high relapse rates are a problem (Marder SR. Antipsychotic drugs and relapse prevention.Schizophr Res 35, S87.S92, 1999).

This means that even in remission, improved vulnerability is achieved in many patients. It suggests that the drug has not been used, suggesting a weakness of existing antipsychotics. Laruelle showed an increase in dopamine release by amphetamine in patients with acute schizophrenia, but no difference from the normal control group in remission. The role of endogenous rehabilitation is shown to be possible, and it is necessary to replace therapies with an index of symptom suppression in the acute phase to prevent recurrence (Laruelle M. The role of endogenous sensitization m the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Rev 31, 371-384, 2000

 The main cause of schizophrenia (schizophrenia, schizophrenia, Schizophrenia) is due to the vulnerability of the brain in the early stages of the disease. It is formed. Experiencing a psychotic episode during the illness phase is then fed back to maintaining 'vulnerability' after the illness and prepares for a relapse. Such a system is known as a schizophrenia stress vulnerability modenole (Ciompi L. The dynamics of complex bio 丄 ogical-psychosocial systems: Four fundamental psycho-biological mediators in the long-term. Br J Phsychiatry 155,15- 21, 1989).

 No existing antipsychotic drug has achieved such control of the vulnerability of the brain to developing mental illness. Existing antipsychotics generally have poor long-term prognosis and poor quality of life (QOL). Disclosure of the invention

 The present invention is intended to provide a therapeutic agent for a mental disease which compensates for the drawbacks of existing antipsychotics and carries a novel mechanism of action, by focusing on the mechanism of cerebral disease onset vulnerability as described above.

The present invention stably stabilizes the stress response in remission by controlling progressive cerebral dysfunction corresponding to psychiatric disease onset vulnerability to mental illness whose symptoms show a wavy appearance course pattern, Mental illness consisting of a novel mechanism to suppress relapse of symptoms We discovered a new drug for the treatment of the disease, and completed the present invention because this drug is useful for the treatment of schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, and manic depression.

 That is, the present invention

 1. Therapeutic treatment for mental illness in which a compound mainly comprising a compound that has a function of controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness has a wavy pattern of appearance.

2. The therapeutic drug for psychiatric disorders according to 1 above, wherein the control of progressive cerebral dysfunction corresponding to vulnerability to mental illness onset is suppression of cerebral dysfunction equivalent to vulnerability.

 3. A drug is administered in a model animal to cause a progressive cerebral dysfunction corresponding to the vulnerability to the onset of mental illness, and then the candidate compound is administered during the drug withdrawal period, resulting in a subsequent stress load. In contrast, the compound described in the above item 1 or 2 mainly comprising a compound having a pharmacological effect of specifically preventing the formation of behavioral sensitization, which is an indicator of progressive cerebral dysfunction equivalent to the vulnerability to mental illness development Remedies for mental illness,

 4. The therapeutic drug for a psychiatric disorder according to the above item 3, wherein the administration means is administration of an amphetamine compound,

 5. The stress treatment according to the above 3 or 4, wherein the stress load is selected from amphetamine compound administration, apomorphine administration, fleafensin administration, other direct or indirect dopamine agonist administration, and tail cribing.

 6.The mental disease according to any one of the preceding items 1 to 5, wherein the mental disease exhibiting a wavy appearance pattern is schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, manic depression, or autism. Therapeutics for diseases,

 7. The therapeutic agent for a psychiatric disease according to any one of the above items 1 to 6, wherein the compound is a 5-HT3 receptor blocker,

 8.5—The therapeutic agent for a psychiatric disorder according to the preceding clause 7, wherein the HT 3 receptor blocker is ondansetron,

9. Markers for controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness A novel compound or a disease symptom characterized by a wavy appearance course pattern, a screening method of a therapeutic drug for mental illness,

 10. The screening method according to the preceding clause 9, wherein the control of progressive cerebral dysfunction corresponding to vulnerability to mental illness development is suppression of fragile progressive cerebral dysfunction.

 1 1. A drug is administered in a model animal in which a progressive cerebral dysfunction corresponding to psychiatric illness vulnerability is induced, and then the candidate compound is administered during the drug withdrawal period. Select the compound that has a pharmacological effect that specifically prevents the development of behavioral sensitization that is an indicator of progressive cerebral dysfunction equivalent to the fragility of mental illness in response to stress load. The described screen Jung method,

 12. The screening method according to 11 above, wherein the administration means is administration of an amphetamine compound,

 13. The screening according to item 11 or 12, wherein the stress load is selected from amphetamine compound administration, apomorphine administration, nomifu: cinsin administration, other direct or indirect dopamine agonist administration, and tail clipping. Law,

 14. A novel compound obtained by the screening method according to any one of the above items 9 to 13, or a therapeutic drug for a mental disease, wherein the disease symptom shows a wavy appearance course pattern. BRIEF DESCRIPTION OF THE FIGURES

 (Figure 1 )

 The dosing schedule was indicated.

 (Figure 2 )

The behavior evaluation results are shown. Effect of haloperidol, clozapine, and ondansetron given during MAP withdrawal on MAP-induced behavioral sensation. Numerical values are shown as mean soil standard error (n = 10). ** p <0.01, *** p <0.001vs each saline pre-treatment group (t-test), † p <0.05, 卞 By p <0.001vs MAP-haloperidol group (Tukey test). NS, no statistical significance. BEST MODE FOR CARRYING OUT THE INVENTION

'Provision of a therapeutic agent for mental illness comprising the novel mechanism of the present invention was achieved by a neuroscience approach to a stress vulnerability model. That is, at least some of the feed-forward and feed-back loops in schizophrenia (schizophrenia, schizophrenia) are neuroplastic changes common to stimulant psychosis, and Neuroplastic changes in stimulant psychosis are based on the reproducibility of behavioral sensitization in experimental animals. In schizophrenia, a healthy person responds to a small amount of a central stimulant such as amphetamines that does not cause a psychotic condition, and responds to a psychostimulant, and responds sensitively to psychosocial stress. Vulnerability is recognized (Lieberman JA, Seitman BB, Kmon Bd. Neurochemical sensitization in the pathophysiology of schizophrenia: Deficits and dysfunction in neuronal regulation and plasticity. Ne et al. Psychopharmacology 17, 205.229, 1997). Similarly, in stimulant psychosis (Amphetamine Psychosis or Methamphetamine Psychosis), a mental illness is induced in response to a central stimulant more sharply than in a healthy person, and psychosis not recognized in a healthy person by psychosocial stress. A relapse of the state occurs (Sato M, Chen CC, Aki ama K, Otsuki S. Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis. Biol Psychiatr 18, 429-440, 1983.). In experimental animals, once they experience subchronic administration of amphetamines, their behavioral susceptibility to central stimulants they experience increases, and small amounts of the drug cause strong behavioral changes not seen in normal animals. In addition, physical stress loading without drugs causes stress response behavior that is not observed in normal animals (Vanderscuren LJMd, Kaiivas PW. Alternations m dopaminergic and gl tamatergic transmission in the induction and expression of behavioral sensitization; a critical review of preclinical studies. Psychopharmacology 151, 99-120, 2000.). Therefore, neurological changes similar to psychiatric vulnerability in schizophrenia are awake It is presumed that this also occurs in drug psychosis, and it can be judged that cerebral dysfunction corresponding to this vulnerability to mental illness can be experimentally evaluated by subchronic administration of amphetamines to experimental animals.

 Based on the above recognition, the present inventors hypothesized that an experimental animal model for the control of onset vulnerability in mental illness in which the symptoms show a wavy appearance pattern was used in pharmacology during multiple administration of stimulant and stimulant withdrawal period. The relationship between control and relapse of cerebral dysfunction equivalent to mental illness vulnerability was established as an animal model. Using this system, a compound that specifically regulates the cerebral dysfunction equivalent to the fragility to develop mental illness was evaluated, and a therapeutic agent for psychiatric illness having a novel mechanism of action was provided to complete the present invention.

 In the present invention, the cerebral dysfunction corresponding to the psychiatric disease onset vulnerability means the progression of weakening of the psychosis state relapse resistance based on the long-lasting change of the biological function caused by the psychotic state experience. Progression means greater vulnerability and less resistance. The effect of controlling this is, for example, that a drug means for causing progressive cerebral dysfunction corresponding to vulnerability to the onset of mental illness in an animal model system is administered, and thereafter, the candidate compound during the drug withdrawal period of the drug means is This can be confirmed by the presence or absence of a pharmacological effect that prevents the formation of behavioral sensitization, which is an index of progressive cerebral dysfunction equivalent to the fragility of mental illness, in response to stress after drug administration. A compound selected from the candidate compounds based on the presence or absence of such a pharmacological effect can be a therapeutic drug for a psychiatric disorder in which the disease symptom shows a wavy appearance course pattern.

The dosing means in which a progressive cerebral dysfunction corresponding to the fragility of mental illness is induced is performed, for example, by subcutaneous or intraperitoneal administration of an amphetamine compound (eg, amphetamine, methamphetamine). The means varies depending on the model animal.For example, if the animal model is a rat, 0.5 to 10 mg / kg body weight / day for 3 days to several weeks (3 to 5 days in some cases, Or several times (3 to 5 times) over 10 days to 2 weeks). This medication introduces a cause of progressive brain dysfunction corresponding to mental illness vulnerability, and it is presumed that the cerebral dysfunction equivalent to fragility progresses after discontinuation of the medication, that is, during drug withdrawal. You. The therapeutic agent for a psychiatric disorder according to the present invention is specifically selected because it exerts its efficacy by administering the candidate compound during the drug holiday. Therefore, it has the ability to control the progression of cerebral dysfunction equivalent to mental illness vulnerability, and antagonizes the increased vulnerability to progression during the remission period of mental illness. Candidate compounds are dependent on the individual drug, but are generally 0.05 mg to 3 O mg / kg body weight per day for 3 days to several weeks (3-5 days or 10 days depending on the case). (2 to 2 weeks) multiple times (3 to 5 times).

 Complete withdrawal for 3 days to several weeks (3 to 5 days, or 10 days to 2 weeks, depending on the case) after administration of the candidate compound (cerebral dysfunction corresponding to vulnerability to mental illness is induced Neither medication nor medication of psychiatric drug candidates is administered), and then stress is applied. For the stress load, rather mild means of administration, for example, in which progressive cerebral dysfunction corresponding to mental illness fragility is elicited, is sufficient (1/10 to 1/10 in the case of administration of amphotamine compounds). ), Apomorphine administration, fomifensin administration, other direct or indirect dopamine agonist administration, and clipping of the tail may be used. The pharmacological effect of the candidate compound on the progression of cerebral dysfunction equivalent to vulnerability to mental illness, depending on whether it acts to suppress or promote the establishment of behavioral sensitization (eg, locomotor activity) of the model animal to this stress load Is checked.

Thus, a compound having a pharmacological effect of controlling the brain dysfunction corresponding to the onset vulnerability to mental illness and preventing its progression is effective against a mental illness in which the symptoms show a wavy appearance pattern. The therapeutic agent for psychiatric disorders according to the present invention suppresses the cerebral dysfunction equivalent to the vulnerability to the onset of mental illness, and suppresses the stress during the remission phase of psychiatric illness for mental illness in which the symptoms show a wavy pattern. It has the effect of stabilizing the response continuously and suppressing the relapse (relapse) of symptoms. It is known that the mental illness that shows a wavy pattern of appearance is generally schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, manic depression, or autism. Therapeutic agents for psychiatric disorders consisting of compounds that have a mechanism of action such as It is useful as a treatment for schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, manic depression, or autism.

 The remedy for psychiatric disorders of the present invention can be referred to as a psychiatric disorder onset vulnerability control agent or a psychiatric disorder remission stabilizing drug, and prevents relapse by being administered during the remission phase of psychiatric disorders. As the administration method, generally known oral and parenteral preparations are prepared by pharmaceutical improvement, but oral administration is preferable due to its function as a prophylactic agent. The dose is determined by the correlation between the optimal dose of each candidate compound and the ability to suppress the progression of fragility of mental illness and toxicity. Generally, for oral use, 0.01 to lmg / kg is envisaged.

In the present invention, as a result of analysis using the above system (stimulant-induced abnormal behavior), a 5-HT ₃ receptor blocker is a compound having an effect of controlling the progression of brain dysfunction corresponding to onset vulnerability, However, it has been confirmed that it may be a therapeutic agent for mental illness showing a wavy appearance progress pattern. The Exemplary 5-HT ₃ receptor blocker but Onda Nsetoron is illustrated as concrete, are also included in the present invention a novel 5-HT ₃ receptor blocker later developed.

The present invention clarified the relationship between the effect of controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness onset and a therapeutic agent for mental illness in which the disease symptom shows a wavy appearance pattern. The use of a marker as a marker for controlling the progressive cerebral dysfunction corresponding to disease onset vulnerability is useful as a screening method for a novel compound or a therapeutic drug for a psychiatric disorder in which the disease symptom shows a wavy appearance course pattern. This involves the application of medications that cause progressive cerebral dysfunction equivalent to the above-mentioned psychiatric disease vulnerability, the administration of candidate compounds during this drug withdrawal, and the re-stressing and response to stress. It is possible to make a car and screen-jung. As a suitable system, there can be used a model system in which a cerebral illness that is susceptible to mental illness and progressive brain dysfunction is caused by multiple administration of an amphetamine compound to a mammal. Thus, a novel compound obtained by such a screening method or a therapeutic drug for a psychiatric disorder in which the disease symptoms show a wavy appearance progress pattern is provided. (Example)

 Hereinafter, the present invention will be described in detail with reference to Examples, which are representative examples, and the present invention is not limited to these Examples. Example 1

 (experimental method)

 Materials and methods

 Dosing and evaluation were performed based on the experimental schedule in FIG. Wistar male rats (n = 10) were treated with methamphetamine (MAP: 2.0 mg / kg body weight) once a day for 10 days from the age of 24 days after birth (physiological saline used as a MAP solvent as a control). ) Was administered subcutaneously. Thereafter, the MAP administration was suspended for 20 days, while the candidate compound was continuously administered for 10 days. The administered compounds were haloperidol (1.0 mg / kg body weight), clozapine (20 mg / kg body weight), ondansetron (ondansetoron) (0.1 mg / kg body weight), control (vehicle: A saline solution containing 0.1 NHCL used as a solvent and the pH was adjusted to near neutral with NaOH) was intraperitoneally administered once a day. After a further drug-free period of 10 days, all animals were subcutaneously administered a small amount of methamphetamine (0.16 mg / kg) again on day 31 (54 days after birth). Behavior (spontaneous locomotor activity) for 20 minutes after administration was measured and evaluated as the number of light passages in a transparent breeding cage using a small animal locomotion measurement system (Merquest, Toyama).

Behavioral evaluation (spontaneous movement) was performed by statistical analysis as follows. Spontaneous locomotor data was used for each drug treatment to detect the Si echo of the drug treatment (haloperidoL clozapine ^ ondansetron or vehicle Tia 'administration) on the effect of pretreatment (saline or MAP subchronic administration). There was no t-test, and the presence or absence of a sense of behavior under each drug treatment condition was individually determined. If the effect of drug treatment was found, multiple comparisons using Tukey's test were performed for each saline or MAP pretreatment, and the significance of the difference between drug treatments was determined. As a result of the evaluation, in the vehicle-treated animals as controls, the spontaneous locomotion induced by the MAP challenge was significantly increased in the MAP pretreatment group compared to the saline pretreatment group, It was confirmed that a feeling of behavior was created by subchronic administration of P. In the animals treated with haloperidol and clozapine, sensitization of MAP behavior was similarly achieved, whereas in animals treated with ondansetron, MAP sensitization was not observed. Furthermore, haloperidol treatment significantly increased the motility induced by the MAP behavioral animals as compared to the vehicle treatment group, while the haloperidol treatment significantly increased the saline pretreatment animals between the drug treatment groups. No differences were detected, indicating that haloperidol treatment enhanced MAP behavioral sensitization (Figure 2).

 Haloperidol and clozapine, which are typical examples of typical and atypical antipsychotics, are both sensitized to cerebral dysfunction, a model of cerebral dysfunction equivalent to onset vulnerability when administered during the discontinuation period after MAP subchronic administration It was suggested that these antipsychotics could antagonize the positive symptoms in the acute phase, but could not be expected to improve the vulnerability of the disease, although they could be antagonized. It has been reported that the atypical antipsychotic clozapine has a lower recurrence rate than the typical antipsychotic haloperidol, but in this study, haloperidol administered during the withdrawal period caused behavioral sensitization. Rather, it was shown to be a factor in the high recurrence rate in haloperidol-treated patients as well as poor compliance as well as increased vulnerability to development.

 In this study, ondansetron, a 5-HT 3 receptor blocker, prevented the onset of behavioral sensitization that progressed during MAP withdrawal. Industrial applicability

Based on the above data, the present inventor has established the concept of a remission-phase stabilizing agent, a psychostabilizer, as a new type of therapeutic agent for psychiatric disorders that compensates for the disadvantages of existing antipsychotics. In other words, as in the protocol used in this study, the administration during the withdrawal period after subchronic administration of amphetamines inhibits the development and establishment of behavioral sensitization. Drugs that are effective are schizophrenia (schizophrenia, schizophrenia,

Schizophrenia) and stimulant psychiatric psychiatric drugs that antagonize the onset of developmental vulnerabilities that progress during the remission phase and that prevent relapse while maintaining a high quality of life (QOL) are not found in existing antipsychotic drugs The effect can be expected. Thus, the present invention provides a therapeutic agent for a psychiatric disorder having a novel mechanism of action, and a cerebral disease-equivalent progressive brain using a model animal system involved in a psychiatric disorder showing a wavy pattern of appearance with the progression of the onset vulnerability. To provide a screening method for a novel compound or a therapeutic agent for a psychiatric disorder using the control of dysfunction as a marker, and to provide a screened novel compound or a therapeutic agent for a psychiatric disorder, thereby providing innovative technologies for treating a psychiatric disorder It is.

Claims

The scope of the claims 1. A therapeutic drug for mental illness in which a disease symptom mainly comprising a compound having an action of controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness exhibits a wavy appearance pattern.  2. The therapeutic drug for a mental disease according to claim 1, wherein the control of the progressive cerebral dysfunction corresponding to the vulnerability to mental illness onset is suppression of the progressive cerebral dysfunction corresponding to the vulnerability.  3. A drug is administered in a model animal to cause a progressive cerebral dysfunction corresponding to psychiatric illness vulnerability, and the subsequent stress load is caused by the administration of the candidate compound during the drug withdrawal period of the drug. In contrast, claims 1 or 2 mainly include a compound that has a pharmacological effect that specifically prevents the formation of behavioral sensitization, which is an indicator of progressive cerebral dysfunction equivalent to mental illness vulnerability. The therapeutic agent for a mental disease according to the above.  4. The therapeutic agent for a mental disease according to claim 3, wherein the administration means is administration of an amphetamine compound.  5. The mental disease according to claim 3 or 4, wherein the stress load is selected from amphetamine compound administration, apomorphine administration, flea fensin administration, other direct or indirect dopamine agonist administration, and tail clipping. For remedies.  6. The method according to any one of claims 1 to 5, wherein the mental disorder exhibiting a wavy pattern of appearance is schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, manic depression, or autism. For mental illness. 7. Mental disorders for the treatment agent according to any one of the compounds 5-HT ₃ receptor blocker in the range 1-6 of claims is. 8. 5-HT ₃ receptor blockers, therapeutic agent for mental disorders according to claim 7 of claims is Ondanse Tron. 9. Screening of a novel compound or a therapeutic agent for mental illness showing a wavy pattern of appearance of disease symptoms characterized by using as a marker the effect of controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness onset Law. 10. The screening method according to claim 9, wherein the control of progressive cerebral dysfunction corresponding to mental disease onset vulnerability is suppression of fragile progressive cerebral dysfunction.  1 1. A drug is administered in a model animal in which a progressive cerebral dysfunction corresponding to psychiatric illness vulnerability is induced, and then the candidate compound is administered during the drug withdrawal period. Claims 9 or 1 to select a compound that possesses a pharmacological effect that specifically prevents the development of behavioral sensitization, which is an indicator of progressive cerebral dysfunction equivalent to mental illness vulnerability, to stress load. The screenling method according to 0.  12. The screening method according to claim 11, wherein the administration means is administration of an amphetamine compound.  13. The screening method according to claim 11 or 12, wherein the stress load is selected from amphetamine compound administration, apomorphine administration, nomifensin administration, other direct or indirect dopamine agonist administration, and tail clipping. 14. A novel compound obtained by the screening method according to any one of claims 9 to 13, or a therapeutic agent for a mental disease in which the disease symptom shows a wavy appearance course pattern.