(S)-hydroxynefazodone antipsychotic therapy

Details (S)-hydroxynefazodone antipsychotic therapy (S)-hydroxynefazodone antipsychotic therapy

2001-11-14

2003-07-01

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06586437

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods of treating psychoses using (S)-hydroxynefazodone.
BACKGROUND OF THE INVENTION
Clinicians recognize a distinction among mental illnesses—in particular between psychoses (e.g. schizophrenia, dementia, obsessive-compulsive disorder, Tourette's disorder, bipolar disorder and schizoaffective disorder) and psychiatric disorders (e.g. depression, anxiety, social phobia and panic disorder). The two types of mental illnesses are treated quite differently. Psychoses are treated with D2 antagonists, the “typical” antipsychotics and “atypical” antipsychotics. Psychiatric disorders, i.e. mental illnesses other than psychoses, are treated with drugs that inhibit the neuronal reuptake of mono amines, particularly of serotonin, such as SSRI's.
Antipsychotic agents are employed in the treatment of psychoses. All of the common antipsychotic agents are antagonists at post-synaptic D
2
receptors, and this is accepted in the art as the mechanism by which they exert their antipsychotic activity. Antipsychotic agents are commonly considered to fall into one of two classes: “typical” and “atypical”.
Haloperidol is the archetype of the “typical” antipsychotic. It is an antagonist at post-synaptic D
2
receptors, but it is indiscriminate. Dopamine receptors are distributed throughout the nervous system, and in addition to being in cortical areas, both in neocortex and paleocortex (limbic areas), they are also present in areas associated with motor functions, such as the striatum. Blockade of dopamine receptors in the striatum gives rise to many of the side effects associated with the use of haloperidol, the so-called extrapyramidal side effects. Other “typical” antipsychotics include fluphenazine, perphenazine and trifluoperazine.
“Atypical” antipsychotics are differentiated from “typical” by their less acute extrapyramidal side effects, especially dystonias. Clozapine is the prototypical atypical antipsychotic. Other atypical antipsychotics include: olanzapine, risperidone, sertindole, quetiapine and ziprasidone. Neither nefazodone nor hydroxynefazodone has been reported to be effective as an antipsychotic.
The core symptoms of schizophrenia are considered to include hallucinations, agitation and delusions. Typical antipsychotics purely block the D
2
receptor and work fairly well for core symptoms. They do very little for the so-called negative or secondary symptoms of schizophrenia, which include apathy, the lack of ability to experience pleasure and the lack of motivation. In fact, these secondary symptoms may be more significant to the overall morbidity of the illness in terms of loss productivity and quality of life than the core symptoms. Because they appear more effective against the secondary symptoms, the atypical antipsychotics are often preferred. In addition to both the core and secondary symptoms of schizophrenia, many persons with schizophrenia also suffer with disturbances of mood and affect that can be clinically significant. As a result, many persons with schizophrenia and schizoaffective disorder are treated with antidepressants for the mood symptoms.
Psychiatric disorders other than psychoses, such as depression, anxiety, social phobia and panic disorder are treated with drugs that inhibit the neuronal reuptake of monoamines (e.g. serotonin, norepinephrine and dopamine). These reuptake inhibitors are referred to collectively as MRI's (monoamine reuptake inhibitors). Selective serotonin reuptake inhibitors (SSRI's) are a particularly preferred subclass of MRI's. The most widely known SSRI's, in addition to nefazodone, are fluoxetine, venlafaxine, milnacipran, citalopram, fluvoxamine, paroxetine, and sertraline.
Nefazodone, the metabolic parent of hydroxynefazodone, is approved for the treatment of depression by the United States Food and Drug Administration. It is available under the trade name SERZONE® from Bristol-Myers Squibb. Studies have shown that nefazodone is extensively metabolized in the body. [See, for example, Green, D. S. and Barbhaiya, R. H.,
Drug Disposition,
1997, 260-275 (1997)]. One of these metabolites is the hydroxylated derivative 2-[3-[4-(3-chlorophenyl)1-piperazinyl] propyl]-5-(1-hydroxyethyl)-2,4-dihydro-4-(phenoxyethyl)-3H-1,2,4-triazol-3-one, I, CAS Registry Number 98159-82-1, also known as hydroxynefazodone.
The stereochemistry of the metabolite I has not to date been defined in the literature. Use of hydroxynefazodone as an antidepressant is disclosed in U.S. Pat. No. 4,613,600. Neither hydroxynefazodone (racemic) nor either of its stereoisomers is commercially available at the present time. Nefazodone has been shown to antagonize alpha
1
-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that nefazodone had no significant affinity for the following receptors; alpha
2
and beta adrenergic, 5-HT
1A
, cholinergic, dopaminergic, or benzodiazepine. Nefazodone hydrochloride is rapidly and completely absorbed, but because of extensive metabolism, its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour, and the half-life of nefazodone is 2-4 hours. Nefazodone and hydroxynefazodone exhibit nonlinear kinetics for both dose and time, with AUC and C
max
increasing more than proportionally with dose increases and more than expected upon multiple dosing over time, compared to single dosing.
While nefazodone can be an effective treatment psychiatric disorders, it can give rise to certain adverse effects. The most frequently reported adverse effects associated with nefazodone are headaches, dry mouth, somnolence, nausea and dizziness. Other adverse affects are headache, asthenia, infection, flu syndrome, chills, fever, neck rigidity, hypotension, pruritus, rash, nausea, constipation, dyspepsia, diarrhea, increased appetite, nausea and vomiting, peripheral edema, thirst, arthralgia, insomnia, lightheadedness, confusion, memory impairment, paresthesia, vasodilatation, abnormal dreams, decreased concentration, ataxia, incoordination, psychomotor retardation, tremor, hypertonia, decreased libido, pharyngitis, cough, blurred vision, abnormal vision, tinnitus, taste perversion, visual field defect, urinary frequency, urinary tract infection, urinary retention, vaginitis and breast pain. In addition, nefazodone is known to cause sinus bradycardia and postural hypotension.
The primary clinical use of nefazodone is in the treatment of depression, but the use of nefazodone for treatment of various other psychiatric disorders has been disclosed in the patent literature. Nefazodone for the treatment of headache disorders is described in U.S. Pat. No. 5,854,248, for the treatment of post traumatic stress disorder, in U.S. Pat. No. 5,852,020, for the treatment of sleep disorders in U.S. Pat. No. 5,116,852, and for treating panic disorders, in European Pat. application EP 769 297. Thus the literature has considered nefazodone effective in treating psychiatric disorders, but not an antipsychotic.
SUMMARY OF THE INVENTION
It has now been discovered that (S)-hydroxynefazodone is an effective treatment for psychoses and secondary features of psychosis including, but not limited to apathy, anhedonia, lack of motivation, depression, agitation, and suicidal ideation.
The present invention relates to a method for treating psychosis. The method comprises administering to a person a need of therapy a therapeutically effective amount of (S)-hydroxynefazodone or a pharmaceutically acceptable salt thereof Psychoses include obsessive-compulsive disorder, dementia, bipolar disorder, mania, schizophrenia and schizoaffective disorder. The use of (S)-hydroxynefazodone results in fewer extrapyramidal side effects and little or no increase in serum prolactin revels, both of which are common when treating psychoses with a D
2
receptor antagonist.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for treating one or more psycho

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