HK1087931A - Therapeutic combinations of atypical antipsychotics with gaba modulators, anticonvulsants or benzodiazapines - Google Patents

Description

Therapeutic combinations of atypical anti-psychotic agents and GABA modulators, anticonvulsants or benzodiazepines *

Technical Field

The present invention relates to pharmaceutical combinations comprising ziprasidone or a prodrug thereof or ziprasidone or a pharmaceutically acceptable salt of said prodrug, and a GABA modulator or a prodrug thereof or a GABA modulator or a pharmaceutically acceptable salt of said prodrug, an anticonvulsant or a prodrug thereof or an anticonvulsant or a pharmaceutically acceptable salt of said prodrug and/or a benzodiazepine * class of drugs or a prodrug thereof or a benzodiazepine * class of drugs or a pharmaceutically acceptable salt of said prodrug, kits containing these combinations, and methods of using these combinations to treat therapy-resistant anxiety disorders, psychotic disorders or symptoms, or psychological disorders or symptoms in patients, including humans. The present invention also relates to combinations of adjunctive and synergistic effects comprising ziprasidone or a prodrug thereof or a pharmaceutically acceptable salt of ziprasidone or said prodrug and a GABA modulator or a prodrug thereof or a GABA modulator or a pharmaceutically acceptable salt of said prodrug, which combinations of adjunctive and synergistic effects are useful in the treatment of patients, including humans, suffering from treatment-resistant anxiety disorders, psychiatric disorders or conditions, or psychological disorders or conditions.

Background

Schizophrenia is a common and serious disorder of the mind characterized by a lack of contact with real conditions (paradoxical), hallucinations (false perception), delusions (false imagination), abnormal thinking, bland feeling, reduced irritation and disturbed working and social functioning.

Atypical antipsychotics have some clinical beneficial effects over conventional antipsychotics, which is also a major reason for their popularity over the past decade. The main mechanism for many of the clinically beneficial effects of atypical drugs is that they have antipsychotic effects without extrapyramidal side Effects (EPS). Significant advantages over traditional antipsychotics include great progress in negative and cognitive symptoms, better antidepressant and psychostabilizing effects, reduced risk of parkinsonian side effects and tardive dyskinesia, and better efficacy in otherwise refractory or treatment-resistant patients.

Clinical differences between atypical and conventional antipsychotics can be understood in terms of their different pharmacological properties. Conventional antipsychotic drugs antagonize dopamine only (D)₂) Receptor, atypical antipsychotic drug having D₂At the same time as antagonism, different binding kinetics are possible for these receptors and activity is also possible for other receptors, in particular 5-HT_2A、5-HT_2cAnd 5-HT_1D(Schmidt B et al，Soc.Neurosci.Abstr.24：2177，1998)。

Atypical antipsychotics include clozapine (clozapine *), risperidone (risperidone *), olanzapine (reprolopram *), quetiapine (sirik 57345;), aripiprazole (abilify *), and ziprasidone (geodon *). Ziprasidone, an atypical antipsychotic, has been shown to be effective in the treatment of schizophrenia through a number of short and long term clinical trial studies. Ziprasidone is indicated for the treatment of schizophrenia or psychotic disorders, and ziprasidone is widely used for the treatment of various psychological disorders, psychiatric syndromes and severe personality disorders.

U.S. patents 4,831,031, 4,883,795, 6,245,766 and 6,126,373, which are incorporated herein by reference, disclose the use of ziprasidone in the treatment of treatment-resistant anxiety, psychiatric and psychological disorders, respectively.

Unless otherwise indicated, the term "ziprasidone" herein includes the free base of the compound ziprasidone and all pharmaceutically acceptable salts thereof.

GABA is a major inhibitory neurotransmitter in the Central Nervous System (CNS) of patients. GABA receptors are found in 60-80% of CNS neurons. Allosteric propulsion of GABA receptors occurs at specific sites where compounds capable of binding act as sedatives and anxiolytics in general.

The prior art has disclosed that GABA modulators may be useful as antiepileptics in central nervous system disorders including epilepsy, huntington's chorea, cerebral ischemia, parkinson's disease, tardive dyskinesia, and spasticity. GABA agonists are also disclosed in the prior art as being useful as antidepressants, anxiolytics and antipsychotics.

U.S. Pat. No. 4,024,175, incorporated herein by reference, discloses that GABA modulators are useful in the treatment of drug-resistant anxiety disorders, psychiatric disorders or symptoms, and psychological disorders or symptoms.

GABA modulators known in the art include muscimol, progabide, riluzole, baclofen, gabapentin (gabapentin *), vigabatrin, valproic acid (sodium dipropylacetate *, sodium divalproate *), tiagabine (tiagabine)^*) Lamotrigine (rititone *), pregabalin, topiramate (tolitamide *) and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of these GABA modulatorsA salt thereof.

Benzodiazepines * class of drugs have been used for decades to treat many diseases. The known main effects of benzodiazepines * class of drugs are anticonvulsant, muscle relaxing, sedative, hypnotic, anxiolytic and antipsychotic. The mechanism of action of benzodiazepine * class of drugs is currently unknown, but is thought to be involved in the GABA system of the CNS.

When either anxiolytic or antipsychotic effects are desired, there is often a problem that the sedative and hypnotic effects of benzodiazepine * class drugs limit their high dose use or that patient hospital access must be ensured when high doses of the drug must be used to achieve a desired therapeutic effect. The sedative effect of benzodiazepine * class of drugs may be undesirable even at doses used to treat diseases or conditions such as anxiety.

According to DSM-IV, generalized anxiety disorder is characterized by persistent and excessive anxiety symptoms, with fear of many things and activities occurring for a period of up to at least 6 months. Anxiety is one of the most common mental disorders in the united states, and more than one thousand nine million adults acquire it each year. Treatment of anxiety disorders includes selective 5-hydroxytryptamine reuptake inhibitors (SSR1s), buspirone, venlafaxine, and benzodiazepine *. Typical and atypical antipsychotics studied as therapeutic agents for anxiety indicate that they have more tolerable side effects and lower incidence of tardive dyskinesia. The serotoninergic nature of ziprasidone makes it useful for treating anxiety.

Since the reported complete remission rates for benzodiazepine * class drugs and antidepressants are low, alternative improvement strategies are warranted to reduce disability and reduce chronic distress.

Post-traumatic stress disorder (PTSD) is a serious and frequently occurring chronic psychiatric disorder. PTSD remains at a 10% incidence throughout the united states, becoming one of the most prevalent psychiatric disorders. The most common traumatic stresses are rape, household violence, childhood addiction, aggression, accidents and catastrophes. PTSD has three symptoms: insertional, avoidant and arousal. Insertional symptoms (hallucinations, nightmares, intervening thoughts, physical and psychological arousals resulting from trauma reminders) are considered to be the symptoms characteristic of PTSD and absent in other psychiatric disorders. Although classified as anxiety according to DSM-IV, PTSD and psychotic symptoms are present in almost half of patients at the same time. Treatment includes selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) such as sertraline, GABA modulators and benzodiazepine * class of drugs. Additional treatment of psychotic symptoms with antipsychotics is provided. Thus, the combination product has practical application value for such a patient population.

Psychological disorders, also known as affective disorders, are a dysmorphism, a typical recurrent disorder, including unipolar (depression) and bipolar (manic depression) disease, dysthymia and cyclothymic disorder, the symptoms of which are generalized mood disorders, conscious movement disorders and vegetative symptoms. Psychological disorders can affect women 20% of the time and men 12% of the time during a person's lifetime. They are The most common psychiatric disorders, which explains why up to 65% of psychiatric outpatients and 10% of total patients are in non-psychiatric medical units (The Merck Manual, 17The, Merck & co.1999, p.1526).

The standard of care for mental disorders has a response rate to lithium of only 50%, and lithium causes some side effects. Anticonvulsants are used as mood stabilizers in the treatment of psychological disorders, suggesting utility in the treatment of bipolar disorders. For example, valproic acid and its derivatives such as sodium α -n-propylvalerate dimer or carbamazepine have been shown to have limited efficacy when given in a daily dose of 500-2000 mg. Antipsychotics are also used clinically to treat these patients. A combination product comprising an anticonvulsant and an atypical antipsychotic would have significant efficacy in treating these patients.

Not all patients respond similarly to the same treatment, and psychosis is therefore particularly difficult to treat. Patients often require multiple medications for treatment. There are also a large number of untreated individuals and treatment-resistant patients in need of effective treatment.

The patient's noncoordination is one cause of the disease condition. For example, it is generally accepted that most psychiatric patients are not or only partially compliant with their medications. Poor compliance may lead to recurrence of the condition, thus negating any beneficial effects achieved during the first phase of treatment.

The simplification of drug therapy by using a plurality of agents in combination reduces the chance of patient noncompliance in a more rigorous schedule. There is a need for pharmaceutical combinations or kits using atypical antipsychotics to effectively treat, for example, treatment-resistant anxiety disorders, psychiatric disorders or symptoms and psychological disorders.

The present invention relates to compositions that reduce or overcome these disadvantages in the treatment of drug-resistant anxiety disorders, psychiatric disorders or conditions, psychological disorders or conditions, in a novel pharmaceutical combination of ziprasidone and a GABA modulator, anticonvulsant or benzodiazepine * class of drugs.

Summary of The Invention

The present invention relates to pharmaceutical compositions, methods of drug treatment and kits using atypical antipsychotics and GABA modulators, anticonvulsants or benzodiazepines * class of drugs.

According to the present invention, it has surprisingly been found that the pharmaceutical compositions of the present invention have synergistic and additive effects and have less side effects and reduced dosages when used in combination with psychotropic drugs such as antidepressants, sedatives and mood stabilizers such as lithium.

Thus in one aspect the present invention provides a combination of an atypical antipsychotic and a GABA modulator, an anticonvulsant or a benzodiazepine * class of drugs. Atypical antipsychotics which may be used in the present invention include olanazapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, amisulpride and ziprasidone. Generally, it is preferred to use ziprasidone as the first therapeutic agent in pharmaceutical compositions and methods of treatment.

Another aspect of the present invention is a method of reducing the amount of an atypical antipsychotic drug required to produce an anti-anxiety, antipsychotic and mood stabilizing effect comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of the present invention.

Another aspect of the present invention is the use of these pharmaceutical compositions to enhance the effect of the atypical antipsychotic used, thereby allowing a reduction in the amount of said antipsychotic agent used and thus allowing better control of drug related toxicity and side effects.

The present invention has many advantages over previous methods of treating neuropsychiatric disorders. For example, in the treatment methods of the present invention, atypical antipsychotics counteract the sedative and hypnotic effects typical of benzodiazepine * class drugs. Other aspects and advantages of the invention will be apparent from the following detailed description and claims.

Detailed Description

The present invention relates to a pharmaceutical composition comprising: an amount of ziprasidone, a prodrug thereof, or a pharmaceutically acceptable salt of ziprasidone or said prodrug, and an amount of a GABA modulator, an anticonvulsant, and/or a benzodiazepine * class of drug, a prodrug thereof or a pharmaceutically acceptable salt of said GABA modulator, anticonvulsant, or benzodiazepine * class of drug, and a pharmaceutically acceptable excipient, carrier or diluent.

The present invention relates to therapeutic methods and pharmaceutical compositions comprising ziprasidone and a GABA modulator for the treatment of treatment-resistant (therapeutic-resistant) anxiety disorders; therapeutic methods and pharmaceutical compositions comprising ziprasidone and an anticonvulsant for the treatment of a psychological or psychiatric disorder; and therapeutic methods and pharmaceutical compositions comprising ziprasidone and a benzodiazepine * class of agents effective in treating drug-resistant anxiety disorders and/or psychiatric disorders or conditions.

The invention also relates to therapeutic methods and pharmaceutical compositions comprising ziprasidone and a GABA modulator for treating treatment-resistant anxiety disorders.

The invention also relates to methods of treatment and pharmaceutical compositions comprising ziprasidone and a benzodiazepine * class of agents useful in treating a psychotic disorder or condition, or in treating-resistant anxiety disorders.

The invention also relates to therapeutic methods and pharmaceutical compositions comprising ziprasidone and an anticonvulsant for treating a psychological disorder or condition, a psychiatric disorder or condition, or a psychotic condition.

The present invention also relates to a kit for performing a therapeutic effect on a patient comprising an amount of ziprasidone, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; a second unit dosage form comprising an amount of a GABA modulator, anticonvulsant or benzodiazepine * drug, a prodrug thereof or a pharmaceutically acceptable salt of said GABA modulator, anticonvulsant or benzodiazepine * drug, and a pharmaceutically acceptable excipient, carrier or diluent; and a container.

The present invention also relates to a method of treating a patient in need thereof comprising administering to said patient an amount of a first drug and an amount of a second drug, the first drug being ziprasidone, a prodrug or a pharmaceutically acceptable salt thereof, the second drug being a GABA modulator, an anticonvulsant or a benzodiazepine * class of drug or a prodrug thereof or a pharmaceutically acceptable salt of said GABA modulator, anticonvulsant or benzodiazepine * class of drug.

The present invention also relates to a method of treating a patient in need thereof comprising administering to said patient an amount of a first compound and an amount of a second compound, the first compound being ziprasidone, a prodrug thereof, ziprasidone, or a pharmaceutically acceptable salt of said prodrug, the second compound being a GABA modulator, an anticonvulsant, or a benzodiazepine * class of drug, a prodrug thereof, or a pharmaceutically acceptable salt of said GABA modulator, anticonvulsant, or benzodiazepine * class of drug or said prodrug; wherein the first and second compounds are each optionally independently used with a pharmaceutically acceptable excipient, carrier or diluent.

The present invention also relates to a method of treating a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising:

a) a quantity of a first compound that is ziprasidone, a pharmaceutically acceptable salt of ziprasidone, a prodrug of ziprasidone, or a pharmaceutically acceptable salt of a prodrug of ziprasidone; and

b) an amount of a second compound, the second drug being a GABA modulator, an anticonvulsant or a benzodiazepine * class of drug, a prodrug of said GABA modulator, anticonvulsant or benzodiazepine * class of drug or a pharmaceutically acceptable salt of a GABA modulator, an anticonvulsant or benzodiazepine * class of drug or of said prodrug; and, optionally

A pharmaceutically acceptable excipient, carrier or diluent.

The methods of the invention comprise drug treatment of treatment-resistant anxiety disorders. Treatment-resistant anxiety disorders that may be treated using the methods of the present invention include, inter alia, treatment-resistant obsessive-compulsive disorders or treatment-resistant post-traumatic stress disorders.

The methods of the invention include drug treatment of the psychiatric disorder or condition. Psychotic disorders treatable using the methods of the invention include, inter alia, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder.

The methods of the invention include drug treatment of a cardiac disorder or condition. Psychological disorders are a diverse group of diseases, including unipolar (depressive) and bipolar (manic-depressive) disorders, characterized by generalized mood disorders, conscious movement disorders, and vegetative symptoms. When depression and happiness become the core part affecting the emotion, anxiety disorders and erethism will appear with equal chance, according to the previous pharmacopoeia named "affective disorders".

Preferred GABA modulators for use in the combinations, pharmaceutical compositions, methods and kits of the present invention include: muscimol, progabide, riluzole, baclofen, gabapentin (gabapentin *), vigabatrin, valproic acid, tiagabine (tiagabine *), lamotrigine (rititone *), pregabalin, phenytoin (dilantin *), carbamazepine (carbamazepine *), topiramate (tolitate *), prodrugs thereof and GABA modulators and pharmaceutically acceptable salts of prodrugs thereof.

More preferred GABA modulators for use in the combinations, pharmaceutical compositions, methods and kits of the present invention include: gabapentin, tiagabine, lamotrigine, topiramate, pregabalin, prodrugs thereof and GABA modulators and pharmaceutically acceptable salts of prodrugs thereof.

Particularly preferred GABA modulators for use in the combinations, pharmaceutical compositions, methods and kits of this invention are pregabalin, a prodrug thereof and a pharmaceutically acceptable salt of pregabalin or a prodrug thereof.

Another particularly preferred GABA modulator for use in the combinations, pharmaceutical compositions, methods and kits of this invention is gabapentin (gabapentin *), a prodrug thereof and a pharmaceutically acceptable salt of gabapentin (gabapentin *) or a prodrug thereof.

Preferred anticonvulsants for use in the combinations, pharmaceutical compositions, methods and kits of the invention include: examples of such drugs include phenytoin (dilantin *), 3-methylbenzethotoin (mephenytoin *), succinimidyl drugs such as ethosuximide (ethosuximide *), oxazolidinediones such as trimethoprim (trimethadione *), carbamazepine (carbamazepine *), busoline (paminone *), valproic acid (divalproex sodium *), prodrugs thereof, and anticonvulsants and pharmaceutically acceptable salts of prodrugs thereof.

More preferred anticonvulsants for use in the combinations, pharmaceutical compositions, methods and kits of the invention include: phenytoin and valproic acid, prodrugs thereof, anticonvulsants and pharmaceutically acceptable salts of prodrugs thereof, and pharmaceutically acceptable salts of prodrugs thereof.

A particularly preferred anticonvulsant for use in the combinations, pharmaceutical compositions, methods and kits of the present invention is valproic acid, a prodrug thereof or a pharmaceutically acceptable salt of valproic acid or a prodrug thereof.

Another particularly preferred anticonvulsant for use in the combinations, pharmaceutical compositions, methods and kits of the present invention is phenytoin, a prodrug thereof or a pharmaceutically acceptable salt of phenytoin or a prodrug thereof.

Preferred benzodiazepine * class of agents useful in the combinations, pharmaceutical compositions, methods and kits of the present invention include: alprazolam, methotrexate, clonazepam, chlordiazepoxide, diazepam, halazepam, lorazepam, temazepam and oxaxepam, prodrugs thereof and benzodiazepine * class drugs and pharmaceutically acceptable salts of prodrugs thereof.

More preferred benzodiazepine * classes of drugs for use in the combinations, pharmaceutical compositions, methods and kits of the present invention include clonazepam, diazepam and lorazepam, prodrugs thereof and anticonvulsants and pharmaceutically acceptable salts of prodrugs thereof.

A particularly preferred benzodiazepine * class of drugs for use in the combinations, pharmaceutical compositions, methods and kits of the present invention is clonazepam, a prodrug thereof or a pharmaceutically acceptable salt of clonazepam or a prodrug thereof.

Another particularly preferred benzodiazepine * class of agents for use in the combinations, pharmaceutical compositions, methods and kits of the present invention is lorazepam, a prodrug thereof or a pharmaceutically acceptable salt of lorazepam or a prodrug thereof.

The combination of the invention comprises at least two active ingredients: ziprasidone, a prodrug or a pharmaceutically acceptable salt thereof, and a GABA modulator, a prodrug or a pharmaceutically acceptable salt thereof; or ziprasidone, a prodrug or a pharmaceutically acceptable salt thereof, and an anticonvulsant, a prodrug thereof, or a pharmaceutically acceptable salt of an anticonvulsant and a prodrug thereof; or ziprasidone, a prodrug or a pharmaceutically acceptable salt thereof, and a benzodiazepine * class of drugs, a prodrug or a pharmaceutically acceptable salt thereof. The combination of the invention includes a pharmaceutically acceptable excipient, carrier or diluent.

The synergistic effect produced by the combination allows less use of atypical antipsychotics to achieve the same psychotropic effect. The dosage of the atypical antipsychotic may be reduced by about 25-90%, for example about 40-80%, and particularly about 50-70%. The amount of antipsychotic agent required to be reduced will depend on the amount of the second therapeutic agent used.

The amounts of the first and second therapeutic agents are selected to reduce or ameliorate the disease or condition in the patient. As is known, the amount of each component used will depend on several factors such as the potency of the particular compound selected, the method of administration, the age and weight of the patient, the severity of the condition being treated, and the like. This is considered to be within the skill of the person skilled in the art and the person skilled in the art will be able to determine the optimum amount of each ingredient based on the teaching of the present literature for each ingredient. Methods of synthesis and amounts of the components of the compositions are disclosed in the patent literature and physician's instructions, 57 th edition, Thompson, 2003, which are incorporated herein by reference, for completeness of disclosure. Preferably, when ziprasidone is selected as the active agent, the daily dose is from about 5mg to about 460 mg. More preferably, the first component comprises from about 20mg to about 320mg of ziprasidone per dose; more preferably, each dose contains from about 20mg to about 160mg of ziprasidone. The amount of children is relatively less. For example, the maximum dose allowed per day for such a dosage form is 1 or 2 oral doses.

The following are listed for the commonly used doses and some preferred doses of atypical antipsychotics, GABA modulators, anticonvulsants, benzodiazepines *. This table is not comprehensive, but is intended to guide any desired combination of the present invention.

Olanzapine: about 0.25 to about 100mg, once per day; preferably, from about 1 to about 30mg, once per day; more preferably from about 1 to about 25mg, once per day;

and (3) chlorinated leveling: about 12.5 to about 900mg per day; preferably, from about 150 to about 450mg per day;

risperidone: about 0.25 to about 16mg per day; preferably about 2-8mg per day;

sertindole: from about 0.0001 to about 1.0mg/kg per day;

quetiapine: from about 1.0 to about 40mg/kg, once per day or in divided doses;

chlorine oxygen flat: about 0.005 to about 60mg per day in total, administered in single or divided doses;

carbamazepine: about 200 to about 1200mg per day; preferably about 400mg per day;

valproic acid: about 250 to about 2500mg per day; preferably about 1000mg per day;

lamotrigine: about 50 to about 600mg, 1 to 2 doses per day; preferably from about 200 to about 400 mg; more preferably about 200 mg;

gabapentin: about 300 to about 3600mg per day in 2 to 3 divided doses; preferably 300 to about 1800mg per day; more preferably about 900mg per day;

and (3) adding sulfur and guest: from about 2 to about 56mg per day, 2 to 4 divided doses; preferably from about 32 to about 56mg per day; more preferably about 56 mg.

Topiramate: about 200 to about 600mg, 2 doses per day; most preferably about 400mg per day.

The following table is an additional dosage range:

name of drug		Dosage range
			Trade name	Common name
Clonazepam	Clonazepam	Maximum value: 0.25mg minimum: 20mg of
			Potassium clodronate	Chlorodiazone dipotassium salt	Maximum value: 3.75mg minimum: 60mg of
Diazepam	Benzodiazepine	Maximum value: 1mg minimum: 40mg of
			Alprazolam	Methyltriazoldiazepam	Maximum value: 0.25mg minimum: 4mg of
Tiagabine	Tiagabine	Maximum value: 4mg minimum: 56mg
			Gabapentin	Gabapentin	Maximum value: minimum value of 100 mg: 2400mg of

Diilantine	Phenytoin	Maximum value: 50mg minimum: 1200mg
			Carbamazepine capsule	Amimipramine ER	Maximum value: minimum 200 mg: 1200mg
Divalproex sodium	Valproic acid	Maximum value: minimum of 250 mg: 2000mg
			Felbamate esters	Non-urethanes	Maximum value: minimum 1200 mg: 3600mg
Keppra	Levetiracetam	Maximum value: minimum 1000 mg: 3000mg of
			Carbamazepine	Amimipramine	Maximum value: minimum 200 mg: 1200mg
Tuotai (a medicine for treating cancer)	Topiramate	Maximum value: minimum 25 mg: 400mg of
			tin-Langting	Methanethium succinate	Maximum value: minimum 150 mg: 1200mg
More than one	Oxcarbazepine	Maximum value: minimum 300 mg: 2400mg of
			Zonisamide	Zonisamide	Maximum value: minimum value of 100 mg: 600mg
Libitong medicine	Lamotrigine	Maximum value: minimum 200 mg: 400mg of
			Ethosuximide capsule	Ethosuximide	Maximum value: minimum of 250 mg: 1500mg

In further combinations, the skilled person is able to arrive at the pharmaceutical combination of the invention by selecting the dosage of the first and second component compounds in accordance with the above guidelines.

The atypical antipsychotics of the present invention are useful for the treatment of schizophrenia, bipolar disorder and dementia.

A preferred atypical antipsychotic of the present invention is ziprasidone. Ziprasidone (5- [2- [4- (1, 2-benzisothiazol-3-yl) piperazin-1-yl)]Ethyl radical]-6-chloroindolin-2-one hydrochloride hydrate) is an atypical antipsychotic of the benzisothiazolylpiperazine type, having 5-HT in vitro_1AReceptor agonist activity, is an inhibitor of 5-hydroxytryptamine and norepinephrine reuptake (see, e.g., U.S. patent 4,831,031). Postsynaptic 5-HT_1AReceptors are associated with both depression and anxiety (NM Barnes, T Sharp, 38 Neuropharmacology1083-152, 1999). Ziprasidone has an oral bioavailability of about 60%, a half-life of about 6-7 hours, and very broad protein binding.

Ziprasidone is effective in treating patients with schizophrenia and schizophrenic psychological disorders, resistant schizophrenia, cognitive deficits in schizophrenia, affective and anxiety symptoms associated with schizoaffective and bipolar disorders. This drug is considered a safe and effective atypical antipsychotic (Charles & chandra cooper, 36 ann. pharmacother.839-51, 2002).

The present invention is useful for treating psychiatric disorders and conditions, which are readily treatable using ziprasidone. Accordingly, the present invention is incorporated herein by reference into the following patent applications, which disclose the use of ziprasidone: U.S. Pat. Nos. 6,245,766, 6,245,765, 6,387,904, 5,312,925, 4,831,031 and European patent EP0901789, published 3, 17 1999.

Other atypical antipsychotics that may be used include, but are not limited to: olanzapine, 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2, 3-b ] [1, 5] benzodiazepine *, a known compound and disclosed in U.S. patent No. 5,229,382, is useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety and psychosis. U.S. Pat. No. 5,229,382 is incorporated herein by reference in its entirety;

chlorazapine, 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [ b, e ] [1, 4] diazepine *, disclosed in U.S. Pat. No. 3,539,573, the entire disclosure of which is incorporated herein by reference. Clinical efficacy in the treatment of schizophrenia is described (Hanes, et al, psychopharmacol. bull., 24, 62 (1988));

U.S. patent 4,804,663, which is incorporated herein by reference in its entirety, discloses risperidone, 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidino ] ethyl ] -2-methyl-6, 7, 8, 9-tetrahydro-4H-pyrido- [1, 2-a ] pyrimidin-4-one, and its use in the treatment of psychiatric disorders;

U.S. Pat. No. 4,710,500 discloses sertindole, 1- [2- [4- [ 5-chloro-1- (4-fluorophenyl) -1H-indol-3-yl ] -1-piperidinyl ] ethyl ] imidazolin-2-one. Us 5,112,838 and 5,238,945 disclose their use in the treatment of schizophrenia. U.S. patents 4,710,500, 5,112,838 and 5,238,945 are incorporated herein by reference in their entirety;

U.S. Pat. No. 4,879,288, which is incorporated herein by reference in its entirety, discloses quetiapine, 5- [2- (4-dibenzo [ b, f ] [1, 4] thiazepin-11-yl-1-piperazinyl) ethoxy ] ethanol, and its use in the treatment of schizophrenia as demonstrated by analytical experiments. Quetiapine is commonly used in the form of its (E) -2-butanediolate salt (2: 1);

aripiprazole, 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] -butoxy } -3, 4-dihydroquinolone or 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] -butoxy } -3, 4-dihydro-2 (1H) -quinolinone, which is an atypical antipsychotic drug for the treatment of schizophrenia, both of which are disclosed in U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528, which are incorporated herein by reference in their entirety;

us patent 4,401,822 discloses amisulpride;

oxapicrin, trans-5-chloro-2-methyl-2, 3, 3a, 12 b-tetrahydro-1H-diphenyl [2, 3: 6, 7 oxepino [4, 5-c ] pyrrole. U.S. Pat. Nos. 4,145,434 and 5,763,476, the entire contents of which are incorporated herein by reference, disclose the preparation and use of oxychlorosene.

A preferred combination is ziprasidone and a GABA modulator. The term "GABA" as used in the specification and claims of this application is synonymous with the term "gamma-aminobutyric acid". These two terms are used interchangeably throughout the specification and claims.

The term "GABA modulator" as used herein refers to a compound which structurally associates with the neurotransmitter GABA but does not interact with GABA receptors (e.g. gabapentin), or interacts with GABA receptors, or is metabolically converted to GABA or GABA agonists, or is an inhibitor of GABA absorption or degradation, or is a GABA receptor subtype selective antagonist and/or agonist. The above definitions include pharmaceutically acceptable salts, prodrugs or pharmaceutically acceptable salts of the prodrugs.

Suitable GABA modulators for use herein include, but are not limited to, muscimol, progabide, riluzole, baclofen, gabapentin (gabapentin)^*) Vigabatrin, tiagabine (tiagabine *), lamotrigine (rititone *), pregabalin, topiramate (tulip)Tai *), a prodrug thereof, or a pharmaceutically acceptable salt of a GABA modulator or a prodrug thereof. Those skilled in the art will recognize, in light of the present teachings, that other GABA agonists may be used in the combinations, pharmaceutical compositions, methods and kits of the present invention.

The GABA modulators described herein may be prepared according to methods known to those skilled in the art. In particular, the following patents and patent applications illustrate GABA modulators useful in the combinations, pharmaceutical compositions, methods and kits of this invention and methods of preparing such GABA modulators: U.S. patent 3,242,190 (designated muscimol), U.S. patent 4,094,992 (designated pregabalin), U.S. patent 4,370,338 (designated riluzole), U.S. patent 3,471,548 (designated baclofen), U.S. patent 4,024,175 (designated gabapentin), U.S. patent 3,960,927 (designated vigabatrin), U.S. patent 5,010,090 (designated tiagabine), U.S. patent 4,602,017 (designated lamotrigine), U.S. patent 6,028,214 (designated pregabalin), and U.S. patent 4,513,006 (designated topiramate), which patents and patent applications are incorporated herein by reference.

Gabapentin, 1- (aminomethyl) cyclohexaneacetic acid, is an anticonvulsant drug, indicating its adjunctive therapeutic effect in the treatment of partial seizures with or without secondary epilepsy in adults. Gabapentin and methods of use thereof are described in U.S. Pat. Nos. 4,024,175 and 4,087,544, which are incorporated herein by reference in their entirety.

It is important to note that the GABA modulators used in the pharmaceutical compositions, methods and kits of the present invention comprise a free carboxylic acid or free amine group as part of the chemical structure. Thus, the invention includes pharmaceutically acceptable salts of these carboxylic acid or amine groups.

For pharmaceutical use, the compounds prepared according to the invention may be pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, for example, prepared by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid, for example, hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. In addition, the compounds of the present invention may contain an acidic moiety, the pharmaceutically acceptable salts of which include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts with suitable organic ligands such as quaternary ammonium salts.

When the GABA modulators used in the present invention contain at least one asymmetric center, enantiomers exist. If the compounds of the invention have two or more asymmetric centers, they also have diastereoisomers. It is understood that all such isomers and mixtures in any proportion are included within the scope of the present invention. Gabapentin may be in the crystalline monohydrate form as described in EP340677 or in the anhydrous crystalline form as described in WO 03031391, which are incorporated herein by reference.

The phrase "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The phrase "pharmaceutically acceptable cationic salt" can be defined as, but is not limited to, alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, salts formed with organic amines such as benzathine (N, N' -diphenylethylenediamine theophylline), choline, diethanolamine, ethylenediamine theophylline, meglumine (N-methylglucamine), benzphetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), and procaine. The phrase "pharmaceutically acceptable acid addition salts" can be defined as, but is not limited to, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mindsura) and p-toluenesulfonate (toluenesulfonate).

Pharmaceutically acceptable cationic salts of GABA modulators comprising free carboxylic acids can be readily prepared by the following method: the free acid form of the GABA modulator is reacted with an appropriate base in a cosolvent, typically 1 equivalent. Representative bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine, and tromethamine. The salt is isolated by concentration to dryness or by addition of a non-solvent. In many instances, it is preferred to prepare the salt by: mixing the acid solution with a solution of different cationic salts (e.g., sodium or potassium ethylhexanoate, magnesium oleate), adding a solvent (e.g., ethyl acetate) to precipitate the desired cationic salt, or separating the cationic salt by concentration and/or addition of a non-solvent.

The pharmaceutically acceptable acid addition salts of GABA modulators comprising a free amine group can be readily prepared by the following method: reacting the free base form of the GABA modulator with an appropriate acid. When the salt is a mono (e.g. hydrochloride, hydrobromide, p-toluenesulfonate, acetate), di (e.g. hydrogensulfate, succinate) or tri (e.g. dihydrogen phosphate, citrate), at least one molar equivalent of the acid is used, usually in molar excess. However, when it is desired that these salts are sulfates, hemisuccinates, hydrogen phosphates or phosphates, an appropriate and stoichiometric amount of acid is typically used. The free base and acid are usually reacted in a co-solvent and the desired salt is then precipitated or isolated by other concentration and/or addition of a non-solvent.

The anticonvulsants disclosed herein are prepared according to methods known to those skilled in the art. In particular, the following patents and patent applications, which are incorporated herein by reference, illustrate anticonvulsants useful in the combinations, pharmaceutical compositions, methods and kits of the present invention and methods for preparing such anticonvulsants:

anticonvulsants useful as the second component include, but are not limited to, phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate;

carbamazepine, 5H-diphenyl [ b, f ] azepine * -5-carboxamide, is a commercially available anticonvulsant and analgesic agent for the treatment of trigeminal neuralgia; U.S. patent 2,948,718 (incorporated herein by reference in its entirety) discloses carbamazepine and methods of use thereof;

phenytoin, 5, 5-diphenyl-2, 4-imidazolidinone, is a known anticonvulsant; U.S. patent 2,409,654, which is incorporated herein by reference in its entirety, discloses phenytoin and methods of use thereof;

valproic acid, 2-valproic acid or dipropylacetic acid, is a known antiepileptic drug that dissociates valproate ions in the gastrointestinal tract; U.S. Pat. No. 4,699,927 discloses various pharmaceutically acceptable salts; valproic acid may be prepared according to the methods disclosed in Carraz et al, Therapie, 1965, 20, 419, which is incorporated herein by reference in its entirety;

lamotrigine, 6- (2, 3-dichlorophenyl) -1, 2, 4-triazine-3, 5-diamine, is an antiepileptic drug and is used as an adjuvant therapy in the treatment of partial seizures in adults. U.S. patent 4,486,354, which is incorporated herein by reference in its entirety, discloses lamotrigine and its use; and

topiramate, 2, 3: 4, 5-di-O- (1-isopropylidine) -3-D-fructopyranosylsulfamic acid, an antiepileptic drug useful in the treatment of treatment-resistant partial seizures with or without secondary disease, is disclosed in U.S. Pat. No. 4,513,006, which is incorporated herein by reference in its entirety.

Benzodiazepines * class of drugs are used as anxiolytic drugs and in psychiatric disorders where anxiety is a prominent feature. For example, treatment is usually carried out using a combination of a benzodiazepine * class of drug and a typical antipsychotic drug (usually haloperidol IM 5-10mg + lorazepam 1-2 mg). However, this combination may cause very serious side effects, especially acute dystonia caused by conventional antipsychotic drugs and over-sedation caused by benzodiazepine * class of drugs. Also, some clinicians avoid using benzodiazepines * class drugs in agitation states associated with intoxication.

Benzodiazepines * class of drugs are also associated with excessive sedation, confusion, disinhibition, movement disorders, nausea and vomiting, respiratory depression, asymptomatic tachypnea and tachycardia (J.Modell, J.Clin Psychopharmacol.6: 385 387, 1986). According to the present invention, it has surprisingly been found that atypical antipsychotics counteract the typical sedative and hypnotic effects of benzodiazepines * class of drugs.

Thus, by administering atypical antipsychotics such as ziprasidone and benzodiazepines * to patients in accordance with the principles of the present invention, it is possible to administer effective doses of benzodiazepines * even when high doses are necessary to achieve the desired effect without losing normal daily life for the patient due to the elimination of the sedative and hypnotic effects.

The term "benzodiazepine * drug" or "benzodiazepine * drug" as used herein refers to benzodiazepine * and derivatives thereof which are generally classified as benzodiazepine * drugs in pharmaceutical texts such as ErnstMutschler, arzhemitteiwirkung, Lehrbuch der pharmaceutica markalogie and Toxikologie, aug.5, 1986, Wissenschaftliche verlagisselschaft mbk, Stuttgart, including for example diazepam, chlordiazepam, chlordiazepoxide, chlozazamide, meddarzepam, fluzepam, oxazepam, clonazepam, nitrazepam, flunitrazepam, astazolam, bromodiazepam, alprazam, lorazepam, chlordiazepam, temazepam, triazolam, halazepam, and diazepam. The term benzodiazepine * class of drugs also refers to compounds of the benzodiazepine * class of drug receptor subtype, pharmaceutically acceptable salts of benzodiazepine * class of drugs, prodrugs of benzodiazepine * class of drugs, and pharmaceutically acceptable salts of prodrugs of benzodiazepine * class of drugs, as defined herein.

Some benzodiazepine * drugs use their sedative and hypnotic effects, and these benzodiazepine * drugs have a generally short half-life. Other benzodiazepines * class of drugs are used for other effects, where sedative and hypnotic effects are considered undesirable or even considered as side effects of benzodiazepine * class of drugs. These benzodiazepine * -type drugs are, for example, diazepam, chlordiazepoxide salt, chlordiazepide, medakazepam, oxazepam, clonazepam, estazolam, bromoazepam, alprazolam, lorazepam, chlordiazepam, oxazepam, brotizolam, chlordiazepam, halazepam or pramazepam.

Benzodiazepine * class of drugs can treat a variety of diseases due to their many effects. The principles of the present invention are important in diseases where the sedative and hypnotic effects of benzodiazepine * class drugs are undesirable. In particular the treatment of the following diseases needs to be accomplished using the pharmaceutical combination therapy of the present invention: treatment-resistant anxiety disorders, psychotic disorders or symptoms, psychotic symptoms. The use of a combination of benzodiazepine * class drugs and atypical antipsychotics according to the principles of the present invention to treat these diseases can produce beneficial effects, while it is known that high doses of benzodiazepine * class drugs are required to produce beneficial effects when using benzodiazepine * class drugs to treat these diseases. On the other hand, however, if atypical antipsychotics are not used at the same time as the benzodiazepine * class of drug treatment, high doses of benzodiazepine * class of drugs can produce the serious drawbacks described above due to sedative and hypnotic effects.

It is of great importance that psychiatric disorders or conditions such as schizophrenia, schizoaffective disorders, schizophreniform disorders and the typical symptoms of schizophrenia are treated with benzodiazepines * class of drugs such as clonazepam. According to the present invention, these symptoms may be treated with a combination of an atypical antipsychotic and a benzodiazepine * class of drugs.

The atypical antipsychotic can be used simultaneously with the benzodiazepine * class of drugs in a kit product in separate dosage forms or in a single combined dosage form comprising the atypical antipsychotic and the benzodiazepine * class of drugs.

The effect of the pharmaceutical compositions of the present invention comprising ziprasidone and a GABA modulator or ziprasidone and a benzodiazepine * class of drugs can be tested using one or more published models of anxiety disorders known in the art. The effect of the pharmaceutical compositions of the present invention comprising ziprasidone and a benzodiazepine * class of drugs or ziprasidone and an anticonvulsant can be tested using published models of one or more psychiatric disorders or conditions known in the art. The effect of the pharmaceutical compositions comprising ziprasidone and an anticonvulsant of the present invention can be tested using published models of one or more psychological disorders known in the art, such as bipolar disorder.

The pharmaceutical compositions of the present invention comprising ziprasidone and a GABA modulator or ziprasidone and a benzodiazepine * class of drugs are particularly suitable for preventing, slowing the progression of or reversing treatment-resistant anxiety disorders, and are therefore particularly suitable for treating obsessive-compulsive disorder or post-traumatic stress disorder. The effect can be demonstrated, for example, by determining markers on the clinical administration PTSD scale or the Eysenck individual list, as shown in clinical studies (MIButterfield et al, 16 Int' l Clin Psychopharmacol 197, 203, 2001).

The pharmaceutical compositions of the present invention comprising ziprasidone and an anticonvulsant or ziprasidone and a benzodiazepine * class of drugs are particularly useful for preventing, slowing the progression of, or reversing a psychotic disorder, condition or symptom, and are therefore particularly useful for treating schizophrenia, schizophreniform disorder, schizoaffective disorder, or delusional disorder. This effect can be demonstrated, for example, by measuring markers or BPRS scores on the positive and negative symptoms scale (PANSS) and negative symptoms scale (SANS) (Kay et al, Schizophrania Bulletin 13: 261-276, 1987), or by various animal models such as the PCP or methamphetamine-induced exercise test or the conditional avoidance response test.

The pharmaceutical compositions of the present invention comprising ziprasidone and an anticonvulsant are particularly suitable for preventing, slowing the progression of, or reversing a psychological disorder, and thus are particularly suitable for treating bipolar disorder, bipolar depression, or unipolar depression. It can be demonstrated, for example, by measuring symptom images or using various animal models such as the "mouse habit despair test".

Generally, the daily dose of ziprasidone employed in the combinations, pharmaceutical compositions, methods and kits of the invention is from about 20 to about 460mg, preferably from about 40mg to about 200mg, most preferably from about 40mg to 160mg, and a therapeutically effective amount of the second therapeutic agent in a single or divided dose.

The term "therapeutically effective amount" as used herein refers to an amount of a compound sufficient to treat treatment-resistant anxiety, psychological and psychiatric disorders or conditions at a reasonable benefit/risk ratio applicable to any drug treatment.

The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated, the severity of the disease, the activity of the specific compound employed, the specific composition employed, and the age. However, depending on the condition of the patient to be treated, some variation in the dosage will necessarily occur. In any event, the person responsible for administration should determine the appropriate dosage for the patient.

The following dosage values and other dosage values disclosed in this specification and the appended claims are for a typical human being weighing from about 65kg to about 70 kg. The amount of dosage required for a patient weighing outside the range of 65kg to about 70kg can be readily determined by the skilled physician based on the patient's medical history. All dosages disclosed herein and in the appended claims are by daily dosage.

Generally, the above GABA modulators for use in the combinations, pharmaceutical compositions, methods and kits of this invention will be administered in dosages of from about 4mg/kg patient body weight per day to about 60mg/kg patient body weight per day, in single or divided doses, according to this invention. However, depending on the patient's symptoms, age, and factors that may alter absorption, distribution, metabolism, and excretion pharmacokinetics, some variation in dosage will necessarily occur. In any event, the person responsible for administration will determine the appropriate dosage for the individual patient. In particular, when used as a GABA modulator in the present invention, the dosage of pregabalin is from about 100mg to about 1500mg per day, preferably from about 300mg to about 1200mg per day; the dosage of gabapentin is from about 100mg to about 4000 mg/day, preferably from about 600mg to about 3600 mg/day.

In accordance with the present invention, the aforementioned anticonvulsants generally used in the combinations, pharmaceutical compositions, methods and kits of the present invention are administered in dosages of from about 1mg/kg patient body weight per day to about 10mg/kg patient body weight per day, in single or divided doses. However, depending on the condition of the patient, some variation in the dosage will necessarily occur. In any event, the person responsible for administration will determine the appropriate dosage for the individual patient. In particular, when used as an anticonvulsant in the present invention, the dose of phenytoin is from about 10mg to about 1500 mg/day, preferably from about 50mg to about 1200 mg/day, or the blood concentration is from about 10 to 20 mcg/mL; the dose of valproic acid is from about 1 mg/kg/day to about 100 mg/kg/day, preferably from about 5 mg/kg/day to about 70 mg/kg/day.

In general, the above-described benzodiazepine * class of drugs used in the combinations, pharmaceutical compositions, methods and kits of the present invention are administered in dosages of from about 0.001mg to about 200mg, in single or divided doses, according to the present invention. However, depending on the condition, age and pharmacokinetics of the patient which alter the physiology of the patient, certain variations in dosage will necessarily occur. In any event, the person responsible for administration will determine the appropriate dosage for the individual patient. In particular, when used as a benzodiazepine * class of drug in the present invention, the dose of diazepam is from about 1mg to about 40mg per day; the dose of clonazepam is from about 0.001 mg/kg/day to about 1 mg/kg/day, preferably from about 0.01 mg/kg/day to about 0.2 mg/kg/day.

The exact dosage form, route of administration and dosage can be selected by the physician in accordance with the patient's condition. Dosage values and dosage intervals can be adjusted to achieve plasma levels with an active effect sufficient to maintain a therapeutic effect, depending on the individual condition. It will be recognized by those skilled in the art that free base forms or other salt forms of the above GABA modulators, anticonvulsants and benzodiazepines * class of drugs may also be used in the present invention. Dosage values for GABA modulators, anticonvulsants and benzodiazepines * drugs in free base or other salt form can be readily calculated by simple scaling of the molecular weights of the species involved.

The product of the invention can be used for treating and/or preventing various central nervous system diseases. The disorders include treatment-resistant anxiety disorders such as obsessive compulsive disorder, stress disorders including post-traumatic and acute stress disorders, and generalized or substance-induced anxiety disorders, neurological disorders, depressive disorders or bipolar disorders such as single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II mania, and cyclothymic disorder.

The products of the invention have the advantage of surprisingly faster relief of anxiety than could be expected with the compounds alone. They are useful in reducing complications associated with treatment-resistant anxiety disorders, including premature mortality and suicide.

The term "treatment-resistant" in "methods of treating a disease" refers to reversing, alleviating, or inhibiting the development of a disease or one or more symptoms of a disease. For example, in certain clinical studies it has been defined as the primary DSM-IV diagnosis of generalized anxiety disorder in patients who do not respond adequately (4-8 weeks) after full testing of the primary anti-anxiety drug, e.g., SSRIs, buspirone or benzodiazepines *. In this context, the term also includes, depending on the condition of the patient, preventing the disease, including preventing the onset of the disease or any symptoms associated therewith, and reducing the severity of the disease or any symptoms thereof prior to onset or preventing the recurrence of the disease.

Examples of treatment-resistant anxiety disorders that may be treated by the present invention include, but are not limited to, treatment-resistant obsessive-compulsive disorders, treatment-resistant post-traumatic stress disorders, systemic or substance-induced anxiety disorders, neurological disorders, and acute anxiety disorders.

DSM-IV-TR discloses the cause of classifying anxiety disorders into different types and subtypes, the contents of which are incorporated herein by reference. ("diagnostic and statistical Manual of psychosis", 4 th edition, American psychiatric Association, Washington, 2002, p.429-484).

Examples of psychotic disorders that can be treated by the invention include, but are not limited to, schizophrenia, e.g., paranoid, schizophrenic, tonic, poorly differentiated or residual schizophrenia; schizophreniform disorder; schizoaffective disorder, such as delusional or depressive type; delusional disorder; brief psychotic disorder; shared mental disorder; mental disorders due to common medical conditions; substance-induced psychotic disorders, for example those caused by alcohol, amphetamine, cannabis, cocaine, hallucinogen, inhalants, opioids or phencyclidine; paranoid-type pathological personality disorder; schizotypal pathologic personality disorder; other mental disorders not specifically described.

DSM-IV-TR discloses the reason for classifying mental disorders into different types and subtypes, the contents of which are incorporated herein by reference. ("diagnostic and statistical Manual of psychosis", 4 th edition, American psychiatric Association, Washington, 2002, p.297-343).

Schizophrenia herein refers to a disease that persists for at least 6 months and includes active symptoms for at least 1 month (i.e., two [ or more ] of the following symptoms: delusions, hallucinations, disorganized language, severe schizophrenic or catatonic schizophrenia behavior, negative symptoms) ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

Schizoaffective disorder refers to a disease in which there is a simultaneous onset of psychological attack and active symptoms of schizophrenia, preceded or followed by delusions or hallucinations for at least 2 weeks without prominent psychological symptoms ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

The disease of schizophreniform psychotic disorder is characterized by symptoms comparable to schizophrenia, differing in duration (i.e., the disease lasts for 1-6 months) and in decline in not required function ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

Schizophrenia is typically a lifelong disorder of social and interpersonal deficits characterized by an inability to develop close interpersonal relationships, abnormal behavior, and slight distortion of intuition.

The combination of ziprasidone and an anticonvulsant or ziprasidone and a benzodiazepine * class of drugs of the invention can be used to treat other psychotic disorders such as delusional disorder, brief psychotic disorder, shared psychotic disorder, substance-induced psychotic disorder such as alcohol, amphetamine, cannabinoids, cocaine, hallucinogen, inhalants, papaverine-like or phencyclidine-induced psychosis, psychotic disorder induced by usual medical conditions, pathological personality disorder of paranoid type, pathological personality disorder of schizotypal type and other psychotic disorders not specified.

For example, herein "treating schizophrenia, schizophreniform or schizoaffective disorder" also includes treating one or more symptoms (positive, negative and other relevant features) of the disease, such as treating delusions and/or hallucinations associated therewith. Other examples of symptoms of schizophrenia and schizophreniform or schizoaffective disorders include certain indications of disorganization of language, affective flattening, aphasia, anhedonia, inappropriate emotion, dysphoria (in the form of, for example, depression, anxiety or anger) and cognitive dysfunction.

Delusional disorders are herein characterized by non-aberrant delusions of at least 1 month without other active symptoms of schizophrenia ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

Brief psychotic disorder persists for more than 1 day but less than 1 month ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

Shared psychotic disorder is characterized by a person being affected by other persons with long-term delusional disorders, and therefore there are delusions of similar content ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

Psychotic disorders induced by common medical conditions are characterized by psychotic symptoms judged as a direct physiological consequence of common medical conditions ("diagnostic and statistical manual for psychosis", 4 th edition, american psychiatric association, washington, 2002).

Other unspecified mental disorders are psychotic conditions which do not meet the criteria defined in DSM-IV-TR for any particular mental disorder ("diagnostic and statistics Manual", 4 th edition, American psychiatric Association, Washington, 2002).

In another embodiment, the compounds for use according to the invention are useful for the treatment of other diseases characterized by psychotic symptoms such as Alzheimer's dementia, substance-induced delusional disorders, and major depressive disorders characterized by psychoses.

In a preferred embodiment, the compounds for use according to the invention are used for the treatment of schizophrenia, schizoaffective disorder, schizophreniform disorder or the typical symptoms of schizophrenia.

The combination of ziprasidone and an anticonvulsant is useful in the treatment of psychological disorders previously known as "affective disorders". Although psychological disorders are not a clearly delineated type of disease, including unipolar and bipolar depression, generalized anxiety disorder, and more specific anxiety disorders such as agoraphobia, panic disorder, and social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD). There is a high degree of similarity and co-morbidity between these diseases, which clinicians may consider as a separate type.

DSM-IV-TR discloses the causes of psychological disorders as being divided into different types and subtypes, which are divided into depression ("unipolar depression") and bipolar disorder, generalized anxiety disorder and a number of specific anxiety disorders such as agoraphobia, panic disorder and social phobia, obsessive compulsive disorder and post-traumatic stress disorder (PTSD), the contents of which are incorporated herein by reference ("diagnostic and statistical handbook for psychosis", 4 th edition, american psychiatric association, washington, 2002, p.345-484).

The terms "affective disorder" and "psychological disorder" are used interchangeably herein to refer to a condition characterized by a change in mood with an initial clinical presentation, such as depression.

The phrase "prodrug" refers to a compound that is a drug precursor that releases the drug in vivo by chemical or physiological processes after administration (e.g., a prodrug can be converted to the desired drug form at physiological pH or by enzymatic action).

The present invention includes within its scope the use of prodrugs of ziprasidone, GABA modulators, benzodiazepines * class of drugs or anticonvulsants. Generally, these prodrugs are functional derivatives of the compounds that are readily converted to the compounds in vivo. The selection and preparation of suitable prodrug derivatives is routinely performed, for example as described in Design of produgs, ed.h. bundgaard, Elsevier, 1985, and can be obtained by methods known to those skilled in the art. All such prodrugs are within the scope of the combinations, pharmaceutical compositions, methods and kits of the present invention.

It will also be appreciated by those of ordinary skill in the art that certain compounds within the scope of the present invention may be in zwitterionic form, i.e., the particular compound includes an amine moiety and a carboxylic acid moiety depending on the pH of the solution; it is also possible to use free amines which form ammonium ions by protonation and free carboxylic acids which form carboxylic acid salts by deprotonation or zwitterions. All such zwitterions are included within the scope of the present invention.

It will also be appreciated by those of ordinary skill in the art that the pharmaceutical combinations of the present invention may be different stereoisomers. The specific stereoisomers show better efficacy and safety for the treatment of psychiatric disorders. The invention includes all possible stereoisomers and geometric isomers of the active ingredients of each pharmaceutical combination, including not only racemic compounds but also optical isomers. In the case of tautomers, i.e. where there is an equilibrium between two isomers such that the two isomers can quickly reach equilibrium with one another, the present invention includes all tautomeric forms.

The combination of the invention may be administered by standard methods for the treatment of drug-resistant anxiety disorders, psychiatric disorders, or psychological disorders, for example oral, parenteral, transmucosal (e.g. sublingual or buccal), topical, transdermal, rectal, inhalation (e.g. nasal or deep lung inhalation). Parenteral administration includes, but is not limited to, intravenous, arterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, intraarticular, or by high pressure techniques like powder jet TM.

For buccal administration, the composition may be in the form of conventional tablets or lozenges. For example, tablets or capsules useful for oral administration include conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, starch or the viscose of polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol), lubricants (e.g., magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated according to methods known in the art.

These formulations may also be prepared as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Compositions for inhalation may typically be prepared in the form of solutions, suspensions or emulsions which may be administered as a dry powder or as an aerosol using conventional propellants, such as dichlorodifluoromethane or trichlorofluoromethane. Typical topical or transdermal formulations include conventional aqueous or non-aqueous vehicles such as eye drops, creams, ointments, lotions and pastes, or in the form of medicated pastes, patches or films.

In addition, the composition of the present invention may be formulated as a parenteral preparation for administration by injection or continuous infusion. Injectable formulations may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may include formulatory agents such as suspending, stabilizing and/or dispersing agents. Optionally, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The composition of the present invention may also be formulated into a depot preparation. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils), ion exchange resins, or sparingly soluble derivatives (e.g., sparingly soluble salts).

The soluble form of the aryl heterocyclic compound, such as ziprasidone, a pharmaceutically acceptable salt thereof, a prodrug, or a pharmaceutically acceptable salt of a prodrug thereof, is immediate release (or even faster), which can be prepared as a depot formulation. For example, a kit comprising ziprasidone, a salt or prodrug of ziprasidone, a pharmaceutically acceptable salt of a prodrug of ziprasidone, and a liquid carrier and a viscous substance, wherein the drug can be soluble or insoluble, provided that when the ziprasidone compound is insoluble, the aqueous liquid further comprises a cosolvent.

U.S. patent application Ser. No. 60/42195, filed on Ser. No. 10/25, 2002, describes a suspension form of a ziprasidone depot formulation, which is incorporated herein by reference in its entirety. New injectable depot formulations of ziprasidone are described in U.S. patent application Ser. No. 60/421473, filed on 25/10/2002, which is incorporated herein by reference in its entirety.

For oral administration, the pharmaceutical compositions may be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate also include various disintegrants such as starch, preferably potato or tapioca starch, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are also commonly used in tablets. Solid compositions of a similar type will also employ fillers in soft or hard gelatin capsules, preferred materials including lactose or milk sugar, and high molecular weight polyethylene glycols.

Optionally, the compounds of the present invention may be prepared as oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. In addition, formulations containing these compounds may be presented in dry form for constitution with water or other suitable vehicle before use. These liquid preparations include conventional adjuvants such as suspending agents, for example sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin, glucose/syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminium stearate gel, emulsifying agents such as lecithin, hydrophobic sorbitol monooleate or acacia, non-aqueous vehicles (including edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol and ethanol; and preservatives such as methyl or propyl p-hydroxybenzoate and sorbic acid. Liquid preparations of the compositions of the present invention for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

When aqueous suspensions and/or elixirs are used for oral administration, the compounds of the invention may be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying and/or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerin and the like. Suitable dispersing or suspending agents in aqueous suspension include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The compositions of the invention may also be administered in a controlled release formulation, such as a sustained release or rapid release formulation. Such controlled release formulations of the compositions of the present invention may be prepared according to methods known to those skilled in the art. The attending physician or other person skilled in the art can determine the appropriate method of administration by determining the condition and need of the patient.

The pharmaceutical compositions of the present invention include both immediate release and controlled release properties. Such compositions can be prepared in two forms: the active ingredient is in the size range of nano-to micro-scale and in the form of a large number of pellets of varying release rates. The tablets or capsules of the present invention include an atypical antipsychotic in a sustained release or controlled release dosage form and a second therapeutic agent in an immediate release dosage form. Optionally, the atypical antipsychotic may be an immediate release dosage form and the second therapeutic agent may be a sustained or controlled release dosage form.

The compositions of the present invention may also be administered parenterally. For parenteral administration, solutions of sesame or peanut oil or aqueous propylene glycol may be used, as well as sterile aqueous solutions of the corresponding water-soluble salts thereof. These aqueous solutions may be suitably buffered if necessary, first requiring sufficient salt or glucose to render the liquid diluent isotonic. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this case, the sterile aqueous medium used can be readily obtained by standard techniques known to those skilled in the art.

Methods for preparing various pharmaceutical compositions of specific amounts of active ingredients are known or will be apparent to those skilled in the art in light of the present specification. For example, Remington discloses a method of making tablets: the Science and Practice of pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

Time-release pellets are prepared by coating immediate-release pellets or by matrix systems. The coating can be carried out, for example, in a coating pan or in a fluidized bed coating-dryer. Compression and subsequent spheronization are known methods in the manufacture of pharmaceutical tablets (J.W.Conine et al, Drug & Cosmetic Ind.106, 38-41 (1970)). However, other methods such as tableting techniques may also be utilized. The small particles can be agglomerated together in a high speed granulator or a rotating fluid bed agglomerator to form spherical particles or pellets. These methods are described in K.W.Olson and A.M.Mehta, int.J.Pharm.Tech &. prod.Mfr.618-24, 1985. Pellets can also be prepared by extruding wet pellets or melts and then spheronizing, for example, C.Vervaet, L.Baert & J.P.Remon int.J.Pharm.116(1995) 131-. The auxiliary substances used are typically those which are plastic, such as microcrystalline cellulose, and also mannitol. A small amount of polymeric binder is also typically added. Surfactants such as sodium lauryl sulfate may also be mixed for easier extrusion.

The pharmaceutical compositions of the invention may comprise from 0.1% to 95% of the therapeutic agent of the invention, preferably from 1% to 70%. In any event, the composition or formulation for administration contains an amount of the therapeutic agent of the present invention effective to treat the symptoms or disease in the patient.

Two different compounds of the invention may be used in combination, either simultaneously or sequentially in any order, or as a single pharmaceutical composition comprising, for example, ziprasidone and a GABA modulator as described above, or ziprasidone and an anticonvulsant, or ziprasidone and a benzodiazepine * class of drugs.

While one aspect of the invention relates to the treatment of the diseases/conditions described herein using a combination of active ingredients, wherein the active ingredients can be used separately, the invention also relates to the individual pharmaceutical compositions combined in a kit. The kit comprises two separate pharmaceutical compositions: ziprasidone and a GABA modulator, a prodrug thereof or a pharmaceutically acceptable salt of said GABA modulator and prodrug thereof, or ziprasidone and an anticonvulsant, prodrug thereof or a pharmaceutically acceptable salt of said anticonvulsant and prodrug thereof, a ziprasidone and a benzodiazepine * class of drugs, prodrug thereof or a pharmaceutically acceptable salt of said benzodiazepine * class of drugs and prodrug thereof. The kit comprises one container for containing the individual compositions, e.g. separate bottles or separate foil boxes. Typically, the kit further comprises instructions for administration of the separate components. The kit form appears to be of significant advantage when the separate components are preferably used in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when the prescribing physician desires to titrate the components of the composition.

An example of such a kit is the so-called "blister pack". Blister packs are known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally comprise a sheet of relatively rigid material covered with a layer of preferably transparent plastic. During the packaging process, a groove is formed in the plastic sheet. The groove is the size and shape of the tablet or capsule to be packed. The tablets or capsules are then placed in the recesses and the plastic sheet is sealed with a relatively hard material in the opposite direction to the projections of the recesses on the plastic sheet. As a result, the tablet or capsule is sealed in the recess between the plastic sheet and the relatively hard substance. The strength of the relatively hard substance is preferably such that: when the groove is squeezed by hand, an opening can be formed in the relatively hard substance at the location corresponding to the groove, from which opening the tablet or capsule can leave the blister pack.

It is desirable to provide a memory aid on the cartridge, such as a tablet or capsule number, which corresponds to the date of administration, so that the tablet or capsule can be taken as prescribed. Another example of such a memory aid is a calendar printed on the card, for example in the following order "first week, monday, tuesday. Other forms of memory aids will be apparent to the skilled practitioner. The "daily dose" may be one tablet or capsule or several pills or capsules taken during the day. Likewise, a daily dose of ziprasidone includes one tablet or capsule, a daily dose of an anticonvulsant, a benzodiazepine * class of drugs or a GABA modulator includes several tablets or capsules, and vice versa. The memory aid may reflect these.

In another particular embodiment of the invention, it is provided that the pharmacist dispenses the daily doses of medication at a time in the order they plan. Preferably, the pharmacist is provided with a memory aid so that administration can be more easily accommodated. An example of such a memory aid is a mechanical counter which indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory and a liquid crystal display or audible reminder signal, which may for example read the date of the last day of administration and/or remind the next administration of the dose.

In another embodiment of the present invention, the method of treating treatment-resistant anxiety in a patient of the present invention comprises administering to the patient three pharmaceutical compositions comprising an amount of a first therapeutic agent which is ziprasidone;

an amount of a second therapeutic agent that is a GABA modulator, a prodrug thereof or a pharmaceutically acceptable salt of a GABA modulator and a prodrug; and

an amount of a third therapeutic agent that is a benzodiazepine * class of drug, a prodrug thereof, or a benzodiazepine * class of drug and a pharmaceutically acceptable salt of the prodrug.

In another embodiment of the present invention, the method of the present invention for treating a psychotic disorder or condition in a patient comprises administering to the patient three pharmaceutical compositions comprising an amount of a first therapeutic agent which is ziprasidone;

an amount of a second therapeutic agent that is a benzodiazepine * class of drug, a prodrug thereof, or a benzodiazepine * class of drug and a pharmaceutically acceptable salt of the prodrug; and

an amount of a third therapeutic agent that is an anticonvulsant, a prodrug thereof, or an anticonvulsant and a pharmaceutically acceptable salt of the prodrug.

It will be appreciated that while it is preferred to use a single atypical antipsychotic as the first component compound, a combination of two or more atypical antipsychotics may be used as the first component if needed or desired. Similarly, a single GABA modulator, anticonvulsant or benzodiazepine * class of drugs is preferably used as the second component compound, and combinations of two or more of these drugs may be used as the second component if needed or desired.

The atypical antipsychotic of the present invention may be used alone or in combination with a second antipsychotic agent, such as ziprasidone, a typical antipsychotic agent such as haloperidol, or a dopamine system stabilizer antipsychotic agent such as aripiprazole. In addition, the compositions of the present invention may be used in combination with other anxiety treating agents, i.e., SSRIs or buspirone, and psychiatric or psychological disorder treating agents, i.e., lithium, tricyclic antidepressants. If a second antipsychotic drug is used, it is preferred to use them simultaneously in synergistically effective amounts to the patient. Preferably, the total amount is from about 0.0001 to about 1000 mg/kg/day, more preferably from about 0.01 to about 100 mg/kg/day, and most preferably from about 0.1 to about 60 mg/kg/day.

The pharmaceutical compositions of the present invention comprise one or more active compounds, and a pharmaceutically acceptable carrier. Preferably, these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampules, autoinjectors or suppositories, for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation. For the preparation of solid compositions, e.g., tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to prepare a solid composition formulation comprising a homogeneous mixture of the compound of the present invention or a pharmaceutically acceptable salt thereof.

When referring to the formulation of these compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily divided evenly into effective unit dosage forms such as tablets, pills and capsules. The solid preparation of the composition is then redistributed into the above-described unit dosage forms containing 0.1 to about 2000mg of each ingredient of the present invention. Representative unit dosage forms contain 1-300mg, e.g., 1, 2, 5, 10, 25, 50 or 100mg, of the active ingredient. Tablets or pills of the novel compositions may be coated or otherwise compounded to provide a dosage form affording a delayed release action. For example, a tablet or pill includes an inner layer and an outer layer of ingredients, the outer layer being coated on the inner layer. The two layers separate in the intestine against disintegration in the stomach, so that the inner layer can pass intact into the duodenum or be delayed in release. A variety of materials may be used in the enteric layer or coating, including various polymeric acids and mixtures of polymeric acids and materials such as shellac, cetyl alcohol and cellulose ethyl ester.

When administered in combination, whether as separate or separate pharmaceutical compositions, ziprasidone and a GABA modulator, an anticonvulsant, or a benzodiazepine * drug are combined in a ratio that is consistent with the manifestation of the intended effect. In particular, a suitable weight ratio of ziprasidone to GABA receptor modulator is from 0.001: 1 to 1000: 1, preferably from 0.01: 1 to 100: 1.

The pharmaceutical composition may in a regimen be administered up to 6 times per day, preferably 1 to 4 times per day, more preferably 2 times per day, most preferably 1 time per day.

The term "patient" herein includes animals of economic significance such as cattle, sheep and pigs, preferably animals capable of providing meat, as well as domestic animals (e.g., cats and dogs), sport animals (e.g., horses), zoo animals and humans, most preferably humans.

Example 1

A pharmaceutical composition is prepared by combining ziprasidone with a GABA modulator, which may be (a) gabapentin, (b) pregabalin, or (c) lamotrigine, and a pharmaceutically acceptable carrier. The composition comprises ziprasidone and gabapentin, pregabalin, or lamotrigine in separate doses, in a daily dose of about 20mg to about 160mg ziprasidone and either (a)100 mg to 400mg of gabapentin or (b) 1mg to 500mg of pregabalin, or (c) 2mg to 200mg of lamotrigine. The composition can be administered to a patient for the treatment of schizophrenia 1, 2, 3 or 4 times per day.

It is to be understood that the invention is not limited to the particular embodiments described herein, but includes various changes and modifications which may be made without departing from the spirit and scope of the novel concept as defined by the following claims.

Claims (15)

1. A pharmaceutical composition for the treatment of a psychiatric disorder comprising

(i) An atypical antipsychotic is a first therapeutic agent and (ii) a second therapeutic agent selected from a GABA modulator, a benzodiazepine * class or an anticonvulsant drug, wherein the amounts of (i) and (ii) together are effective to treat the psychiatric disorder, wherein the psychiatric disorder comprises treatment-resistant anxiety disorder, psychiatric disorder or symptom, or psychological disorder or symptom.

2. The method of claim 1A pharmaceutical composition wherein the first therapeutic agent is selected from olanzapine, aripiprazole, clozapine, risperidone, sertindole, quetiapine, amisulpride, chloroxidine and ziprasidone or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt of said prodrug; the second therapeutic agent is selected from the group consisting of muscimol, propranamide, riluzole, baclofen, gabapentin, vigabatrin, tiagabine^*Lamotrigine, pregabalin, topiramate, diazepam, lorazepam, clonazepam, oxazepam, chlordiazepam, chlordiazepoxide, methodiazepoxide, mediazepam, fluvalidiazepam, oxazepam, nitrazepam, flunitazopam, astazolam, bromociclopirox, alprazolam, lorazepam, temazepam, brotizolam, triazolam, chlordiazepam, halazepam, prazepam, valproate, phenytoin, carbamazepine, febuxourethane, levetiracetam, zonisamide, methoximide, oxybromine, nemotrizine, ethosuximide, nemotrizine, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1, wherein the first therapeutic agent is ziprasidone, a prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of said prodrug.

4. A method of treating a mammal suffering from a treatment-resistant anxiety disorder, psychiatric disorder or condition, or psychological disorder comprising administering to said mammal

(i) An effective amount of an atypical antipsychotic as a first therapeutic agent; and

(ii) an effective amount of a drug selected from the group consisting of GABA modulators, benzodiazepines * or anticonvulsants as a second therapeutic agent, wherein the amounts of (i) and (ii) together are effective to treat the disease.

5. The method of claim 4, wherein the method is used to treat a therapy-resistant anxiety disorder selected from the group consisting of a therapy-resistant obsessive-compulsive disorder, a therapy-resistant acute stress disorder, a therapy-resistant generalized anxiety disorder, a therapy-resistant substance-induced anxiety disorder, and other therapy-resistant anxiety disorders.

6. The method of claim 4, wherein the method is used to treat a psychiatric disorder or condition selected from the group consisting of treatment-resistant schizophrenia, treatment-resistant psychotic disorder, treatment-resistant schizoaffective disorder, treatment-resistant delusional psychotic disorder, treatment-resistant brief psychotic disorder, treatment-resistant shared psychotic disorder, treatment-resistant psychotic disorder induced by a drug, other forms of treatment-resistant psychotic disorder.

7. The method of claim 4, wherein the method is for treating a psychological disorder or condition selected from the group consisting of unipolar disorder, bipolar disorder, dysthymic disorder, and cyclothymic disorder.

8. The method of claim 4, wherein the condition being treated is a mental disorder or symptom.

9. The method of claim 4 further comprising an effective amount of a third therapeutic agent which is a benzodiazepine * class of drug wherein the amounts of (i), (ii) and benzodiazepine * class of drug are together effective.

10. The method of any of the preceding claims wherein the atypical antipsychotic is ziprasidone.

11. The method of any of claims 1-9, wherein the atypical antipsychotic is ziprasidone and the daily dose of ziprasidone is from about 5mg to about 460 mg.

12. The method of any of claims 1-9, wherein the atypical antipsychotic is ziprasidone and the daily dose of ziprasidone is from about 20mg to about 200 mg.

13. The method of any of the preceding claims wherein the atypical antipsychotic is ziprasidone, for oral use.

14. The method of any of the preceding claims wherein the atypical antipsychotic is ziprasidone for parenteral use.

15. The method of any of the preceding claims wherein the atypical antipsychotic is oxychloride or a pharmaceutically acceptable salt thereof.