WO2016166679A1

WO2016166679A1 - Use of an acetylcholinesterase inhibitor and pharmaceutical compositions containing said inhibitor

Info

Publication number: WO2016166679A1
Application number: PCT/IB2016/052102
Authority: WO
Inventors: Giuseppe LOTITO
Original assignee: Lotito Giuseppe
Priority date: 2015-04-14
Filing date: 2016-04-13
Publication date: 2016-10-20
Also published as: ITUB20150635A1

Abstract

The present invention concerns an acetylcholinesterase inhibitor for use in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease or dementia. Object of the invention is also a pharmaceutical composition and a kit of parts containing the said inhibitor and the said antipsychotic agent.

Description

USE OF AN ACETYLCHOLINESTERASE INHIBITOR AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID INHIBITOR

The present invention concerns the use of an acetylcholinesterase inhibitor and the pharmaceutical compositions containing said inhibitor. The said inhibitor, in particular, is useful in the treatment or prevention of side effects caused by administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease, or dementia .

Multiple sclerosis, also known as dissiminated sclerosis, is a chronic demyelinating autoimmune disease afflicting the central nervous system and causing a wide range of signs and symptoms. The disease affects rates varying between 2 and 150 cases per 100,000 individuals.

Multiple sclerosis hits nerve cells making difficult the communication between the brain and the spinal cord.

Nerve cells transmit electric signals, defined action potential, through long fibers called axons which are covered with an insulating substance, the myelin sheath.

In individuals afflicted by multiple sclerosis, the immune system attacks and damages the myelin sheath. When this happens, axons are not able to transmit signals effectively.

The name multiple sclerosis derives from the scars (sclerosis, better known as plaques or lesions) that form in the white matter of the spinal cord and of the brain. Even if the mechanism how the disease manifests itself is well understood, the precise etiology is still unknown. Several theories propose both genetic and infectious causes; moreover environmental risk factors have been highlighted as having possible correlations .

In the past multiple sclerosis was treated mainly with administration of steroidal anti-inflammatory drugs. Today, instead, the most commonly used pharmacological therapies envisage the use of drugs based on: interferon beta-la, interferon beta-lb, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide .

In many cases multiple sclerosis is associated with psychiatric disorders like bipolar spectrum disorders or schizophrenia. Individuals suffering from multiple sclerosis associated with psychiatric disorders are generally treated by administering specific drugs for the treatment of the psychiatric pathology and/or of its symptoms (so called antipsychotic agents) , besides the medicines for the treatment of multiple sclerosis.

Multiple sclerosis can manifest itself with a wide variety of neurological symptoms and can advance up to the physical and cognitive disability of the patient.

The progress of multiple sclerosis in individuals suffering from this disease associated with psychiatric disorders is often accompanied by a progressive worsening of the patient's whole clinical situation along with the appearance of additional symptoms such as disorientation, vertigo, dysphagia, reduction and/or absence of moving ability, blurred vision, xerostomia, speech difficulties, hypoacusis and attention reduction .

Though these symptoms are sometimes attributed to a worsening of the basic pathological condition of multiple sclerosis, they are to be considered more likely a manifestation of the side effects of the antipsychotic agents. As these symptoms are generally considered the result of the action led by the antipsychotic agents towards the acetylcholine receptors, the observed effects are also called "anticholinergic effects".

Apart from multiple sclerosis, there are other neurodegenerative pathologies, like Alzheimer's disease and dementia, which often manifest themselves in association with psychiatric disorders. Also in these cases the specific pharmacological treatment of the neurodegenerative pathology can be carried out in combination with the treatment of the psychiatric disorders, through administration of antipsychotic medicines. So, also in these cases afflicted patients can experience the development of the anticholinergic effects described above in the case of multiple sclerosis .

It is known that the treatment with antipsychotic agents of patients suffering from psychiatric disorders in association with neurodegenerative diseases, presents different side effects.

In the publication Curr. Med. Chem. 2012; 19(30) : 5214-8, it has been highlighted, for instance, that administration of antipsychotic agents in patients suffering from schizophrenia or schizophrenia-like illnesses determines anticholinergic side effects (e.g. blurred vision, xerostomia and constipation) over the medium and long term. The study has compared the incidence of anticholinergic effects caused by first generation antipsychotics (so called conventional antipsychotics or typical antipsychotics) and second generation antipsychotics (so called atypical antipsychotics), leading to the conclusion that the anticholinergic effects of antipsychotic drugs are quite common and can potentially impact on the quality of the patient's life. It has also been observed that there are no significant differences in inducing anticholinergic symptoms between the first and the second generation antipsychotics over the medium and long term, with the exception that the antipsychotics of the first generation seem to be significantly associated with blurred vision.

Another study, (Rev. Neurol. (Paris), May 2008; 164(5) : 472-6, has noted that there may be a connection between bipolar disorder and multiple sclerosis. Observation has been carried out on a group of patients suffering from manic-depression syndrome and being treated with antipsychotics, before developing multiple sclerosis. The lesions visualized by means of magnetic resonance imaging suggest a possible implication of the damage in the frontal lobe being itself responsible for the psychiatric disorders; another hypothesis suggests a genetic susceptibility for the association of both pathologies. The onset of a psychiatric pathology seems to be predictive of a first stage of the neurodegenerative disease (multiple sclerosis) . This might thus imply that a patient suffering from both pathologies, treated with antipsychotics, may develop anticholinergic symptoms more easily and quickly than a patient affected only by psychiatric disorder.

In light of the above mentioned state of art, the Applicant's main purpose is to provide a medicament able to treat or prevent symptoms associated with side- effects in the use of antipsychotics agents in patients suffering from psychiatric disorders associated with a neurodegenerative condition as, for example, a condition of multiple sclerosis, Alzheimer's disease or dementia .

Now the Applicant has found out that this and others purposes which will appear more evident later on, can be achieved administering to a patient suffering from psychiatric disorders associated with a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease or dementia, the antipsychotic agent necessary to face the psychiatric disorder in combination with an acetylcholinesterase inhibitor (hereafter also called "AChEI inhibitor") .

It has been observed that the acetylcholinesterase inhibitor, enhancing the cholinergic stimulation at a central level and partially also at a peripheral level, produces advantageous effects on the patient, preventing, alleviating or reducing symptoms associated with the side effects of the use of antipsychotic agents .

Thus, according to a first aspect, the present invention concerns an acetylcholinesterase inhibitor for use in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient affected by psychiatric disorders associated with a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease, dementia or a combination of the said neurodegenerative conditions.

According to a second aspect, the present invention concerns a pharmaceutical composition comprising at least one antipsychotic agent, at least one acetylcholinesterase inhibitor agent and one or more pharmaceutically acceptable excipients for use in the treatment or prevention of psychiatric disorders associated with a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease, dementia or a combination of the said neurodegenerative conditions.

According to a third aspect, the present invention concerns a kit of parts comprising at least one acetylcholinesterase inhibitor agent together with instructions for the simultaneous, separate or sequential use of said inhibitor agent with at least one antipsychotic agent in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient afflicted by psychiatric disorders associated with a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease, dementia or a combination of said neurodegenerative conditions.

For the purposes of the present invention, "neurodegenerative condition (or disease or disorder) " is here intended as a pathology characterized by the progressive deterioration of the nervous system; neurodegenerative conditions include, as an example but are not limited to, multiple sclerosis, Alzheimer's disease, dementia (Alzheimer's dementia, frontotemporal dementia, dementia with Lewy bodies, vascular dementia) and Huntington's disease.

For the purposes of the present invention,

"multiple sclerosis" is here intended as a neurodegenerative disease caused by the onset of plaques (or sclerosis) in the white matter of the spinal cord and of the brain; this disease is characterized by several symptoms, among which a certain degree of paralysis, trembling, nystagmus, diplopia and language disorders. Multiple sclerosis symptoms depend on the specific location of the plaques in the white matter.

For the purposes of the present invention,

"psychiatric disorders associated with a neurodegenerative condition" (e.g. multiple sclerosis) are here intended as the pathologies with neuropsychiatric symptoms which typically affect patients suffering from neurodegenerative diseases, in particular those affected by multiple sclerosis, as for example: cognitive dysfunctions (e.g. memory deficit, attention deficit, visual-spatial abilities deficit) , neurobehavioral disorders (bipolar spectrum disorder, psychosis, schizophrenia) , depression, anxiety and alvus alteration (constipation) .

For the purposes of the present invention, "side effects caused by the administration of an antipsychotic agent" are here intended as the undesired effects deriving from the administration of antipsychotic agents, in particular in patients suffering from psychiatric disorders associated with a neurodegenerative condition, (e.g. multiple sclerosis) . To give examples, such side effects include one or more of the following symptoms: disorientation, dysphagia, constipation, reduction and/or absence of moving ability, blurred vision, diplopia, xerostomia, speech difficulties, and attention reduction.

The present invention originates from the Applicant's observation that the "normal" therapeutic dosage regimens of antipsychotics, that is the therapeutic dosage regimens suggested by the guidelines for treatment of psychiatric disorders, are accompanied by levels of acceptable tolerability of the side effects in patients suffering only from psychiatric disorders (that is, in absence of multiple sclerosis or any other neurodegenerative condition) .

Instead, in patients suffering from psychiatric disorders associated with a neurodegenerative condition, like multiple sclerosis or Alzheimer's disease, the same dosage regimens worsen, sometimes also heavily, the neurological situation already compromised by the neurodegenerative condition. In particular, it has been observed that the administration of normal therapeutic dosages of an antipsychotic agent in patients suffering from psychiatric disorders associated with a neurodegenerative condition, like multiple sclerosis or Alzheimer's disease, can produce for example a worsening of dysphagia (increasing the risk of suffocation) , a worsening of diplopia, a reduction of the patient's movement ability and muscle tone, and also a reduction of his attention capacity, with consequent negative effects on his active participation in everyday life.

Also, it has been observed that in patients suffering from psychiatric disorders associated with neurodegenerative conditions, like multiple sclerosis and Alzheimer's disease, the administration of antipsychotics at dosage regimens so low as to induce tolerable side effects in the patient reveals ineffective for the psychiatric disorders.

So, a more balanced dosage of antipsychotics, that is a dosage such to produce significant therapeutic effects for the psychiatric disorder without causing excessive side effects, is not an adequate therapeutic strategy .

The Applicant has thus observed that in patients suffering from neurodegenerative conditions, like multiple sclerosis or Alzheimer's disease, who undergo treatment with antipsychotic agents, it is possible to obtain beneficial effects if the administration of the antipsychotic agent is effected in combination with at least one acetylcholinesterase inhibitor (AChEI) .

It has been observed that in these patients the cholinergic stimulation through administration of an AChEI at central level and, at least partially, also at peripheral level, leads to a reduction of the side effects induced by the antipsychotic agent.

It is believed that the beneficial effects observed can be due to the ability of the acetylcholinesterase inhibitor to strengthen the paths of transmission of the neural signals which are blocked directly or indirectly by the antipsychotic agent, with a consequent reduction of the side effects of the latter . In consideration of the above said mechanism of action of the AChEI and of further evidences here reported, it is reasonable to expect that the beneficial effects of AChEI inhibitor towards the side effects caused by the administration of antipsychotics may manifest themselves also in patients suffering from psychiatric disorders associated with neurodegenerative conditions different from multiple sclerosis and Alzheimer's disease as, for example, dementia.

In accordance with the present invention, the

AChEI inhibitor is preferably selected from: donepezil, rivastigmine, galantamine, physostigmine, neostigmine, pyridostigmine and combinations thereof. Preferably the AChEI inhibitor is donepezil.

Preferably, donepezil is used in the chlorhydrate form, rivastigmine in the hydrogen tartrate form, galantamine in the bromhydrate form, physostigmine in the salicylate form, neostigmine in methyl sulphate form and pyridostigmine in bromide form.

AChEI inhibitors can be prepared according to the techniques known in the art and are commercially available .

The antipsychotic agent can be a typical antipsychotic (first generation antipsychotic) or an atypical antipsychotic (second generation antipsychotic) , preferably it is an atypical antipsychotic agent.

When a typical antipsychotic agent is used, it is preferably selected from chlorpromazine, thioridazine, mesoridazine, levomepromazine, loxapine, molindone, perphenazine, thiothixene, trifluoperazine, haloperidol, fluphenazine, droperidol, zuclopenthixol and prochlorperazine.

When an atypical antipsychotic agent is used, it is preferably selected from amisulpride, aripiprazole, asenapine, blonanserin, clotiapine, clozapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine and loxapine. Preferably the atypical antipsychotic is quetiapine.

The antipsychotic agents can also be used in association with other active principles ingredients. For example, in the case of the bipolar disorder, the antipsychotic agents are often used in association with a carbolithium having the function of a stabilizer of humor and valproic acid.

In a preferred embodiment of the present invention, the AChEI inhibitor donepezil is used to reduce side effects deriving from the administration of the antipsychotic quetiapine, in particular in a patient suffering from psychiatric disorders associated with multiple sclerosis or Alzheimer's disease.

The dosage regimen of the AChEI inhibitor and of the antipsychotic agent are selected according to different factors, among which: age, weight, gender and general medical condition of the patient; form of administration; pharmacological considerations like activity, effectiveness, pharmacokinetic and toxicological profiles of the specific inhibitor or antipsychotic agent.

Preferably the AChEI inhibitor is administered in doses in the range of 0.1 - 100 mg/day, preferably in the range of 1 - 50 mg/day, even more preferably in the range of 2 - 15 mg/day. The doses can be administered in one or more portions during a day, for example 1 to 4 portions.

Preferably the antipsychotic agent is administered in doses in the range of 5 - 1000 mg/day, preferably in the range of 25 - 800 mg/day, even more preferably in the range of 75 - 600 mg/day, even more preferably in the range of 100 - 500 mg/day. The doses can be administered in one or more portions during a day, for example 1 to 4 portions.

Profitably, when the AChEI inhibitor is administered in accordance with the present invention, the dose of the antipsychotic can be given according to the normal therapeutical levels indicated by the guidelines for the treatment of psychiatric disorders, as it is accompanied by reduced side effects.

Thus, in accordance with the present invention, the treatment with the antipsychotic in a patient suffering from a neurodegenerative condition, in particular a condition of multiple sclerosis, Alzheimer's disease or dementia, can be given at higher dosages compared to the treatment which envisages the administration of the antipsychotic agent alone.

The AChEI inhibitor and the antipsychotic can be administered: orally, topically, transdermally, parenterally, by inhalation (nasal or oral) or rectally, in pharmaceutical compositions containing one or more pharmaceutically acceptable excipients, as carriers, diluents, lubricants, binders, disintegrants , stabilizers, preservatives, etc.. To the purpose of the present invention the term parenteral includes the technique of subcutaneous, intravenous, intramuscular injections or infusions.

The pharmaceutical composition can be solid (e.g. tablets, sublingual tablets, capsules, granules), liquid (for oral or parenteral administration) or in gel form.

The AChEI inhibitor can be administered simultaneously, separately or sequentially with respect to the antipsychotic agent. Preferably the AChEI inhibitor is administered simultaneously with the antipsychotic agent, more preferably orally. In case of oral administration, preferably the AChEI inhibitor and the antipsychotic agent are contained in the same pharmaceutical composition, for example in the same capsule or tablet.

Alternatively, the AChEI inhibitor and the antipsychotic agent can be administered in the form of two separate pharmaceutical compositions, each containing one of the two active principles.

In a further preferred embodiment the AChEI inhibitor is administered transdermally, in order to guarantee a substantially constant level of concentration in the patient's organism over the whole day .

EXAMPLE 1

A patient (male, 60 years old) afflicted by multiple sclerosis associated with bipolar spectrum disorders has been observed.

Multiple sclerosis was diagnosed at the age of 45, when the patient presented with sleep-wakefulness rhythms alteration, states of agitation alternated with states of depression and manic states. The multiple sclerosis condition was successively confirmed by the observation of plaques at central level (through magnetic resonance) and by auto-antibodies present in the liquor. Later, a psychiatric disorder added to the condition of multiple sclerosis, and it was diagnosed as a bipolar spectrum disorder.

The proper treatment of such clinical picture therefore requested not only the administration of interferon (30 mg/week, single dose administration per week) to treat the multiple sclerosis, but also the administration of quetiapine (atypical antipsychotic) in order to treat the bipolar disorder (400 mg/day) .

After the mentioned pharmacological treatment, worsening symptoms were observed in the patient who developed a series of additional disorders, like disorientation, vertigo, dysphagia (with serious risk of suffocation during meals), mobility problems, blurred vision, worsening of diplopia, xerostomia, speech difficulties, hypoacusis and attention reduction, all to be considered as side effects of the antipsychotic agent.

It was also observed that the mentioned symptoms improved in an evident way, although only temporarily, when the patient (a heavy cigarette smoker) inhaled large and close puffs of cigarette smoke. In particular, after inhaling cigarette smoke, a partial recovery of the mobility skills, of sense of balance, as well as of the posture and sight were observed.

After reducing the dose of quetiapine to 200 mg/day, a rapid reduction of the above mentioned symptoms was observed (the patient recovered substantially his mobility skills, being able to walk again and to perform simple activities of everyday life) . This confirmed that the additional symptoms observed were basically side effects of the action of the antipsychotic.

The administration of a reduced dose of the antipsychotic was accompanied by a reduction of the side effects on one side but, on the other side, it resulted insufficient to guarantee an effective treatment of the bipolar spectrum disorder.

Then a dose of quetiapine of 300 mg/day was administered to the patient. At the same time, also rivastigmine (AChEI inhibitor) was administered to the patient transdermally, applying a controlled release patch of rivastigmine (4,6 mg/24 hours) .

Surprisingly, the administration of the AChEI inhibitor revealed to be effective in the treatment of the side effects of the antipsychotic agent, as they manifested themselves in reduced form.

Thus the experiment has demonstrated that, if treated also with an AChEI inhibitor, the patient can be treated with an antipsychotic agent dose sufficient (or also higher) to face the bipolar spectrum disorder without inducing substantial side effects, like the side effects observed in the treatment with quetiapine alone .

Without referring to any particular theory, it is believed that the experiment here above described highlights that quetiapine administered in the normal suggested dosage to patients suffering only from psychiatric disorders, worsens the condition of the already reduced action potential speed in a patient suffering from multiple sclerosis, probably because of the block of D2 receptors at striatal level and of the direct action of the antipsychotic on the cholinergic receptors (central and peripheral) . The antipsychotics, including the second generation ones, though manifesting wide tolerability in patients suffering only from psychiatric disorders, cause, instead, serious side effects (even at low dosages) in individuals afflicted also by multiple sclerosis.

The administration of AChEI inhibitor, due to the fact that it binds to the cholinergic receptors instead of the quetiapine, allows on the contrary a strengthening of the neural pathways, with a consequent limitation of the side effects caused by the antipsychotic .

Thus, the above experiment has shown that an AChEI inhibitor can be effectively administered to treat or prevent the side effects of antipsychotic drugs in patients suffering from psychiatric disorders associated with a condition of multiple sclerosis.

EXAMPLE 2

A patient (female, 82 years old) afflicted by

Alzheimer's disease associated with aggressive psychosis has been observed. The patient was treated with memantine (10 mg twice a day) for her Alzheimer's disease, and quetiapine (100 mg/day) for her psychosis. During the said pharmacological therapy a progressive worsening of the neurological conditions of the patient was observed, in particular of her cognitive ability (the patient became poorly responsive to social stimulations and failed to recognize her relatives, etc. ) .

Because of a femur fracture, the patient had to suspend the pharmacological therapy of the Alzheimer's disease and of the psychosis temporarily.

Following said discontinuation a gradual improvement of the neurological conditions of the patient was observed and she was able again to relate to others and to recognize her relatives.

Later, when the symptoms of agitation occurred again, the therapy with memantine and quetiapine (with the same dosages previously used) was reintroduced, adding also donepezil 5 mg/day in the pharmacological therapy. In a short time (2 weeks) the patient showed a significant reduction of anticholinergic symptoms compared to the therapy with only the active principles of memantine and quetiapine.

EXAMPLE 3

A patient (male, 34 years old) afflicted by frontotemporal dementia associated with schizophrenia has been observed.

The patient was not treated with drugs for dementia and was administered risperidone and haloperidol for treating his schizophrenia.

The patient discontinued the above said pharmacological therapy temporarily, without the knowledge of his relatives and doctors. After the interruption, in the patient the symptoms of schizophrenia occurred again. Anyway the patient also showed improvement cognitive conditions and better space-time orientation than in the period of pharmacological therapy. Later, when the initial therapeutic dosages of medicaments were reintroduced, the patient showed a psychiatric improvement together with a worsening of the cognitive condition.

This observation confirms that the neurological condition of the patient during the pharmacological therapy was mainly due to the anticholinergic effects caused by the antipsychotic agent. Therefore, by analogy with what has been experimentally observed in the case of Example 1 and of Example 2, the administration of an AChEI inhibitor may reduce the side effects of the antipsychotic agents administered to patients suffering from psychiatric disorders associated with a condition of frontotemporal dementia.

Claims

1. Acetylcholinesterase inhibitor for use in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a neurodegenerative condition.

2. Inhibitor according to claim 1 for use in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a condition of multiple sclerosis.

3. Inhibitor according to claim 1 for use in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a condition of Alzheimer's disease.

4. Inhibitor according to claim 1 to be used in the treatment or prevention of side effects caused by the administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a condition of dementia.

5. Inhibitor according to any one of the preceding claims, selected from: donepezil, rivastigmine, galantamine, physostigmine, neostigmine, pyridostigmine and combinations thereof.

6. Inhibitor according to any one of the preceding claims, wherein said antipsychotic agent is a typical antipsychotic selected from chlorpromazine, thioridazine, mesoridazine, levomepromazine, loxapine, molindone, perphenazine, thiothixene, trifluoperazine, haloperidol, fluphenazine, droperidol, zuclopenthixol and prochlorperazine.

7. Inhibitor according to any one of the preceding claims, wherein said antipsychotic agent is an atypical antipsychotic selected from: amisulpride, aripiprazole, asenapine, blonanserin, clotiapine, clozapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine and loxapine.

8. Inhibitor according to claim 1 or 2, wherein said antipsychotic agent is quetiapine and said acetylcholinesterase inhibitor is donepezil.

9. Inhibitor according to any one of the preceding claims to be administered in an amount in the range 0.1 - 100 mg/day, more preferably in the range of 1 - 50 mg/day, even more preferably in the range of 2 - 15 mg/day .

10. Inhibitor according to any one of the preceding claims, wherein said antipsychotic agent is to be administered in an amount in the range of 5 - 1000 mg/day, preferably in the range 25 - 800 mg/day, even more preferably in the range 75 - 600 mg/day, even more preferably in the range 100 - 500 mg/day.

11. Inhibitor according to any one of the preceding claims wherein said psychiatric disorders comprise at least the bipolar spectrum disorders.

12. Pharmaceutical composition comprising at least one acetylcholinesterase inhibitor, at least one antipsychotic agent and one or more pharmaceutically acceptable excipients for use in the treatment or prevention of psychiatric disorders associated with a neurodegenerative condition.

13. Pharmaceutical composition comprising at least one acetylcholinesterase inhibitor, at least one antipsychotic agent and one or more pharmaceutically acceptable excipients for use in the treatment or prevention of psychiatric disorders associated with a condition of multiple sclerosis.

14. Pharmaceutical composition comprising at least one acetylcholinesterase inhibitor, at least one antipsychotic agent and one or more pharmaceutically acceptable excipients for use in the treatment or prevention of psychiatric disorders associated with a condition of Alzheimer's disease.

15. Pharmaceutical composition comprising at least one acetylcholinesterase inhibitor, at least one antipsychotic agent and one or more pharmaceutically acceptable excipients for use in the treatment or prevention of psychiatric disorders associated with a condition of dementia.

16. Kit of parts comprising at least one acetylcholinesterase inhibitor together with instructions for the simultaneous, separate or sequential use of said inhibitor agent in combination with at least one antipsychotic agent in the treatment or prevention of the side effects caused by administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a neurodegenerative condition.

17. Kit of parts comprising at least one acetylcholinesterase inhibitor together with instructions for the simultaneous, separate or sequential use of said inhibitor agent in combination with at least one antipsychotic agent in the treatment or prevention of side effects caused by administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a condition of multiple sclerosis.

18. Kit of parts comprising at least one acetylcholinesterase inhibitor together with instructions for simultaneous, separate or sequential use of said inhibitor agent in combination with at least one antipsychotic agent in the treatment or prevention of side effects caused by administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a condition of Alzheimer's disease.

19. Kit of parts comprising at least one acetylcholinesterase inhibitor together with instructions for simultaneous, separate or sequential use of said inhibitor agent in combination with at least one antipsychotic agent in the treatment or prevention of side effects caused by administration of an antipsychotic agent in a patient suffering from psychiatric disorders associated with a condition of dementia .