WO2003072093A1 - METHOD OF TREATMENT OF HYPERTENSION USING SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) - Google Patents

Abstract

The present application provides a method for treating and/or preventing hypertension in an individual comprising the administration of hypotensive amounts of at least one SSRI, alone or in combination with at least one anti-hypertensive drug. The present invention also relates to the use of at least one SSRI, alone or in combination with at least one anti-hypertensive drug, for the preparation of medicaments for the prevention and/or treatment of hyertension. In both cases, the SSRI is selected from the group consisting of citalopram, fluvoxamine, paroxetine and sertraline. The present invention also relates to methods for preventing and/or treating conditions in which hypertension is a risk factor or a complication. There is a need for new anti-hypertensive therapies, specially if they treat the neurobiological substrate of hypertension such as the present invention. The present invention also relates to methods for preventing and/or of treating hypertension when the subject has also one or more psychiatric condition(s), or non-psychiatric conditions, susceptible to be treated by an SSRI.

Description

METHOD OF TREATMENT OF HYPERTENSION USING SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs)

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION [0001] The invention relates generally to the treatment and prevention of hypertension and more specifically to the use selective serotonin re-uptake inhibitors (SSRIs) alone or in combination with other anti-hypertensive drugs to treat hypertension in a subject.

BACKGROUND INFORMATION

[0002] High blood pressure or hypertension (HT) is the most common chronic medical condition in the industrialized world and the commonest risk factor for cardiovascular disorder, which is the most prevalent cause of death in the industrialized world.

[0003] Depending on the criteria used for diagnosis, it can be said to be present in 20- 30% of the adult population over 40 years of age, and around 50% for the population older than 65 years of age. These percentages account for approximately 50 million adult Americans in the USA ("The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure". National Institutes of Health, U.S.A., 1997). Its pathophysiology is far from being fully understood, especially in regards to Primary or Essential Hypertension, which encompasses 95% of all hypertensive patients. Secondary Hypertension constitutes the remaining 5% and it is diagnosed when the etiology of the disease can be identified.

[0004] In spite of the benefits of available treatments for hypertension, the disease is not satisfactorily controlled in the majority of the cases. For instance, up to 75% of adult Americans treated for Hypertension can not control their blood pressure below 140/90mmHg (Burt VL, Whelton P, Roccella EJ, et al. "Prevalence of hypertension in the US adult population: results from the third National Health and Nutrition Examination Survey, 1988-1991." Hypertension, 25:305-313, 1995). Labile Hypertension, Borderline Hypertension, Hypertensive Paroxysms, and White-Coat Syndrome, are particularly difficult to control. On the other hand, medications to control blood pressure may have significant side effects and undesirable interactions with other medications (Hanes, D. S., Weir, M. R. and Sowers, J. R. , 1996. "Gender considerations in hypertension pathophysiology and treatment". Am J Med 101, 10S-21S).

[0005] In general, the wide range of anti-hypertensive medications can be grouped in the following families: diuretics, beta-blockers, beta and alpha-blockers, angiotensin- converting enzyme inhibitors, subtype II angiotensin receptor blockers, and calcium channel blockers. High blood pressure treatment is tailored to the clinical phase for each patient. Life-style modification is always a relevant component of the treatment of HT: weight loss, stop smoking, low blood cholesterol levels, make regular physical exercise, etc. Furthermore, life-style modification alone can be sufficient to treat mild cases of HT. The pharmacological treatment of HT frequently implies the association of two anti- hypertensive drugs belonging to different therapeutic groups, e.g. a diuretic and a beta- blocker. It is important to point out that although anti-hypertensive drugs are useful in reducing resting blood pressure, the majority of them have low or no effect over pressor responses (elevation of blood pressure), to mental or physical stressors. In conclusion, HT represents a major public health problem in the industrialized world, and providing new and improved treatment options is of primary importance.

[0006] Selective Serotonin Re-uptake Inhibitors antidepressants (SSRIs), are the most widely prescribed antidepressants in the United States, accounting for well over half of all antidepressant prescriptions. The main established action of the SSRIs is to increase synaptic serotonin transmission through inhibition of synaptic serotonin reuptake (Mourilhe, P. & Stokes, P.E., "Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression.", Drug Saf., 18, 57-82,1998). Currently five SSRIs are available: Fluoxetine, Fluvoxamine, Sertraline, Paroxetine, and Citalopram. They have been approved to treat not only depressive disorders but also anxiety and other psychiatric disorders, as well as other non-psychiatric medical conditions.

[0007] The present invention proposes the use of four of these SSRIs: Citalopram, Sertraline, Paroxetine, and Fluvoxamine, for the treatment and/or prevention of Hypertension. It constitutes a novel, non-obvious invention because, as previously stated, antidepressants in general and SSRIs in particular have never been part of the therapeutic approach to hypertension. In fact, the present invention is the result of a novel hypothesis, which proposes that SSRIs could correct or modulate the neurobiological dysfunction that is involved in the pathogenesis of at least a significant percentage of hypertensive patients.

[0008] To the best of the applicant's knowledge, there is no prior art in the scientific literature for the use of the SSRIs: Citalopram, Paroxetine, Fluvoxamine and Sertraline for the prevention and/or treatment of Hypertension. The only exception could be one study that observed that Sertraline produced significant reductions of blood pressure in patients that besides having morbid obesity, they were hypertensive (Jordan J., Messerli FH, Lavie CJ, Aepfelbacher FC, Soria F., Am J Cardiol., 75, 743-4, 1995). Furthermore, the applicant has not found evidence of any clinical trials in humans, or research hypothesis put forward, referred to the potential use of SSRIs for the prevention and/or treatment of Hypertension. This scenario is understandable given that HT has been traditionally treated by different medical specialties, but not psychiatry.

[0009] The following issued or submitted patents have been found related to the proposed use of SSRIs for hypertension: US4329356: "Treatment of Hypertension with Fluoxetine and a 1-5-hydroxytryptophane": This patent covers the use of the SSRI Fluoxetine in combination with 1-5-hydroxytryptophane for the treatment of hypertension. The antihypertensive effects of 1-5-hydroxytryptophane are well known, with numerous publications testing this compound on hypertensive rats (Baron, A., Riesselmann, A. and Fregly, M. J., "Reduction in the elevated blood pressure of Dahl salt-sensitive rats treated chronically with L-5-hydroxytryptophan". Pharmacology 42, 15-22, 1991; Fregly, M. J., Lockley, O. E. and Sumners, C, "Chronic treatment with L-5-hydroxytryptophan prevents the development of DOCA-salt-induced hypertension in rats". J Hypertens 5, 621-628, 1987; Fuller, R. W., Holland, D. R., Yen, T. T., Bemis, K. G. and Stamm, N. B., "Antihypertensive effects of fluoxetine and L-5-hydroxytryptophan in rats". Life Sci 25, 1237-1242, 1979; Salcedo, M., Munoz, M. C, Ruiz de Castroviejo, J., Fontans, J. V., Pozo, R. and Montilla, P., "Effect of brain serotonin on the arterial pressure and plasma renin in normal and hypertensive rats". Rev Esp Fisiol 48, 115-120, 1992). On the other hand, there are very few studies that indicate a significant effect of fluoxetine on hypertension, among them one by the author of the patent in combination with L-5- hydroxytryptophan (Fuller, R. W., Holland, D. R., Yen, T. T., Bemis, K. G. and Stamm, N. B., "Antihypertensive effects of fluoxetine and L-5-hydroxytryptophan in rats". Life Sci 25, 1237-1242, 1979). In fact, there are even publications that describe an increase of the blood pressure induced by fluoxetine in rats ("Tsai, M. L. and Lin, M. T., "Hypertension and tachycardia produced by inhibition of reuptake of 5- hydroxytryptamine by fluoxetine in the rat". Neuropharmacology 25, 799-802, 1986). This effect does not invalidate the principal hypothesis of the present invention regarding the other SSRIs, because the hypertensive effect of fluoxetine seems to be genuine of fluoxetine and has not been reported for other SSRIs. Given the known hypotensive effects of 1-5-hydroxytryptophane and the divergent but potentially adverse effects of fluoxetine on blood pressure, it is surprising that this patent claimed the use of fluoxetine alone. In fact, in the description of the patent the hypotensive effects are attributed to 1-5- hydroxytryptophane, and the claim of fluoxetine by itself for the treatment of HT is the very last claim. Furthermore, the pharmaceutical company that owns the patent has not promoted any clinical trials. These considerations suggest that the claim of fluoxetine alone is more due to a protection strategy of a potentially interesting effect of this drug, than to an understanding of the pathophysiologic mechamsms underlying the effect, as it is the case for the present invention. Furthermore, the fact that the patent doesn't cover any other SSRI for the treatment of HT demonstrates the non-obviousness of the present invention.

[0010] US5597826 "Compositions containing Sertraline and a 5-HT_ID receptor agonist or antagonist": This patent claims the use of Sertraline associated with an agonist or antagonist of the 5-Htιo receptor for the treatment of a large number of diseases, among them hypertension. As opposed to the patent described above for fluoxetine, in this patent Sertraline is never claimed by itself for the treatment of hypertension, but only when combined with a 5-HT_ID receptor ligand. Therefore, this patent does not prevent the present invention. In fact, among both compounds, Sertraline and 5-HT_ID ligand, it is the 5-HT_ID ligand that has been associated with hypertension in scientific publications (Saxena PR, Villalon CM., J Cardiovasc Pharmacol, 15 Suppl 7:S17-34, 1990, referred to as the "5HTl-like receptor") and patents (US5571833: Analogs of Tryptamine, their synthesis and their use as "5-HT^like" or 5-HT₂ receptor agonists). Further to the point, the pharmaceutical company that owns this patent has not promoted any clinical trials for HT based on this patent.

[0011] There is a set of patents issued for the use of SSRIs for prevention or treatment of medical conditions that might be related to hypertension: US5296507 ("Treatment of cerebrovascular diseases", based on Citalopram); WO9903469A1 ("Treatment and prevention of cardiac disorders using Selective Serotonin Re-uptake Inhibitors (SSRI)); EP0768083A3 ("The use of sertraline to treat post myocardial infarction patients"); US6245782 ("Methods of inhibiting platelet activation with selective serotonin reuptake inhibitors"). It should be highlighted that none of these patents claim the treatment or prevention of hypertension by SSRIs.

[0012] In conclusion, the present invention does not arise from obvious extrapolation on the existing patents. The present invention is not derived from prior knowledge in an obvious way, not even for experts in the field of psychiatry or in the medical specialties such as Cardiology or Internal Medicine that traditionally study and treat Hypertension. It constitutes a novel invention that is the result of years of work and efforts in this line of research by the applicant, as described in the next section.

SUMMARY OF THE INVENTION

[0013] The present invention is based on the discovery that SSRIs citalopram, sertraline, paroxetine, or fluvoxamine are useful for the treatment of hypertension. In one embodiment, the invention includes a method of preventing and/or treating hypertension of a subject in need thereof including administering to the subject a hypotensive effective amount of at least one Selective Serotonin Re-uptake Inhibitor (SSRI), or of a pharmaceutically acceptable salt thereof, the SSRI is selected from citalopram, sertraline, paroxetine, or fluvoxamine, and their metabolites or active derivatives thereof.

[0014] In a further aspect, the subject has hypertension and one or more psychiatric or non-psychiatric disorders, and is treated by the method of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention describes a new therapeutic method for the prevention and/or treatment of hypertension, and of diseases or medical syndromes in which hypertension is a risk factor or a complication, using the Selective Serotonin Re-uptake Inhibitors (SSRIs) antidepressants, selected from the group consisting of Citalopram, Fluvoxamine, Sertraline, and Paroxetine (so called by their generic name). The present invention is also related to the use of the above-mentioned mentioned SSRIs for the preparation of medicaments for the prevention and/or treatment of hypertension as well as of the diseases or medical syndromes in which hypertension is a risk factor or a complication.

[0016] The present invention is the result of a novel hypothesis both for the comprehension of the pathophysiology of hypertension, and for its prevention and/or treatment. According to the hypothesis, a neurobiological dysfunction would be responsible for the hypertension in a significant percentage of patients, and the use of drugs such as the SSRIs would correct such a dysfunction. The novelty and the inventive activity of the present invention are based specifically in the originality of linking the neurobiological understanding of the etiology of hypertension with drugs such as SSRIs for its prevention and/or treatment. As previously stated in the previous section, SSRIs are well known antidepressant drugs far removed from the current therapeutic approaches to hypertension. Notably, the general validity of the hypothesized neurobiological mechanism that controls the blood pressure means that the proposed treatment based on SSRIs may have general validity for most HT patients, including patients for whom their hypertension is not the result of a neurobiological dysfunction.

[0017] Hypothesis of a neurobiological dysfunction responsible for hypertension: The neurobiological dysfunction that induces the development of hypertension might be linked, among others, to the level of arousal and stress responses. Arousal defines the level of cortical alertness, presumably as a response to sensorial stimulation through the reticular activation system (a neurological structure in the stem branch). Stress responses include both physical and mental (or psychological) stress responses. The hypothesized neurobiological dysfunction, involves complex networks and systems of the Central, Peripheral and Autonomous Nervous System. Thus, these neuroanatomic, neurotransmitter and neurohormonal networks, which includes structures such as the frontal lobes, the locus coeruleus, and the hypothalamic-pituitary-adrenal axis, would be responsible for a rise in the blood pressure induced by a certain level of arousal and/or stress response. According to the present invention, a high percentage of hypertensive patients would generate excessive levels of response to a given physical and/or mental stimulus, either through arousal or through stress responses. SSRIs would be effective in the prevention and/or treatment of hypertension because they correct this excessive level of response that characterizes the neurobiological dysfunction. Therefore SSRIs, by correcting or regulating the excessive level of response, may correct or regulate high blood pressure in a significant percentage of hypertensive patients.

[0018] As exposed in the previous section, SSRIs are currently the most widely prescribed antidepressants, and their main established pharmacological action is to increase synaptic serotonin transmission. Serotonin neurons are involved in different brain functions such as behavior, sleep, sexual activity and hypothalamic control of neurohormonal pituitary release. The increase of serotonergic transmission is though to be the basis for the efficacy of SSRIs in the treatment of depression or anxiety. However, since serotonergic transmission is involved in multiple functions, SSRIs have also been found to be effective in other pathologies such as eating behavior disorders and diseases related to platelet activation. The inventor hypothesizes that an additional brain function affected by serotonergic transmission might be the neurobiological regulation of blood pressure. By modulating serotonergic transmission, SSRIs might correct the neurobiological dysfunction underlying high blood pressure. Furthermore, even for those patients whose hypertension is due to other factors unrelated to the neurobiological mechanism here hypothesized, SSRIs might still be an effective therapy. The reason is that SSRIs could still modulate blood pressure by acting on said neurobiological mechanism, even if it isn't the main cause of the hypertension.

[0019] Although there is a tendency to identify SSRIs as members of the same family, the fact is that the five SSRIs are not members of the same chemical classes and do not share the same binding characteristics (Stahl SM. "Not so selective serotonin reuptake inhibitors". J Clin Psychiatry, 59:343-4, 1998; Thase ME, Feighner JP, Lydiard RB. "Citalopram treatment of fluoxetine nonresponders". J Clin Psychiatry 62:683-7, 2001; Thase ME, Blomgren SL, Birkett MA, Apter JT, Tepner RG. "Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline". J Clin Psychiatry 58:16-21, 1997; Wheatley DP, van Moffaert M, Timmerman L, Kremer CM. "Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. Mirtazapine-Fluoxetine Study Group". J Clin Psychiatry 59:306-12, 1998; Zarate, C. A., J. C. Kando, et al.. "Does intolerance or lack of response with fluoxetine predict the same will happen with sertraline?" J Clin Psychiatry, 57: 67-71, 1996; Goodwin, G. M. "How do antidepressants affect serotonin receptors? The role of serotonin receptors in the therapeutic and side effect profile of the SSRIs." J Clin Psychiatry, 57(Suppl 4): 9-13, 1996; Mourilhe, P. & Stokes. P.E. "Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression.", Drug Saf., 18, 57-82,1998). Although all of the SSRIs share a presumed primary mechanism of action, their individual postsynaptic binding characteristics, pharmacokinetic profiles, and other secondary pharmacological properties may lead to significances and clinically relevant differences among themselves (Stahl S.M. "Not so selective serotonin reuptake inhibitors". J Clin Psychiatry, 59:343-4, 1998). In fact, it is a common observation that some patients respond differently to different SSRIs, not only due to their side effects, but also to their differential therapeutic efficacy. Consequently, whereas all of them seem to share a common main mechanism of action, at the same time they are different among themselves. Therefore, it is of interest to patent and study the efficacy in the treatment and/or prevention of hypertension for each of them.

[0020] The present invention relates to a new method for the treatment and/or prevention of hypertension comprising the administration of an effective, non-toxic, hypotensive amount of at least one Selective Serotonin Re-uptake Inhibitor (SSRI), or a pharmaceutically acceptable salt thereof, to a human or non- human animal in need thereof. The present invention also relates to the use of at least one SSRI, or a pharmaceutically acceptable salt thereof, for the preparation of medicaments for the prevention and/or treatment of hypertension to a human or non- human animal in need thereof. For the two applications mentioned above, the present invention also relates to the prevention and/or treatment of diseases or medical syndromes in which high blood pressure is a risk factor or a complication.

[0021] In the present invention, unless otherwise specified, the term SSRI or selective serotonin re-uptake inhibitor, as used herein, refers to the group constituted by Citalopram, Paroxetine, Fluvoxamine and Sertraline, including their pharmaceutically acceptable salts and their metabolites or active derivatives of their respective pharmacological classes. Examples of pharmaceutically acceptable salts of SSRIs of Citalopram, Fluvoxamine, Sertraline and Paroxetine are: hydrobromide, hydrochloride, acetate, and maleate. An active derivate of Citalopram is currently marketed as Escitalopram, and would thus be also covered by this invention.

[0022] When the method for preventing and/or treating hypertension and when the manufacture of medicaments for use in the prevention and/or treatment of hypertension, comprise the administration of more than one SSRI.

[0023] When two or more SSRIs are combined, the co-administration might be in a simultaneous, sequential or separated manner. The SSRIs might then be prepared either as a combined pharmaceutical preparation (for example, a tablet that contains the mixture), or be administered independently, each SSRI in its respective formulation.

[0024] Another embodiment of the present invention relates to the co-administration of at least one SSRI and at least one drug or compositions used to treat hypertension, for preventing and/or treating hypertension, its complications, and the diseases or medical syndromes in which hypertension constitutes a risk factor or a complication, to a human or non-human animal in need thereof. This co-administration might be in a simultaneous, sequential or separated manner. For instance, a co-administration of potential interest might be the combination of one SSRI and a beta-blocker, or of one SSRI with a beta- blocker and a diuretic.

[0025] Another embodiment of the present invention relates to the use of at least one SSRI and at least one drug or compositions used to treat hypertension, for the preparation of medicaments for use in the prevention and/or treatment of hypertension, its complications, and the diseases and medical syndromes in which hypertension constitutes a risk factor or a complication, to a human or non-human animal in need thereof. This co- administration might be in a simultaneous, sequential or separated manner. The diseases and medical syndromes in which hypertension constitutes a risk factor or a complication can be selected from a very wide group of diseases constituted by, but not limited to: Cardiovascular diseases, Renal diseases, Diabetes Mellitus, Dyslipidemias, Sleep apnea, Bronchial asthma or Chronic Airway Disease, Gout, Transient Post-Partum Hypertension, as well as individuals under the effects of agents known to induce hypertension such as ***e, amphetamine, immunosuppressive agents, and erythropoietin.

[0026] For example, the group of cardiovascular diseases encompasses among others: cerebrovascular diseases, coronary artery disease (such as myocardial infarction and angina pectoris), left ventricular hypertrophy, cardiac failure, and peripheral arterial disease. In fact, the list of diseases for which hypertension represents a risk factor or a complication is very large if we bear in mind that, besides being the more prevalent chronic disease in the industrialized world, it is also the one that most frequently concurs with other medical conditions. An example would be hypertension comorbidity with obesity or depression.

[0027] The present invention also includes the condition referred to as "White Coat Syndrome" (WCS), which is defined as a persistently elevated clinic pressure together with a normal daytime ambulatory pressure (PickeringTG. "White coat hypertension." Current opinion Nephrol Hypertens 5:192-198, 1996). Some patients become anxious and develop transient hypertension in front of their doctors or other medical professionals, or in work-related or other stressful scenarios. This psychopathological response has been called White Coat Syndrome (Pickering T.G. "Mental stress as a causal factor in the development of hypertension and cardiovascular disease." Curr. Hypertens. Rep., 3:249- 54, 2001), also called "pseudo-hypertension". Approximately 20-30% of hypertensive patients suffer from a pronounced WCS (PickeringTG. "White coat hypertension." Current opinion Nephrol Hypertens 5:192-198, 1996). Although the cardiovascular prognosis of these individuals remains to be determined, their probability of developing Hypertension is increased in comparison with normotensive subjects. Given the psychophysiological basis attributed to this medical condition, the proposed treatment with SSRIs might be particularly beneficial for patients suffering from WCS.

[0028] The terms "treating and preventing" used in the present invention, unless otherwise specified, refers also to a method of improving the quality of life for the hypertensive individuals, or for individuals that suffer diseases or medical syndromes in which hypertension constitutes either a risk factor or a complication. It is believed that SSRIs will improve the quality of life for these patients, regardless of whether they are suffering from clinical depression, anxiety, or high levels of stress. Quality of life can be measured according to any validated scale that is recognized by those skilled in the art. Examples are the Katz activities of daily Living scale ((Katz et al., "Katz Activities of Daily Living Scale", Int. J. Health Serv., 6: 493-507, 1976), or the Sickness Impact Profile (Bergner et al., "Sickness Impact Profile", Med. Care, 14:57-67, 1976).

[0029] The pharmaceutical formulations of the present invention (Citalopram, Sertraline, Fluvoxamine, and Paroxetine, their metabolites or their active derivatives of its pharmacological classes, or their pharmaceutically acceptable salts), can be formulated according to conventional methods, both for oral or parenteral presentations as well as for any other route of administration that might be efficacious, such as rectal, topic, for implant, inhalation, etc. Also, when convenient, pharmaceutical formulations can be prepared for slow-release, depot or retard presentations/administrations. An example is Paroxetine CR (marketed as "Paxil CR"), which is a Controlled Release (CR) preparation. All of the mentioned pharmaceutical formulations can be administered for any route alone or in combination with an appropriate carrier. The mentioned carrier may include for example solid dissolvents or filters, sterile aqueous mediums, various non-toxic organic solvents, etc. For any of the above-mentioned formulations and delivery routes, administration can be done either in single or multiple doses.

[0030] The SSRIs as used in the present invention include enantiomers and other similar molecules. The compounds according to this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The term "stereoisomer" refers to a chemical compound having the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light. However, some pure stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation. The compounds described herein may have one or more asymmetrical carbon atoms and therefore include various stereoisomers. All such isomeric forms of these compounds are expressly included in the present invention. For example, the most active isomer of Citalopram is Escitalopram (currently marketed as Lexapro), and would thus be also covered by this invention.

[0031] Each stereogenic carbon may be of R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned. When chiral centers are found in the derivatives of this invention, it is to be understood that this invention encompasses all possible stereoisomers. The terms "optically pure compound" or "optically pure isomer" refers to a single stereoisomer of a chiral compound regardless of the configuration of the compound.

[0032] The appropriate dosage range of any given case will depend on the selected SSRI or SSRIs, on the selected route of administration, on the co-administration of other drugs, on the severity of the hypertension and on the individual characteristics of the patient.

[0033] The main advantages that SSRIs could provide to the treatment of hypertension in comparison with the available anti-hypertensive drugs or compositions are the following:

[0034] SSRIs might represent a new therapeutic alternative for hypertension. Their use as anti-hypertensive drugs could promote a better understanding of the neurobiological basis of high blood pressure.

[0035] SSRIs may have a strong advantage with respect to the standard antihypertensive drugs in that they are known to improve quality of life, which would facilitate behavioral changes and life-style modifications. These beneficial effects of SSRIs are likely to improve compliance to treatment, including consistent modification of their life-style, which represents a protective factor of major importance in the control of hypertension, and by extension of cardiovascular diseases. Therefore, patients might not only improve compliance with the treatment but also feel more motivated to loose weight, stop smoking, keep blood cholesterol levels, not abuse from alcohol, make regular physical exercise, etc.

[0036] On the other hand, it is feasible that in a significant percentage of patients, sub- threshold depressive or anxiety symptoms might be sufficiently detrimental to induce or aggravate Hypertension, as well as to impair quality of life. Lower quality of life may result in unhealthy behaviors and/or unsatisfactory compliance with the anti-hypertensive treatment. In these cases, the SSRI prescribed for hypertension might correct those symptoms and consequently improve compliance, quality of life and life-style modification. For instance, let us imagine a case of mild hypertension for which an SSRI might be prescribed; in addition to controlling high blood pressure, the SSRI might help in life-style modification which, in a relatively short period of time, may significantly decrease the high blood pressure to the point where the dose of SSRI would be lowered or even stopped.

[0037] SSRIs might constitute first choice medications for any condition in which hypertension co-occurs with any psychiatric condition for which SSRIs are efficacious, including the risk of suffering such psychiatric condition. The present invention also covers comorbidity of Hypertension with other non-psychiatric conditions that could be treated with SSRIs, such as cardiovascular diseases (e.g. cerebrovascular diseases and post myocardial infarction), and medical conditions where there is a need to inhibit platelet activation. Comorbidity represents a clinical situation of major importance, given that the majority of patients suffer from more than one disease at the same time. Psychiatric conditions include a depressive disorder such as major depression, minor depression, subthreshold depression, unipolar depression, bipolar depression, or dysthimia, prevention of relapse following long-term treatment of major depressive disorder, or any human suffering from depression, an anxiety disorder such as generalized anxiety disorder, panic disorder, panic attacks, specific phobias, social anxiety disorder, social phobia, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder (including long-term treatment), an eating disorder such as bulimia, obesity, or anorexia nervosa, or dementias such as multi-infarct dementia, psychiatric symptoms associated with premenstrual disorders such as late luteal phase dysphoric disorder (pmdd) and premenstrual dysphoric disorder. Non-psychiatric conditions susceptible to be treated by an SSRI include cardiac diseases such as post myocardial infarction, cerebrovascular diseases, or medical conditions where there is a need to inhibit platelet activation.

[0038] Therefore, therapeutic approaches based on drugs that can treat two or more comorbid diseases are of major importance to public health. Hypertension is the more common comorbid medical disease. SSRIs are prescribed for depressive and anxiety disorders, which in turn are some of the more prevalent and comorbid diseases in the population. Furthermore, SSRIs are also effective for other many psychiatric conditions such as eating behavior disorders or dementias that might also be comorbid with hypertension. On the other hand, some antihypertensive drugs are even contraindicated when hypertension co-occurs with some psychiatric conditions such as depression. Such is the case of, for example, reserpine or some beta-blockers. Therefore, there is a significant proportion of hypertensive patients that also suffer from some psychiatric conditions for which the use of SSRIs would constitute first-choice drugs.

[0039] SSRIs may be especially beneficial for difficult to control types of Hypertension such as Labile or Borderline Hypertension, Hypertensive Paroxysms, and White-Coat Syndrome. SSRIs as antihypertensive drugs might also be specially beneficial to elderly patients due to the following reasons:

[0040] The high percentage of elder patients that suffer from hypertension (50% for the population older than 65 years of age) frequently suffer from isolated systolic high blood pressure, or labile high blood pressure. These conditions are difficult to manage, and SSRIs might be especially useful.

[0041] White Coat Syndrome occurs more frequently among the elderly, especially among the elderly women, and as previously stated, SSRIs might be also especially useful for this phenomenon. [0042] Geriatric patients are characterized by suffering several psychiatric disorders for which SSRIs are commonly prescribed as a first therapeutic option, such as depressive and anxiety disorders or dementias (such as Alzheimer or multi-infarct dementia). Even more, among this population it is unfortunately common to suffer from more than one condition suitable to be treated by an SSRI, in addition to high blood pressure. An example would be an elderly patient that is depressed and has a multi-infarct dementia; In this case, the use of a single drug such as the SSRIs could treat both illnesses.

[0043] Elderly patients are frequently polymedicated and it has been shown that being an elder and being polymedicated constitutes a predictor of poor control of high blood pressure.

[0044] Geriatric patients are characterized by an impaired quality of life that could be improved by SSRIs, regardless of whether they suffer from psychiatric disorders such as depression.

[0045] In conclusion, SSRIs will most likely become first choice medications for hypertensive geriatric patients not only because there is a likely comorbidity with another disorder treatable by SSRIs, but also because of the additional benefits of SSRIs in improving quality of life, compliance and facilitating life-style modification.

[0046] In cases where an SSRI would be co-administered with another antihypertensive drug, dosages of both drugs might be reduced, thus reducing adverse side effects. An example would be the case of an SSRI administered together with a beta- blocker. As stated above, this scenario might be particularly useful for the elderly.

[0047] SSRIs might be the most useful anti-hypertensive drugs for the treatment of cases in which high blood pressure is associated with the WCS, a phenomenon that available anti-hypertensive drugs do not control.

[0048] Left Ventricular Hypertrophy (LVH) is a typical complication of high blood pressure, particularly of systolic high blood pressure. Also, it has been showed that susceptibility to a hyper-reactive haemodynamic response to mental stress predicts the growth of left ventricular mass among hypertensive individuals (Kop, W. J., J. S.Gottdiener, et al. "Relationship between left ventricular mass and hemodynamic responses to physical and mental stress." J Psychosom Res 48(1): 79-88, 2000; Tennant, C. "Life stress and hypertension." J Cardiovasc Risk 8(1): 51-6, 2001). SSRIs might thus be useful in preventing and reducing LVH.

[0049] Since the introduction of the first SSRI (Fluoxetine) in the mid 80s, more than 35 million patients have been treated with SSRIs (Mourilhe, P. & Stokes, P.E., "Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression.", Drug Saf, 18, 57-82,1998). As a result, safety, toxicology and dosage of these drugs have been extensively evaluated, being globally very satisfactory, which facilitates the implementation of the present invention.

[0050] Pharmaceutical compositions employed as a component of invention articles of manufacture can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the compounds described above as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Compounds employed for use as a component of invention articles of manufacture may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.

[0051] The present invention also provides pharmaceutical compositions comprising at least one invention compound capable of treating a hypertensive disorder, in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

[0052] Invention pharmaceutical compositions may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non- aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.

[0053] In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).

[0054] The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0055] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. .

[0056] The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment.

[0057] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.

[0058] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0059] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.

[0060] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0061] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0062] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0063] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0064] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

[0065] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0066] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0067] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. [0068] The following examples are intended to illustrate but not limit the invention.

EXAMPLE 1

[0069] For the preparation of the present invention, the applicant has confirmed the efficacy of SSRIs in reducing high blood pressure in several patients that suffered from Essential or Primary Hypertension or from Secondary Hypertension.

[0070] For both Primary Hypertension and Secondary Hypertension, the applicant has confirmed the efficacy of SSRIs in controlling the high blood pressure of patients that had been previously assessed and treated by physicians from other disciplines, such as cardiologists, internists and primary care physicians, without reaching a satisfactory control of their systolic and diastolic blood pressures.

[0071] All the patients suffered from anxiety disorders, such as Panic Attack, or depressive disorders, such as Major Depression, that co-occurred with their hypertensive condition. Age range was from adults older than 45 years of age to the geriatric age. When these patients were treated with SSRIs as an indication for their mentioned psychiatric disorders, the applicant observed the following striking finding: Their hypertension improved to the extent of reducing significantly, or even stopping altogether, the anti-hypertension medication they were taking.

[0072] Three patient cases are presented below as examples that illustrate in detail the benefits of the invention.

[0073] Patient #1 :

[0074] A 60-year-old Caucasian women reported suffering a history of dizziness and vertigo since she was 25-years of age, for which extensive investigation had revealed neither neurological nor Oto-Rhino-Laryngological origin. No other relevant medical history. Psychiatric History: Obsessive-Compulsive personality traits. Family History: mother died at 47-years of age due to a constrictive pericarditis promoted by a Thymus Neoplasia. Father died at 82-years of age because an Acute Myocardial Infarction, without a clear history of Hypertension. [0075] According to both the patient and the provided clinical reports, she was suffering a 1-year period of hypertensive paroxysms. At the beginning the episodes occurred 1 to several months apart, but in the last month she was experiencing up to 5 episodes for which she had repeatedly gone to the emergency room. In these episodes, Systolic blood pressure rose to 114-220 mm Hg, and diastolic blood pressure rose to 100- 120 mm Hg. The episodes were accompanied by tachycardia, palpitations, and chest discomfort, but without chest pain or pressure, mild nausea and dizziness. Occasionally frontal-temporal throbbing and tinnitus accompanied the episodes, and in two episodes the patient felt difficulties in language articulation without any other neurological focality. Cardiovascular examination performed while experiencing the hypertensive paroxysms was normal, with the exception of two episodes in which arrhythmia and extrasystolia were detected. The majority of the times, the episodes were satisfactory controlled in the emergency room with sub-lingual nifedipine, although the patient frequently self- medicated herself with one to two capsules of Bromazepam 1.5 mg prior to going to the emergency room. In the six months prior to the psychiatric evaluation conducted by the aplicant, extensive investigation had ruled out cardiovascular, endocrinological (pheocromocitoma, hyperthyroidism, etc), renal or neurological origin of her hypertensive paroxysms. One month prior to this evaluation a beta-blocker, Propanolol: 20 mg/day, had been prescribed. Her primary care physician had also prescribed an antidepressant treatment with Prozac (Fluoxetine), that the patient refused to take, scared about its potential side effects. In the month prior to this evaluation, and in spite of the Propanolol treatment, she experienced 5 hypertensive paroxysms.

[0076] When an extensive psychiatric evaluation was performed, a clear Panic Attack Anxiety Disorder with a prominent cardiovascular profile that accompanied the hypertensive paroxysms was detected. Furthermore, a Major Depressive Disorder spanning the last VΛ year was also diagnosed, which was secondary to the long period of illness and ulterior death of her partner. The depressive episode was characterized by a melancholic pattern, which included intense subjective anxiety, persistent conciliatory and early awakens insomnia, and loss of 5 kg of weight. Thought content was obsessive with intense hypochondriac ideation. Most of the times, the hypertensive paroxysms occurred while experiencing a panic attack characterized by: palpitations, nausea, shortness of breath, chest pressure, trembling, peri-oral tingling sensations, and dizziness, all systematically accompanied by fear of dying, or of suffering a myocardial infarction, or a stroke. The panic attacks and associated hypertensive paroxysms always occurred in her home while she was alone. Since the onset of the panic attacks and hypertensive paroxysms, she progressively self-confined herself at home out of fear of suffering panic attacks away from her home. As a result, she developed agoraphobia. In summary, the diagnosis was a psychiatric comorbidity case characterized by: a severe Major Depressive episode with melancholic pattern that complicated grief, co-occurring with a Panic Attack Disorder associated with hypertensive paroxysms, and complicated by Agoraphobia.

[0077] An antidepressant treatment with Prozac (Fluoxetine) in progressively higher amounts, beginning with 12.5 mg day, was prescribed together with 2.5 mg/day of Lorazepam, a more potent anxiolytic bezodiazepine than the Bromazepam that she was taking. After 8 weeks of treatment with 20 mg of Fluoxetine and between 3 to 5 mg of Lorazepam per day, a significant improvement of the depressive and panic attack with agoraphobia disorders was observed. However, mild depressive symptoms persisted and she still suffered from up to three panic attacks accompanied with hypertensive paroxysms in this period of time, making impossible the reduction of Lorazepam. Therefore, a substitution of the antidepressant was decided. Maprotiline was prescribed in increasing amounts beginning with 25 mg per day. In the next 5 weeks a daily dose of 150 mg/day of Maprotiline was reached with a reduced dose of 1 mg/night of Lorazepam. Since then, the depressive and anxiety disorders were successfully controlled as well as the hypertensive paroxysms. However, after being asymptomatic during almost 8 months while still on the mentioned antidepressant treatment, she began again to suffer panic attacks with hypertensive paroxysms, with systolic blood pressure between 114-220 mm Hg, and diastolic blood pressure between 100-120 mm Hg. Maprotiline, was progressively withdrawn and substituted by Sertraline, in increasing doses beginning with 25 mg/day. By the time the dose of Sertraline reached 50 mg/day, no more panic attacks or hypertensive paroxysms were reported. In 5 weeks, a daily dose of 100 mg of Sertraline was reached, and Maprotiline was completely withdrawn, sustaining 0.5-1 mg of Lorazepam at bedtime. Patient persisted free of symptoms, with blood pressure stabilized in 110/65 mm Hg, with no hypertensive paroxysms. During the next month, Lorazepam was progressively withdrawn. During the following 5 months she kept only a daily dose of 100 mg of Sertraline persisting free of symptoms. At that time, she began to suffer gastrointestinal side effects attributable to Sertraline, and the dose was progressively reduced to a well-tolerated dose of 25 mg per day, which was sustained during the next 6 months. Throughout all this period of time she was free of symptoms. Then, Sertraline was progressively withdrawn. During the next year, the patient persisted free of medication and of symptoms, with her blood pressure stable around 110/60 mm Hg, without experiencing again any hypertensive paroxysm.

[0078] It seems that the treatment with the SSRI antidepressant Sertraline was strikingly effective in controlling blood pressure to the extent of stopping the antihypertensive treatment. Fluoxetine was only partially effective and Maprotiline was only temporarily effective. Even more, it seems important to mention that only with Sertraline the patient reported that she experienced a kind of "feeling less", and "being less reactive" to any kind of stimuli, including startle responses.

[0079] Patient #2:

[0080] A 77-year-old Caucasian woman with a history of Diabetes Mellitus (DM) since she was 45 years of age. During the first 12 years her DM did not need insulin to be treated (DMNID), but in the last 20 years the DMNID had evolved to an insulin dependant Diabetes (DMID), which was treated both with oral anti-diabetics and insulin. She suffered from hypertension for several years, which was being treated with 5 mg of Enalapril, an Angiotensin Converting Enzyme (ACE) inhibitor, twice a day. However, her blood pressure was unsatisfactorily controlled, with high systolic blood pressure ranging between 180 to 200 mm Hg and high diastolic blood pressure ranging between 95-100 mm Hg. Five months prior to this psychiatric evaluation she suffered a Transient Ischemic Accident (TIA). In the 4 months prior to this psychiatric evaluation she was suffering a sciatic syndrome in her right inferior limb, which produced intense pain that was treated in a pain clinic with several drugs, although the pain persisted. She was moderately overweight without any other relevant medical illness. [0081] Psychiatric history: depressive syndrome secondary to retirement at 72-years of age, that was untreated. Cognitive impairment within the year that preceded this psychiatric evaluation, which was aggravated since the TIA.

[0082] The family asked for psychiatric consultation given that they noticed depressive symptoms and impairment in her cognitive performance, in the 4 months prior to this evaluation. With increasing frequency, the patient had become disoriented to both time and place, and occasionally, she suffered isolated episodes of confusion and disorientation with her environment that were accompanied by intense anxiety and sometimes even psychomotor agitation.

[0083] Extensive neurological and psychiatric examinations were performed that included hemogram, extensive biochemistry including thyroid profile, and Nuclear Magnetic Resonance (NMR). The diagnosis was Major Depression of moderate severity with melancholic pattern, and a Multifactorial (Multi-infarct and Alzheimer-type) Dementia. Sertraline was prescribed, in increasing doses beginning with 12.5 mg/day, doubling the dose every five-day period until reaching a dose of 150 mg/day. The patient responded very favorably to treatment, showing not only a resolution of the depressive episode but also a significant improvement of her cognitive impairment. Notably, the treatment also had a profound effect on her Hypertension. Her blood pressure was reduced to the extent that her primary care physician first reduced the anti-hypertensive treatment, and ultimately stopped it altogether after only 4 weeks of treatment with 150 mg/day of Sertraline. The patient's blood pressure level remained stable around 140-145 mmHg systolic blood pressure and 80-90 mmHg diastolic blood pressure for a full year, during which the same treatment with Sertraline was sustained.

[0084] Patient #3:

[0085] A 65-year-old woman with a history of Bronchial Asthma and Intestinal Diverticulosis, which required surgery 7 years prior to this evaluation. Irritable Bowel Syndrome since her youth. Labile Hypertension accompanied with the White Coat Syndrome phenomenon since she was 30 years of age, treated only with life-style modification without pharmacological treatment. Three months prior to her psychiatric evaluation, she suffered an Acute Cholecistitis followed by surgery one month later due to an underlying Colelitiasis, with severe post-surgical complications.

[0086] Psychiatric history: Obsessive-Compulsive personality traits. Mild to moderate alcohol consumption. Never smoking. Family history: Father was hypertensive and died at 81 years of age due to an acute myocardial infarction. One brother diagnosed with Essential Hypertension.

[0087] All along the last three months, every time that her blood pressure was measured, either by herself or in the physician's office, she presented high blood pressure levels that ranged between 180-200 mmHg of systolic blood pressure and 100-120 mmHg of diastolic blood pressure. After ruling out an organic cause and during the last month, her primary care physician prescribed anti-hypertensive treatment with 75 mg/day of Captopril, an inhibitor of the Angiotensin Converting Enzyme. However, the patient remained with high blood pressure levels (180/100 mmHg) every time it was measured, although slightly lower than prior to the anti-hypertensive treatment.

[0088] The family convinced the patient to undergo a psychiatric evaluation as they noticed anxiety and depressive symptoms with intense hypochondriac ideation that significantly impaired the patient's global functioning since she was discharged from the hospital after surgery.

[0089] After the psychiatric evaluation, a Severe Major Depressive episode with melancholic pattern was diagnosed. The depressive episode was characterized by severe somatic anxiety (lump in the throat, palpitations, sweating, nausea, distal tremor in superior limbs), and obsessive thought centered on hypochondriac fears experienced with high levels of subjective anxiety. No panic attacks. Weight loss of 5 kg during the last three months.

[0090] Antidepressant treatment with Sertraline was prescribed, beginning with 12.5 mg/day during the first week, doubling the dose to 25 mg/day in the second week, increasing the dose progressively 25 mg every week to reach 150 mg/day. From the beginning an anxiolytic benzodiazepine, Lorazepam 1 mg, was also prescribed. The initial dose of 1.5 mg/day of Lorazepam (0.5mg-0.5mg-0.5mg) was increased from the second to the sixth week to 2.5-5 mg/day as needed, while the optimal dose of Sertraline was reached. The anxiolytic treatment was meant to control the intense anxiety and persistent insomnia that characterized the depressive episode. Accordingly, Lorazepam dosage was progressively reduced from the sixth week, to 2 mg/day the seventh week, and to 1 mg/day the twelfth week until it was stopped two weeks later.

[0091] Strikingly, a progressive reduction in blood pressure levels was observed from the very first week of treatment. The first week blood pressure levels were already lower from 180/100 prior to treatment to 180/90 mmHg, measured 3 different days. From the eight week of treatment, when she was taking 150 mg/day of Sertraline blood pressure levels were normalized at 130-140 mmHg of systolic blood pressure and 80 mmHg of diastolic blood pressure. Interestingly, measurement of the blood pressure either by herself, the pharmacist or the primary care physician resulted in normal levels. This means that the prescribed treatment with Sertraline was effective not only in controlling patient's labile Hypertension, but also patient's White Coat Syndrome. Notably, these results led the primary care physician to reduce progressively the anti-hypertensive treatment to 25 mg/day of Captopril.

[0092] The depressive episode was resolved after ten days of being treated with 150 mg/day of Sertraline, approximately at the end of the ninth week of treatment. Since the seventh month of treatment, the dose of Sertraline was reduced to 100 mg/day, because she presented digestive intolerance to the 150 mg/day dose. The patient remained euthymic and with normalized blood pressure.

[0093] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of preventing and/or treating hypertension of a subject in need thereof, comprising the administering to the subject a hypotensive effective amount of at least one Selective Serotonin Re-uptake Inhibitor (SSRI), or of a pharmaceutically acceptable salt thereof, wherein the SSRI is selected from the group consisting of citalopram, sertraline, paroxetine, and fluvoxamine, and their metabolites or active derivatives thereof.

2. The method of claim 1, wherein SSRIs are administered orally.

3. The method of claim 2, wherein the SSRI or a pharmaceutically acceptable salt thereof is administered orally in a dose of about lOmg/day to about 2,500mg/day.

4. The method of claim 1 , wherein the route of administration of the SSRIs or of the pharmaceutically acceptable salts is a parenteral, rectal, topical, transdermal or an inhalation route.

5. The method of claim 1, wherein the formulations for administering the SSRIs or the pharmaceutically acceptable salt thereof, comprise controlled-release, slow- release, or sustained formulations.

6. The method of claim 1, wherein hypertension is selected from primary or essential hypertension and secondary hypertension, including isolated systolic hypertension, labile hypertension, borderline hypertension, and hypertensive paroxysms.

7. The method of claim 1, wherein hypertension is a risk factor or a complication of conditions that are selected from cardiovascular diseases, renal diseases, diabetes mellitus, dyslipidemias, sleep apnea, bronchial asthma or chronic airway disease, gout, transient post-partum hypertension, and use of ***e, amphetamine, immunosuppressive agents, or erythropoietin.

8. The method of claim 7, wherein the group of cardiovascular diseases associated to hypertension include cerebrovascular diseases, coronary artery disease, left ventricular hypertrophy, cardiac failure, and peripheral arterial disease.

9. The method of claim 1 wherein SSRIs are effective in reducing left ventricular hypertrophy.

10. The method of claim 1 wherein SSRIs are effective for preventing and/or treating the "white coat syndrome" or "pseudo-hypertension", especially when hypertension is further complicated by this condition.

11. A method of preventing and/or treating hypertension of a subj ect in need thereof, comprising the administration to the subject an effective hypotensive amount of at least one Selective Serotonin Re-uptake Inhibitor (SSRI), or of a pharmaceutically acceptable salt thereof, and at least one other composition used for treating or preventing hypertension, wherein the SSRI is selected from the group consisting of citalopram, sertraline, paroxetine, and fluvoxamine, and their metabolites or active derivatives thereof

12. The method of claim 11, wherein SSRIs are administered orally.

13. The method of claim 12, wherein the SSRI or a pharmaceutically acceptable salt thereof is administered orally in a dose of about lOmg/day to about 2,500mg/day.

14. The method of claim 11 wherein the route of administration of the SSRIs or of the pharmaceutically acceptable salts is a parenteral, rectal, topical, transdermal or an inhalation route.

15. The method of claim 11 wherein the formulations for administering the SSRIs or the pharmaceutically acceptable salt thereof, comprises controlled-release, slow- release, or sustained formulations.

16. The method of claim 11 wherein co-administration can be in a separate, sequential or simultaneous manner.

17. The method of claim 11 wherein hypertension is selected from the group consisting of primary or essential hypertension and secondary hypertension, including isolated systolic hypertension, labile hypertension, borderline hypertension, and hypertensive paroxysms.

18. The method of claim 11 wherein hypertension is a risk factor or a complication of conditions that are selected from the group consisting of cardiovascular diseases, renal diseases, diabetes mellitus, dyslipidemias, sleep apnea, bronchial asthma or chronic airway disease, gout, transient post-partum hypertension, as well as subjects under the effects of agents known to induce hypertension such as ***e, amphetamine, immunosuppressive agents, and erythropoietin.

19. The method of claim 18 wherein the group of cardiovascular diseases associated to hypertension include cerebrovascular diseases, coronary artery disease, left ventricular hypertrophy, cardiac failure, and peripheral arterial disease.

20. The method of claim 11 wherein SSRIs are effective in reducing left ventricular hypertrophy.

21. The method of claim 11 wherein SSRIs are effective for preventing and/or treating the "white coat syndrome" or "pseudo-hypertension", especially when hypertension is further complicated by this condition.

22. The method of claim 11 wherein the compositions for preventing and/or treating hypertension are selected from the group consisting of diuretics, beta-blockers, beta and alpha-blockers, angiotensin-converting enzyme inhibitors, subtype II angiotensin receptor blockers, and calcium channel blockers.

23. The use of at least one SSRI, for the preparation of a medicament for preventing and/or treating hypertension of a subject in need thereof, wherein the SSRI is selected from the group consisting of citalopram, sertraline, paroxetine, fluvoxamine, their metabolites or their active derivatives from their respective pharmacological classes

24. The use of claim 23, wherein SSRIs are administered orally.

25. The use of claim 24, wherein the SSRI or a pharmaceutically acceptable salt thereof is administered orally in a dose of about lOmg/day to about 2,500mg/day.

26. The use of claim 23 wherein the route of administration of the SSRIs or of the pharmaceutically acceptable salts is parenteral, rectal, topical, transdermal or an inhalation route.

27. The use of claim 23 wherein the formulations for administering the SSRIs or the pharmaceutically acceptable salt thereof, comprises controlled-release, slow-release, or sustained formulations.

28. The use of claim 23 wherein hypertension is selected from the group consisting of primary or essential hypertension and secondary hypertension, including isolated systolic hypertension, labile hypertension, borderline hypertension, and hypertensive paroxysms.

29. The use of claim 23 wherein hypertension is a risk factor or a complication of conditions that are selected form the group consisting of cardiovascular diseases, renal diseases, diabetes mellitus, dyslipidemias, sleep apnea, bronchial asthma or chronic airway disease, gout, transient post-partum hypertension, as well as subjects under the effects of agents known to induce hypertension such as ***e, amphetamine, immunosuppressive agents, and erythropoietin.

30. The use of claim 29 wherein the group of cardiovascular diseases associated to hypertension is selected from the group consisting of cerebrovascular diseases, coronary artery disease, left ventricular hypertrophy, cardiac failure, and peripheral arterial disease.

31. The use of claim 23 wherein SSRIs are effective in reducing left ventricular hypertrophy.

32. The use of claim 23 wherein SSRIs are effective for preventing and/or treating the "white coat syndrome" or "pseudo-hypertension", especially when hypertension is further complicated by this condition.

33. The use of at least one SSRI, for the preparation of a medicament for preventing and/or treating hypertension of a subject in need thereof, comprising the administration to the subject of an effective hypotensive amount of at least one Selective Serotonin Re-uptake Inhibitor (SSRI), or of a pharmaceutically acceptable salt thereof, and at least one other composition used for treating or preventing hypertension, wherein the SSRI is selected from the group consisting of citalopram, sertraline, paroxetine, fluvoxamine, their metabolites or their active derivatives from their respective pharmacological classes.

34. The use of claim 33, wherein SSRIs are administered orally.

35. The use of claim 34, wherein the SSRI or a pharmaceutically acceptable salt thereof is administered orally in a dose of about lOmg/day to about 2,500mg/day.

36. The use of claim 33 wherein the route of administration of the SSRIs or of the pharmaceutically acceptable salts is the parenteral, rectal, topical, transdermal or an inhalation route.

37. The use of claim 33 wherein the formulations for administering the SSRIs or the pharmaceutically acceptable salt thereof, comprises controlled-release, slow-release, or sustained formulations.

38. The use of claim 33 wherein the co-administration can be in a separated, sequential or simultaneous manner.

39. The use of claim 33 wherein hypertension is selected from the group consisting of primary or essential hypertension and secondary hypertension, including isolated systolic hypertension, labile hypertension, borderline hypertension, and hypertensive paroxysms.

40. The use of claim 33 wherein hypertension is a risk factor or a complication of conditions that are selected form the group consisting of cardiovascular diseases, renal diseases, diabetes mellitus, dyslipidemias, sleep apnea, bronchial asthma or chronic airway disease, gout, transient post-partum hypertension, as well as subjects under the effects of agents known to induce hypertension such as ***e, amphetamine, immunosuppressive agents, and erythropoietin.

41. The use of claim 40 wherein the group of cardiovascular diseases associated to hypertension is selected from the group consisting of cerebrovascular diseases, coronary artery disease, left ventricular hypertrophy, cardiac failure, and peripheral arterial disease.

42. The use of claim 33 wherein SSRIs are effective in reducing left ventricular hypertrophy.

43. The use of claim 33 wherein SSRIs are effective for preventing and/or treating the "white coat syndrome" or "pseudo-hypertension", especially when hypertension is further complicated by this condition.

44. The use of claim 33 wherein the compositions for preventing and/or treating hypertension are selected from the group consisting of diuretics, beta-blockers, beta and alpha-blockers, angiotensin-converting enzyme inhibitors, subtype II angiotensin receptor blockers, and calcium channel blockers.

45. The method of any of claims 1 , 11 , 23 or 33, wherein the subject has also one or more psychiatric condition(s), or non-psychiatric condition(s), susceptible to be treated by an SSRI.

46. The method of claim 45, wherein the psychiatric condition is a depressive disorder such as major depression, minor depression, subthreshold depression, unipolar depression, bipolar depression, dysthimia, prevention of relapse following long-term treatment of major depressive disorder, or any human suffering from depression, an anxiety disorder such as generalized anxiety disorder, panic disorder, panic attacks, specific phobias, social anxiety disorder, social phobia, agoraphobia, obsessive- compulsive disorder, post-traumatic stress disorder (including long-term treatment), an eating disorder such as bulimia, obesity, or anorexia nervosa, or dementias such as multi- infarct dementia, psychiatric symptoms associated with premenstrual disorders such as late luteal phase dysphoric disorder (pmdd) and premenstrual dysphoric disorder.

47. The method of claim 45, wherein the non-psychiatric condition susceptible to be treated by an SSRI is selected from cardiac diseases such as post myocardial infarction, cerebrovascular diseases, or medical conditions where there is a need to inhibit platelet activation.