MXPA01009484A - Treatment of posttraumatic stress disorder, obsessive-compulsive disorder and related neuropsychiatric disorders - Google Patents

Abstract

The present invention describes a novel treatment for neuropsychiatric disorders, including anxiety disorders, mood disorders, psychotic disorders, somatoform disorders, and neuropsychiatric symptoms resulting from movement disorders. The treatment of the present invention utilizes any agent that simultaneously act as NMDA-type glutamate receptor antagonists and GABA-A receptor agonists. Preferably these two activities are characteristic of a single agent, for example acamprosate (calcium N-acetylhomotaurinate). Alternatively, separate agents having these activities can be combined as a compound or mixture and thereby administered together. The invention also provides for a third agent that acts as a non-competitive NMDA-receptor blocking agent or ion channel blocker, that augments the effect of the primary treatment. A particularly preferred ion channel blocking agent is magnesium.

Description

F TREATMENT OF POST-TRAUMATIC STRESS DISORDER, OBSESSIVE-COMPULSIVE DISORDER AND RELATED NEUROPSYCHIATRIC DISORDERS DESCRIPTION OF THE INVENTION 5 The present application is a request for continuation of part of co-pending US Patent Application Serial No. 09 / 006,641, filed on January 13, 1998, the complete contents of which are incorporated herein for reference. The present invention relates to novel drug treatments for neuropsychiatric disorders, for example, anxiety disorders, psychotic disorders, mood disorders and somatoform disorders. These treatments relieve symptoms of disorders characterized by thoughts, perceptions or behaviors, retrospective, stereotyped, unwanted, inopportune, or involuntary scenes. These include post-traumatic stress disorders, obsessive-compulsive disorder, somatization disorder, hypochondriasis, and body dysmorphic disorder. The contemporary drug therapy of these conditions is limited in efficacy, with many patients continuing to have symptoms despite treatment. Antidepressants, mood stabilizers, anti-anxiety drugs, and drugs antipsychotics have all been used to treat them. Even when they provide some relief, the persistent, untimely persistent mental phenomenon may remain as a distressing symptom. Thus, when a person with post-traumatic stress disorder is treated with an antidepressant, the mood may improve while the "flashback" of the traumatic event continues. Clearly, there is a need for the efficacies of additional drugs for the treatment of these disorders, and especially for drugs that suppress or eliminate unwanted, inopportune, or involuntary thoughts, perceptions, and behaviors of these disorders. Such medications can also be used to reduce such symptoms when they occur as part of another psychiatric syndrome, such as depression or schizophrenia, or when they are incidental to a neurological disorder such as Tourette's syndrome or Huntington's disease. The review of the prototypical conditions for which the novel treatment is useful has begun: Post-Traumatic Stress Disorders (PTSD) Description of PTSD Post-traumatic stress disorder is an immediate or delayed response to a catastrophic event, characterized by the following characteristics: "re-experiencing trauma, psychic insensitivity or evasion of stimulus associated with trauma, and increased excitement." The phenomenon of re-experimentation includes impertinent memories, flashbacks, nightmares, and psychological or physiological anguish in response to memories. The impertinent memories are spontaneous, unwanted, distressing memories of the traumatic event.Repeated nightmares contain highly accurate and detailed trauma or recreation motifs of current events or events.Retrospective scenes are dissociated states in which the components of the event They are remembered, and people feel as if he or she experienced the event for a few seconds as long as days. Reactivity to the stimulus related to trauma can involve intense emotional distress or physical symptoms similar to those of a panic attack, when the patient is exposed to observations, sounds, smells or events that occurred during the traumatic event. Evasion can include thoughts, feelings, situations or activities that are memories of the trauma. Insensitivity can occur through amnesia, emotional disinterest, restricted affection, or loss of interest in activities. The increased excitement may include insomnia, irritability, hypervigilance, increased fright response, or impaired concentration. This disorder can have pervasive effects on the interpersonal behavior of individuals and all spheres of their lives. "(Charney DS et al .: Neurobiological mechanisms of human anxiety.) In Fogel BS, Schiffer RB, Rao SM: Neuropsychiatry, Baltimore: Williams & Wil ins, 1996, pp. 257-286). Epidemiology of PTSD Among American veterans of the Vietnam War, the prevalence ratio of PTSD is estimated at 31% in men and 27% in women; the current estimated prevalence is 15% and 8.5%, respectively. In a summary of female victims of crime, the prevalence of life of PTSD is 13% and the current prevalence is 3%. Overall, PTSD affects 2% or more of the North American population (Charney et al., Supra). Among people with work-related injuries, the PTSD ratio may exceed one third, or even one half, if people with partial PTSD syndromes are included (Asmundson GJ, et al .: Postraumatic stress disorder and work-related injury. J Anxiety Disord, 12: 57-69, 1998 Jan-Feb). Evidently, PTSD is a significant public health problem. Complications and co-orbility There is a strong association between PTSD and substance abuse, especially alcoholism (Coffey SF, et al: Screening for PTSD in a substance abuse sample: psychometric properties of a modified version of the PTSD Sy ptom Scale Self- Report J Trauma Stress, 11: 393-9, 1998 Apr). In addition, chronic PTSD can increase a long-term risk to people from a wide range of chronic diseases. The repeated long term of men exposed to various stresses related to severe combat showed that PTSD significantly increases the risk of developed disorders of the circulatory, digestive and respiratory systems, as well as, infectious diseases, and neurological and psychiatric disorders other than PTSD ( Boscarino JA: Diseases among men 20 year after exposure to severe stress: implications for clinical research and medical care Psychosom, Med., 59-605-14, 1997 Nov-Dec). Several studies over the past decade have identified risk factors for the development of PTSD following an acute traumatic event. This includes inferior intelligence, a less developed narrative of the traumatic event, a history of previous trauma, and an elevated heart rate at the time of post-traumatic medical examination. If a person develops an acute stress disorder after a major traumatic event (ie, immediately shows symptoms resembling those of PTSD), that individual is likely to continue to have symptoms, and eventually justify, a diagnosis of PTSD. These considerations imply that a population at high risk for PTSD can be identified. If there is a non-toxic drug that significantly and specifically reduces the symptoms of PTSD, it could be used in this high-risk population to prevent the development of PTSD. Pathophysiology of PTSD The pathophysiology of PTSD involves disturbances in the brain systems involved with the stress reaction, including the ipotalámico-pituitary-adrenal axis, and systems involving norepinephrine, serotonin, endogenous opiates, and endogenous ligands for benzodiazepine receptors. PTSD involves the hyperactivity of the noradrenergic excitation systems, in relation to the low activity of the hypothalamic-pituitary-adrenal axis (Henry JP: Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an investigation into problems of human bonding, Acta Physiol Scand Suppl, 640: 10-25, 1997). On the other hand, the low activity of endogenous opiate mechanisms may contribute to the symptoms of PTSD. (Baker DG, et al: Cerebrospinal fluid and plasma beta-endorphin in combat veterans with post-traumatic stress disorder Psychoneuroendocrinology, 22: 517-29, 1997 Oct). Experiments in animals suggest that processes mediated by the NMDA receptor are likely to be involved in establishing behavior as anxiety following stressful events. The latter induces long-term potentiation (LTP) that affects connections within the amygdala, and between the amygdala and its efferents. A natural deduction is that the processes mediated by the NMDA receptor are involved in the development of PTSD in humans (Adamec R: Transmitter systems involved in neural plasticity underlining increased anxiety and defense: implications for understanding anxiety following trauma traumatic stresses) Nauroscience and biobehavioral reviews 21 (6): 755-65, 1997). In a recent review, two Israeli researchers described a central role of NMDA receptors in post-traumatic stress disorder, as well as schizophrenia, alcoholism, and major depression. They proposed that agents that modulate NMDA receptor function could be useful in treating all these disorders (Heresco-Levy U, Javitt DC: The role of N-Methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes Eur Neuropsychophar acol 1998 May; 8 (2): 141-52). However, they propose acamprosate in the treatment of PTSD, without the combination of the NMDA receptor and actions of the GABA-A receptor in the treatment of these disorders. In addition to the amygdala and its connections, PTSD involves dysfunction of the caudate nucleus. Lucey et al. (1997) in a SPECT study, showed that PTSD symptoms were negatively correlated with caudate blood flow, with the strongest correlation on the right side. (Lucey JV, et al .: Brain blood flow in anxiety disorders, OCD, panic disorder with agoraphobia, and post-traumatic stress disorder on 99mTcHMPAO single photon emission tomography (SPET) .Br J Psychiatry, 171: 346-50, 1997 Oct ). The role of GABA in the pathophysiology of PTSD has not been established. Benzodiazepines can relieve anxiety associated with PTSD. However, they usually do not give much for the specific symptoms of the disorder. In a study of trauma survivors, the early administration of high-potency benzodiazepines following the trauma does not prevent the development of PTSD, yet this reduces physiological arousal, eg resting heart rate (Gelpin E, et al .: Treatment of recent trauma survivors with benzodiazepines: A prospective study J Clin Psychiatry, 57: 390-4, 1996 Sep). In addition, the flumazenil benzodiazepine antagonist does not produce an increase in anxiety of PTSD symptoms in patients with PTSD (Randall PK, et al .: Effects of the benzodiazepine antagonist flumazenil in PTSD. Biol Psych 38 (5): 319-24 , nineteen ninety five). PTSD drug treatment PTSD drug treatment has had limited success. Not surprisingly, in view of this, a wide range of medications have been tested. Individual patients benefit from several drugs, but none has emerged as a standard treatment. Perhaps the most predictable benefits are treating apparent anxiety and depression with anti-anxiety and antidepressant drugs, and treating psychotic symptoms with antipsychotic drugs. These treatments relieve suffering and can improve function, but they can not in general change the core symptoms of undesirable thoughts and images, hyper-excitement and emotional insensitivity. Classes of medications that have helped individual patients with PTSD include benzodiazepines, dopamine antagonists (neuroleptics), reuptake inhibitors of specific serotonin (SSRIs), tricyclic antidepressants, antiepileptic drugs (AEDs), lithium, beta-adrenergic blockers and clonidine (an alpha 2-adrenergic agonist), to name a few. Cyproheptadine, a serotonin receptor blocker, has shown efficacy for the suppression of nightmares in patients with PTSD (Gupta S, et al,: Efficacy of ciproheptadine for nightmares associated with posttraumatic stress disorder.) Psychiatry, 39: 160-4, 1998 May-Jun) Recently, risperidone, an atypical neuroleptic, showed that it represses the unwanted mental phenomenon in children and adolescents with PTSD - but not completely (Horrigan J, presentation at the American Academy of Child and Adolescent Psychiatry annual meeting, October 1998; reported in Psychiatric News, December 18, 1998). A full-text patent search on "treatment" and "post-traumatic stress disorder" yielded 13 relevant patents (US Patents Nos. 5,028,612, 4,962,128, 5,484,794, 5,488,056, 5,574,028, 5,574,029, 5,574,053, 5,708,014, 5,726,193, 5,763,457, 5,776,969. 5,852,036; 5,852,037), none of which deal with glutamate or GABA related mechanisms. Several patents in chemistry affecting NMDA glutamate neurotransmission include PTSD in a large list of psychiatric disorders potentially treatable with these chemicals. To date, however, no specific glutamate antagonist has been tested as a treatment for PTSD in humans. In particular, there is no literature that suggests or reports the combination of NMDA receptor antagonists and GABA-A agonists, or the use of a drug with combined NMDA-agonist GABA-A antagonist actions, in the treatment of PTSD. A recent publication reviewed "The role of NMDA receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes" (Heresco-Levy U, Javitt, DC, European Neuropsychophar acology 8 (1998): L 141-152). The authors note that NMDA antagonists infused into the amygdala can block the acquisition of an improved shock response, and conclude that long-term glutamate-dependent potentiation can be critical for the development of conditioned fear and the coding of traumatic memories. However, they suggest that neurotransmission enhancers mediated by the NMDA receptor may have therapeutic effects in PTSD. They continue to declare that the NMDA over-regulators of neurotransmission can also reverse or avoid the cognitive deficits associated with PTSD. Heresco-Levy and Javitt also describe the hypothesis that schizophrenia is a hypoglutamatergic state, while proposing that excessive NMDA glutamate neurotransmission may underlie certain cases of major depression. D-cycloserine, a mixed agonist-antagonist that binds to the glycine site at the NMDA receptor, is advanced as a treatment for both conditions. It is evident from these and other reviews (not listed here) that NMDA glutamate neurotransmission abnormalities are associated with psychiatric symptoms and syndromes and the various modulators of glutamate-NMDA neurotransmission are candidates for therapeutic use in mental disorders. However, the available literature does not propose that NMDA antagonists may be therapeutic for PTSD, OCD, or repetitive thoughts, perceptions, and actions that may occur as part of other neuropsychiatric disorders. The literature is totally secretive in the treatment with agents that combine NMDA antagonism with GABA-A agonism. In summary, PTSD is a common disorder with significant morbidity and frequent complications, which include physical illnesses and substance abuse. The available drug treatment is limited in efficacy. Although a role for glutamate and NMDA receptors in the establishment of PTSD is suggested by animal models, specific NMDA receptor antagonists have not been reported as a treatment for PTSD in human patients. There is a need for additional drugs to treat PTSD, which can provide relief of specific symptoms of the disorder, without unacceptable toxicity. An effective drug treatment can not only treat PTSD, but it can be avoided if stress is given quickly afterwards. Obsessive-Compulsive Disorder OCD Description Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent obsessions or compulsions sufficient to cause marked distress. These behaviors are time consuming, or significantly interfere with the person's normal functioning, social activities, or relationships. Obsessions are recurring ideas, thoughts, images, or impulses that enter the mind and are persistent, undesirable, and unwelcome. Attempts have been made to ignore or suppress thoughts, or to neutralize them with some other thought or action. The individual recognizes them as a product of his own mind. Compulsions are repetitive, determined behaviors performed in response to an obsession, and are designed to neutralize or avoid discomfort or some frightening event or situation. However, the activity is excessive, or not realistically connected to that which is designed to prevent. The affected person recognizes that their behavior is not reasonable. (Robertson MM, Yakely J: Gilles de la Tourette syndrome and obsessive-compulsive disorder.) In: Fogel BS, Schiffer RB, Rao SM: Neuropsychiatry. Baltimore: Williams &; Wilkins, 1996, pp.827-870). Epidemiology of OCD The estimate of the prevalence of OCD life in North America has ranges from 1.9% to 3.2%. Lighter forms of obsessive-compulsive behavior are even more common. The lifetime risk of developing OCD with a normal life span has been estimated at 5.4% (Bland RC, Newman SC, Orn H: Epidemiology of psychiatric disorders in Edmonton, Acta Psychiatr Scand 77 (Suppl): 338, 1988). The disorder is usually chronic, with only about 1/3 of patients having spontaneous remissions (Robertson and Yakely, supra). OCD Pathophysiology The OCD is currently thought to be due to excessive activity in neural circuits involving the orbital frontal cortex, the region marked with anterior circles, the caudate nuclei and the thalamus. The recurrent activity in these circuits produces the recurrent characteristic, stereotypical obsessions and compulsions. This location of the OCD has been supported by a number of brain imaging studies with differing methodologies and overlapping results (Saxena et al .: Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder, Br. J Psychiatry Suppl 1998; ): 26-37). Saxena and colleagues hypothesize the hyperactivity of a frontal-subcortical orbital circuit, due to an imbalance of tone in direct-to-indirect striated-pale trajectories. Neuropsychological tests also suggest dysfunction of orbital-frontal structures and their subcortical connections (Schmidtke K, et al .: Cognitive frontal lobe dysfunction in obsessive-compulsive disorder Biol Psychiatry, 43: 666-73, 1998 May I; Purcell R, et al .: Cognitive deficits in obsessive-compulsive disorder on tests of frontal- striatal function, Biol Psychiatry, 43: 348-57, 1998 Mar 1). From the point of view of the neurotransmitter function, the broader scientific consensus supports a role of serotonergic system dysfunction in OCD. (Robertson and Yakely, supra). Of greater importance is the observation that serotonin reuptake inhibitors (SRIs) are the most consistently effective drug treatments of the disorder. In addition, studies have shown differences in serotonergic transmission between OCD patients and controls. As an example of many, patients with OCD who have a lower increase in prolactin after stimulating with d-fenfluramine than normal controls. (D-fenfluramine is an SRI). In addition, patients with greater weakening of the prolactin response tend to have worse OCD symptoms (Monteleone, et al .: Prolactin response to d-fenfluramine in obsessive-compulsive patients, and outcome of fluvoxamine treatment, Br J Psychiatry 170: 554-7, 1997 Jun). Dopamine may also have a role in the production of OCD symptoms. Direct and indirect dopamine agonists, including levodopa and amphetamine, can produce "ritual-like" stereotypic behaviors in animals, and the use of stimulants in humans has been documented to produce repetitive actions resembling OCD's compulsive behaviors (Robertson nd Yakely , supra). The ability of dopamine antagonists to increase the therapeutic effects of SRIs is compatible with a hypothesis of dopaminergic hyperactivity at synapses involved in the production of the symptom. The most recent research has suggested a role for glutamate in the production of OCD symptoms, and perhaps a subordinate role for a GABA deficiency. Moore et al. (J. Am Acad, Child Adolesc, Psychiatry, June, 1998 37 (6): 663-667) report a case of a 9-year-old boy with OCD studied by PET analyzer before and after successful treatment with paroxetine, an inhibitor of reuptake of specific serotonin (SSRI). They found greater changes in glutamate resonance in the caudate region. They infer that the interaction of serotonin-glutamate is implicated in the pathophysiology of OCD. In a study of benzodiazepine receptors in lymphocyte membranes of patients with anxiety disorders, including OCD, patients with OCD had 25% less of the benzodiazepine binding sites than the normal controls (Rocca P et al .: Peripheral-type benzodiazepine receptors in anxiety disorders Acta Psychiatrica Scandinavica 84: 6: 537-544, 1991 Dec). This result suggests that the bound inhibition of GABA may be deficient in patients with OCD, as well as with other anxiety disorders. Drug treatment of OCD SRIs (ie, SSRI plus clomipramine, a tricyclic antidepressant with predominant serotonin reuptake inhibition) are the mainstay of drug treatment for OCD. However, not all patients with OCD respond to SRIs, some do not tolerate them, and many have only a partial response. (Rasmussen SA, Eisen JL: Treatment strategies for chronic and refractory obsessive-compulsive disorder J Clin Psychiatry, 58 Suppl 13: 9-13, 1997). In a 1997 review, Henrietta Leonard observes that "The only agents that have shown significant improvement as agents of increasing an SRI / SSRI in systematic tests have been clonazepam and haloperidol." (Leonard H: New developments in the treatment of obsessive-compulsive disorder, J Clin Psychiatry, 58 Suppl 14: 39-45, discussion 46-7, 1997). Clonazepam is a GABA-A agonist with effects on serotonergic transmission; haloperidol a dopamine receptor blocker. Other secondary lines, or augmentation agents, for which there is less evidence of support, include other dopamine antagonists, lithium, clonidine (an alpha 2-adrenergic agonist), monoamine oxidase inhibitors (MAOIs), buspirone (a serotonin agonist IA) , and several other drugs that affect serotonergic transmission. Dopamine antagonists may be more useful in increasing the response of OCD to SSRI in patients with a personal or family history of tics (McDougle CJ: Update on pharmacologic management of OCD: agents and augmentation J Clin Psychiatry, 58 Suppl 12 : 11-17, 1997).

Somatoform Disorders: Somatization Disorder, Conversion Disorder, Hypochondriasis, and Body Dysmorphic Disorders Description of Somatoform Disorders Somatoform disorders are conditions characterized by physical symptoms without a known physiological explanation, and are presumed to be triggered by physiological processes. "The common characteristic of somatoform disorders is the presence of physical symptoms that suggest a general medical condition (hence the term somatoform) and are not fully explained by a general medical condition, by the direct effects of a substance, or by another mental disorder (for example, Panic Disorder). " (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Washington, DC, American Psychiatric Association, 1994). Somatoform disorders are divided into a number of syndromes; formal diagnostic criteria, complete for those that can be found in the Manual of Diagnosis and Statistics of Mental Disorders (American Psychiatric Association, supra). Relevant to this request are three disorders in which repetitive, unwanted stereotyped thoughts (in this case thoughts around somatic symptoms) are prominent: 1) Somatization disorders is a chronic condition with attack before age 30 and duration greater than 6 months, characterized by numerous somatic diseases without demonstrable general medical causes, involving several different organ systems, and including four painful symptoms, two gastrointestinal symptoms, one sexual symptom, and one neurological symptom. 2) Conversion Disorder: unexplained sensory or motor disease without a demonstrable general medical or neurological cause. Diseases are valued by the clinician as it relates to psychological factors. 3) Hypochondriasis is an unhealthy concern with fears of having, or believing that you already have, a serious illness. This is accompanied by misinterpretation of bodily symptoms and evidence of physical examination and laboratory tests that exclude the disease with which the individual is concerned. Fears or beliefs provoke anguish and / or deterioration, the last 6 months or more, and are not relevant for medical evaluation and safety. 4) Body Dysmorphic Disorder: it is an unhealthy concern with a defect imagined in appearance, or disproportionately large compared to a current minor physical anomaly. It is frequently associated with compulsive behaviors such as pruritus on the skin, seeking safety and reflective verification (Phillips KA: Body dysmorphic disorder: diagnosis and treatment of imagined ugliness J Clin Psychiatry, 57 Suppl 8 (): 61-4). Epidemiology of somatoform disorders Estimates of prevalence vary, depending on the population studied. Obviously, disorders are much more common in clinical samples than in the general population. However, still in the general population, the predominance is substantial. A few recent studies illustrate this point. 1) In a society study conducted by general practitioners in two neighborhoods in Florence, Italy, the authors reported the following 1-year prevalence figures: 0.7% for somatization disorder, 0.3% conversion disorder, 4.5 % for hypochondriasis, and 0.7% for body dysmorphic disorders. (Faravelli C, et al .: Epidemiology of somatoform disorders: a community survey in Florence, Soc Psychiatry Psychiatr Epidemiol, 32 (l): 24-9 1997 Jan). 2) The predominance of somatoform disorders in two rural primary care practices was 11.1% (Philbrick JT, et al .: The prevalence of mental disorders in rural office practice J Gen Intern Med, 11 (1): 9-15 1996 Jan). 3) A community summary of American Chinos living in Los Angeles showed a predominance of 3.6% of "neurasthenia", a non-specific somatoform disorder in the Diagnostic and Statistical Manual of Mental Disorders, but widely recognized as a discrete syndrome. Neurasthenia has characteristics in common with hypochondriasis and somatization disorder. From observation, these individuals were examined to exclude anxiety or depression disorders as the cause of their somatic symptoms. Relationship of PTSD to Somatization Somatoform disorders, such as PTSD, involve unwanted thoughts, perceptions and behaviors that are repetitive, undesirable or involuntary stereotyped. In addition to this similarity, PTSD, somatization, and dissociation frequently occur together in some patients. In a study of 500 individuals who had been exposed to traumatic experiences, PTSD, dissociation, somatization, and no affected regulation were highly interrelated, (van der Kolk BA, et al .: Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma, Am J Psychiatry, 153 (7 Suppl): 83-93 (1996 Jui) The authors concluded that "PTSD, dissociation, somatization, and non-regulation affect a spectrum of adaptations to trauma. traumatized individuals may suffer from several combinations of symptoms for hours "Victims of torture, more extreme stress, often develop a combination of somatization and PTSD (Priebe S; Esmaili S: Long-term mental sequelae of torture in Iran-who seeks treatment? J Nerv Ment Dis, 185 (2): 74-7 1997 Feb). Pathophysiology of Somatoform Disorders Research on regional brain function in somatoform disorders in general has been surprisingly small. However, there has been much work on regional brain function in clinical and experimental pain, using such techniques as analyzing PET and functional MRl (fMRI). Similarly, much more is known about the neurochemistry of pain than the neurochemistry of somatoform disorders. The study of pain is a valuable source of ideas related to the treatment of somatoform disorders, but obviously analgesics are not ipso facto treatments for somatoform disorders, nor are treatments for somatoform disorders necessarily analgesic. The important link is that emotional distress related to somatic perception is a common feature of pain and the somatoform disorders mentioned here. The underlying physiological mechanism of emotional distress in somatization disorders is likely to involve the core of the limbic system and the trajectories related to the emotional aspects (as opposed to the simple sense) of pain perception. The following section summarizes some facts about the pain transmission relevant to the present invention. GABA, - Glutamate, and Pain Patients with some types of somatoform disorders experience pain. The transmission of pain and modulation in the spinal cord are strongly affected by GABA and glutamate. The processes mediated by the NMDA receptor are involved in the development of pain hypersensitivity states. "Information concerning amplification systems in the spinal cord, such as the NMDA receptor, is a step towards understanding why and how a painful response is not always equal to stimuli." Such events have parallels with other such plastic events. as long-term potentiation (LTP) in the hippocampus "(Dickenson AH, et al .: The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord Gen Pharmacol, 28 (5) : 633-8 1997 May). Finally, the balance of NMDA-mediated amplification and GABA-mediated attenuation determines the intensity of the pain signal transmitted from the spinal cord to the brain. Dickenson et al. (supra) notes that under inflammatory conditions, the activity of GABA is increased, which highlights the increase in glutamate activity, while in neuropathic pain, no. This corresponds to the clinical observation that neuropathic pain may be more acute than pain due to tissue damage and inflammation. Spinal cord stimulation is used clinically to relieve intractable pain, for example, cancer. In animal models, the effect of spinal cord stimulation is to decrease the release of glutamate and aspartate to the dorsal defenses, and to increase the release of GABA (Cui JG, et al .: Spinal cord stimulation attenuates augmented dorsal horn) of excitatory amino acids in mononeuropathy via GABAergic mechanism, Pain, 73 (1): 87-95 (1997 Oct) This supports the idea that more GABA and less glutamate (in the vicinity of NMDA receptors) is associated with analgesia The spontaneous activity of the dorsal defense neurons is suppressed by GABA and increased by glutamate, through a mechanism dependent on the NMDA receptor.The increased release of GABA partially explains the analgesic benefits of transcutaneous electrical nerve stimulation (TENS). In a cat model, the analgesic effects of electrical stimulation of peripheral nerves were partially blocked by picrotoxin, a GABA-A antagonist - which ugiere a component mediated by GABA-A (Jeong Y, et al .: Effects of iontophoretically applied naloxone, picrotoxin and strychnine on dorsal horn neuron activities treated with high frequency conditioning stimulation in cats. Yonsei Med J, 36 (4): 336-47 1995 Sep).

Based on similar studies involving the brain as well as the spinal cord, central pain, due to damage to the brain or spinal cord, has been attributed to a combination of glutamatergic and GABAergic mechanisms. "Recent evidence suggests that central pain, that is, pain due to damage to the central nervous system, may be due to a deranged neurotransmission between the sensory thalamus and the sensory cortical areas.The central pain can be controlled either by opposing the neurotransmission of GABAergic transmission potentiation or glutamate It is speculated that a relative hypofunction of GABAergic inhibition at thalamic and cortical levels leads to an excitatory hypertonus in those same areas A mixture of the two would mark each patient A pharmacological dissection approach on condition of that should optimize the treatment, until now globally poor of central pain "(Cañavero S, Bonicalzi V: The neurochemistry of central pain: evidence from clinical studies, hypothesis and therapeutic implications, Pain, 74 (2-3): 109-14 1998 Feb) . Drug Treatment of Somatoform Disorders Among the somatofor disorders, Body Dysmorphic Disorder has the best established drug treatment, SRIs. (Phillips, supra; Phillips KA, et al .: Efficacy and safety of fluvoxamine in body dysmorphic disorder. J Clin Psychiatry, 59 (4): 165-71 1998 Apr; Perugi G, et al .: Fluvoxamine in the treatment of body dysmorphic disorder (dysmorphophobia) Int Clin Psychopharmacol, 11 (4): 247-54 1996 Dec). This is perhaps not surprising, in view of its similarity to the OCD, which also responds to SRIs in many cases. Phillips points out that the increase with buspirone or neuroleptics can be attentive in the Body Dysmorphic Disorder just as it is in OCD. However, the researchers cited above observe that only 2/3 of the treated patients improve with SRIs. For the other somatoform disorders, antidepressants of various kinds are more frequently used. They are often justified because patients have major depression or concurrent dysthymia, but they can clearly work in cases where somatic symptoms are not accompanied by obvious depression. The concept of "masked depression" or "depressive equivalence" has been useful for decades to explain these responses (Downes-Grainger E, et al .: Clinical factors associated with short-term changes in outcome of patients with somatized mental disorder in primary care Psychol Med, 28 (3): 703-ll 1998 May.) When somatic complaints from patients and concerns of delirium ratios reached, they can get relief from neuroleptic drugs. This, of course, has problematic long-term side effects such as tardive dyskinesia. Some patients may get temporary relief from somatic symptoms and from opiates or benzodiazepines. Unfortunately, they develop tolerance.

Dependence of the prescription drug or abuse may result. The use of SIRs for Body Dysmorphic Disorder represents a significant progress; so that the consciousness that many patients whose amplified symptoms will benefit from antidepressant drugs, even if they do not show overt depression. However, not all patients will respond to these treatments. For Somatization Disorder, Conversion Disorder, and Hypochondriasis, drug treatment to date has been less satisfactory. The Context of the Invention In summary, PTSD, OCD and four somatoform disorders - Somatization Disorder, Conversion Disorder, Hypochondriasis and Body Dysmorphic Disorder, and neuropsychiatric disorders characterized by thoughts, perceptions and undesirable behaviors, stereotyped retrospective scenes that cause significant distress and incapacity for a substantial portion of the general population. A broadly effective and tolerable drug treatment could significantly improve treatment prospects for patients suffering from these neuropsychiatric disorders. further, would offer a new significant treatment option in psychopharmacology - different from antidepressants, anti-anxiety drugs, mood stabilizers (eg, lithium, valproate), and neuroleptics. Thus, it will offer a new method of treating residual symptoms of patients partially sensitive to treatment with any of these established classes of psychotropic agents. The present invention provides a method for treating: (1) neuropsychiatric disorders such as post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) and somatoform disorders, to relieve characteristic symptoms; and (2) symptoms of other neuropsychiatric disorders such as Schizophrenia, Major Depression and Bipolar Disorder, when their symptoms include unwanted, undesirable thoughts, perceptions or behaviors or recurrent involuntary stereotyping. More generally, the present invention provides a method for treating any neuropsychiatric disorder, including any anxiety disorder, psychotic disorder, mood disorder or somatoform disorder.

In one aspect, the invention provides a method for treating neuropsychiatric disorders by administering a pharmacological agent, which (i) acts directly or indirectly as an agonist to GABA-A receptors and (ii) decreases the neurotransmission of NMDA-type glutamate by a mechanism direct, indirect or modulator. Specific examples include calcium N-acetylhomotaurinate (acamprosate), magnesium N-acetylhomotaurinate, other N-acetylhomotaurinate salts, N-acetylhomotaurinate derivatives with similar pharmacodynamic effects in GABA and NMDA-type glutamate neurotransmission, and prodrugs that are metabolized in the liver, blood, or brain to produce N-acetylhomotaurinate or a derivative with similar pharmacodynamic effects. In another aspect, the present invention provides methods for treating neuropsychiatric disorders by administering more than one pharmacological agent that, in combination, acts to increase GABA-A neurotransmission and decreases the neurotransmission of NMDA-type glutamate. The present invention also provides a method for treating neuropsychiatric disorders by combining memantine, magnesium, or a non-competitive NMDA receptor antagonist with acamprosate, or another compound or mixture thereof (specifically including those listed in the previous paragraph) that simultaneously decreases the post-response. -synaptic to glutamate to NMDA type receptors and also directly or indirectly increase GABA-A transmission. In preferred embodiments, magnesium is used as a non-competitive NMDA receptor antagonist. Alternatively, a GABA-A agonist can be combined with a compound having NMDA antagonist activity and GABA-A agonist activity. In other preferred embodiments, the present invention establishes that magnesium can increase the effect of pharmacological agents used to treat neuropsychiatric disorders including anxiety disorders such as post-traumatic stress disorder and obsessive-compulsive disorder, somatoform disorders, mood disorders. , psychotic disorders and other disorders with thoughts, perceptions or stereotyped recurrent behaviors, which are unwanted, undesirable, or involuntary. The synergistic activity of magnesium and pharmacological agents that act to simultaneously decrease the neurotransmission of glutamate NMDA and increase the neurotransmission of GABA-A has been previously demonstrated in the treatment of movement disorders. (This is detailed in co-pending application Serial No. 09 / 193,892, which is incorporated herein by reference). Thus, in the present invention, magnesium is combined with pharmacological agents that act to simultaneously decrease the neurotransmission of NMDA glutamate and increase the neurotransmission of GABA-A to treat neuropsychiatric disorders. In other embodiments, any combination of agents that act as NMDA receptor antagonists together with one or more agents that facilitate GABA-A neurotransmission (acting as GABA-A receptor agonists, increasing GABA-A, inhibiting the re-incorporation of GABA from the synapse, or increasing the post-synaptic response to stimulation of the GABA-A receptor), with or without magnesium, are used for the treatment of neuropsychiatric disorders. A pill combining agents that act as antagonists of the NMDA-type glutamate receptor, GABA agonists and magnesium are proposed as a specific vehicle for the release of this combination therapy. In addition, other oral preparations are suggested; the mixture can be supplied in a syrup, elixir, or release time capsule. The latter is suggested as a method to prolong the duration of action of a dose of the mixture. In a final embodiment, agents or combinations of agents having the activity of NMDA antagonism and GABA-A agonism are used to prevent the development of PTSD in individuals exposed to extreme stress. Alternatively, compositions with combined NMDA antagonism and GABA-A agonism are used to avoid symptoms of an acute stress reaction from the continuation or evolution of PTSD. It is particularly preferred that these agents are used to prevent the development of substance abuse, for example, alcoholism, subsequent to extreme stress or as a complication of post-traumatic stress disorder. Definitions "Effective": "Effective" as used herein in reference to doses sent to the administration of a specific amount of a pharmacologically active agent tailored to each patient exhibiting symptoms of neuropsychiatric disorder, sufficient to cause a reduction or improvement in any of the associated symptoms, with tolerable adverse effects. Experimentally, acamprosate doses ranging from 333 mg to 666 mg administered three to four times daily are effective. A person skilled in the art will recognize that the optimal dosage of a pharmaceutical agent administered will vary from one individual to another. The dose in individual patients will take into account the height, weight, speed of absorption and metabolism of the patient of the drug in question, and the phase of disorder to be treated, as well as that other pharmacological agents are administered simultaneously. "Non-toxic": As used herein, "non-toxic" refers to the administration of a dose of a medicament in question, wherein the active components in the composition do not cause intolerable adverse effects to the patient to whom they are administered, or judge by the doctor to be a contraindication to continue the medication. "Acamprosate": As used herein, "acamprosate" refers to calcium N-acetylhomotaurinate.

These two terms can be used interchangeably. "N-acetylhomotaurinate" and "acetylhomotaurinate" are used interchangeably. "Acamprosate and related compounds": "Acamprosate and related compounds" refer to calcium actilhomotaurinate, magnesium acetylomotaurinate, other salts of N-acetylhomotaurinate, and acetylhomotaurine base, and those derived from homotaurine or acetylhomotaurine having similar pharmacodynamic activity with respect to to GABA-A and the neurotransmission of glutamate of type and NMDA, and prodrugs that are metabolized in the blood, liver, or brain to produce acetylhomotaurinate or derivatives with similar pharmacodynamic activity with respect to GABA-A and the transmission of glutamate of the NMDA type . Acamprosate decreases the intracellular response of neurons stimulated by glutamate to the NMDA receptor, and improves GABA-A transmission, at least in part by an antagonistic effect on pre-synaptic GABA-B inhibitory autoreceptors. For ease of expression, it refers to acamprosate and similar compounds with similar CNS pharmacodynamics by various terms which as used herein should be respected as synonyms: "GABA agonists and NMDA antagonists", "GABA-A agonists and antagonists NMDA "," agents that increase GABA transmission and decrease the transmission of NMDA-type glutamate "," GABA agonists and glutamate antagonists ", and" on GABA transmission regulators and down regulators of NMDA-type glutamate transmission " . "GABA-A transmission": GABA-A transmission refers to the pharmacodynamic phenomenon associated with the activation of GABA-A receptors by GABA. The increased transmission of GABA-A may involve increasing the release of GABA, decreasing its metabolism, decreasing the re-incorporation of GABA from the synapse, increasing the binding receptor, or increasing the cellular effects of the receptor. link. "GABA-A receptor agonist": "GABA-A receptor agonist", as used herein, refers to molecules that are capable of enhancing the transmission of GABA-A (as defined above). "NMDA receptor antagonist": As used herein, "NMDA receptor antagonist" is any molecule that inhibits or decreases the post-synaptic response of glutamate receptors of the NMDA-to-glutamate type.

"NMDA-type glutamate neurotransmission": "NMDA-type glutamate neurotransmission" is used herein to broadly mention anything that would decrease the transmission of NMDA glutamate, if it acts before the synapse, to the binding site of the NMDA. receptor, with the ion channel, with the cell membrane, or inside the neuron. This includes anything that reduces the release of glutamate to the synapse with NMDA receptors, alters the binding of glutamate to NMDA receptors or alters the number of NMDA receptors. "Neuropsychiatric disorder": As used herein, "neuropsychiatric disorder" is used synonymously with "mental disorder," or "psychiatric disorders" the term "neuropsychiatric disorders, which encompass any anxiety disorder (e.g., Panic Attack). , Agoraphobia, Panic Disorder without Agoraphobia, Panic Disorder with Agarofolsia, Agoraphobia without a History of Panic Disorder, Specific Phobia, Social Phobia, Obsessive-Compulsive Disorder, Post-traumatic Stress Disorder, Acute Stress Disorder, Anxiety Disorder Generalized, Anxiety Disorder Due to a General Medical Condition, and Anxiety-Induced Anxiety Disorder and Anxiety Disorder of Another Unspecified Form), any psychotic disorder (eg, Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delirium Disorder, Disorder Brief Psychotic, Shared Psychotic Disorder, Psychotic Disorder Due to Condi General Medical, and Substance-Induced Psychotic Disorder and Other-Specified Psychotic Disorder) and any mood disorder (Major Depressive Disorder, Dysthymic Disorder, Depressive Disorder of Another Unspecified Form, Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, Mood Disorder Due to a General Medical Condition, Substance-Induced Mood Disorder and Mood Disorder Another unspecified form) known in the art. The "Neuropsychiatric Disorder" is used herein to refer to any neurological disease or mental disorder in which a major symptom is the occurrence of undesired thoughts, perceptions, or unwanted, undesirable, or involuntary stereotyped behaviors. Exemplary symptoms of these disorders specifically include obsessions, reflections on fears of illness, post-traumatic "retrospective" scenes, experiences of recurrent pain in the absence of somatic illness, compulsions, and tics, particularly the preferred mental disorders with such symptoms characteristic aspects include Obsessive-Compulsive Disorder (OCD), Post-Traumatic Stress Disorder (PTSD), Hypochondria, Pain Disorder, and Somatization Disorder Other preferred mental disorders that may have such symptoms include, but are not limited to Schizophrenia , Major Depression, and Bipolar Disorder The neurological disorders characterized by such symptoms include tics, Tourette Gilles Syndrome (TS), and focal dystonia; Other neurological disorders that can have many symptoms include Huntington's disease. "Post-Traumatic Stress Disorder": The term "post-traumatic stress disorder" or "PTSD" as used herein to describe an anxiety disorder characterized by an immediate or delayed response to a catastrophic event, characterized by returning to experience the trauma, psychic insensitivity or avoidance of stimulus associated with the trauma, and increased distress. The phenomenon of returning to experience includes unwanted memory, retrospective, nightmares, and psychological or physiological anguish in response to remembered traumas. Such responses are anxiety that produces and can have significant, chronic and acute impact, or on the quality of life and physical and emotional health of the patient. "Obsessive-compulsive disorder": "Obsessive-compulsive disorder" or "OCD" is an anxiety disorder characterized by obsessions or recurrent compulsions sufficient to cause marked distress in the individual.

They consume time or significantly interfere with a person's normal functioning, social activities, or relationships. Obsessions are recurring ideas, thoughts, images, or impulses that enter the mind and are persistent, undesirable, and unwelcome. Attempts are made to ignore or repress thoughts, or to neutralize them with other thoughts or action. The individual recognizes them as a product of his own mind. Compulsions are repetitive, purposeful behaviors performed in response to an obsession, and are designed to neutralize or avoid discomfort or some frightening event or situation. A common obsession with thoughts of pollution, excessive hand washing is a common compulsion. "Late Dyskinesia": As used in this "tardive dyskinesia" means including late dystonia and other movement disorders related to long-term neuroleptic use. The abbreviation TD may be used in place of the term "tardive dyskinesia" "Tourette's syndrome": "Tourette's syndrome" as used herein is synonymous with "Gilles de la Tourette syndromes", "Tourette syndrome", " Tourette's disorder ", and similar expressions. The abbreviation TS can be used in place of any of these terms. "Blefarospasma": As used in the present "blefarospasma" includes Meige syndrome, which is a combination of blepharospasm and dystonia of the face and / or neck. "Tic disorder": The "Tic disorder" as used herein, refers to a movement, gesture or repetitive abrupt expression that often mimics a fragment of the resolved behavior. The tics are characterized by movements, stereotyped, repetitive, but irregularly rhythmic. They include motor tics and vocal tics (phonic). The tic disorders include, for example, simple tics, multiple tics and Gilles de la Tourette syndrome, defined as multiple tics with vocalizations. "Movement Disorder": "Movement disorder", as used herein, is used to refer to all abnormal and involuntary forms of movement, including vocalizations. Movement disorders include, for example, tardive dyskinesia (TD), tics, Gilles de la Tourette syndrome (TS), Parkinson's disease, Huntington's disease, and focal dystonias such as blepharospasm. The present invention relates to the treatment of any neuropsychiatric disorder (e.g., any anxiety disorder, any psychotic disorder, any mood disorder or any somatoform disorder) wherein a major symptom is the occurrence of repetitive thoughts, perceptions or behaviors. , unwanted, undesirable or involuntary stereotyped. In particular, the present invention provides treatments for neuropsychiatric disorders including PTSD, OCD, and somatoform disorders, and treatment for such thoughts, perceptions and repetitive behaviors when they occur as symptoms of other disorders include for example Schizophrenia, Major Depression, and Bipolar Disorder. In one aspect of the present invention, it has been discovered that an agent used for the treatment of abstinent alcoholics, and more recently for the treatment of movement disorders (see pending U.S. Patent Application, serial number 09 / 006,641), and not is contemplated for use in treatment of neuropsychiatric disorders is effective in reducing symptoms associated with neuropsychiatric disorders. Years ago, it was hypothesized that tardive dyskinesia, other neuroleptic induced movement disorders, and spontaneous movement disorders that resemble each other, represent a form of non-linear oscillation in neural circuits involving the basal ganglia, and that the oscillation may be reduced by agents that block the excitatory neurotransmission. Studies to examine PET have shown increased metabolism in pale globes and main motor cortex in schizophrenic patients with TD, but not in those without TD (Pahl et al., J Neuropsych Clin Neurosci 7: 457, 1995). This suggests that TD is associated with hyperactivity in a motor control circuit, which functions as a nonlinear oscillator. As noted above, we have advanced the hypothesis that agents that act to reduce the gain in a motor control circuit through the striatum, may have a beneficial action in TD and related movement disorders (eg, Tourette syndrome and tics). ). GABA is an inhibitory neurotransmitter in the striatum. Support for the hypothesis comes from animal evidence indicating that agents that directly or indirectly stimulate GABA receptors can decrease neuroleptic induced dyskinesias (Gao et al., J Neural Transmission 95:63, 1993).; Stoessl, Pharmacol. Biochem. Behav. , 54: 541, 1996). Rats with neuroleptic induced dyskinesia demonstrated decreased striatum levels of glutamic acid carboxylase, the enzyme that limits the rate of GABA production (Delfs et al., Exp. Neurol., 133: 175, 1995). It is proposed, without limiting the biochemical mechanism of the invention, that the drugs that act to reduce the gain in the oscillator circuit make hypotheses by reducing the involuntary movements of tardive dyskinesia. GABA, glutamate, and dopamine are the main neurotransmitters in the circuit. Other neurotransmitters, including norepinephrine, serotonin, acetylcholine, and endogenous opiates hypothesize to have indirect actions in the oscillator circuit. In co-pending patent applications, Nos. 08 / 861,801, and 09 / 193,892, the teachings of which are incorporated herein by reference, it is disclosed that certain excitatory neurotransmitter antagonists are effective in treating movement disorders and cognitive factors associated with TD, late dystonia, and related movement disorders. In the present application, it is proposed in a non-limiting manner that antagonist-type drugs that act to reduce the gain in the oscillator circuit can be used to treat a wide variety of neuropsychiatric disorders that fall under a wide range of classifications. The support for this hypothesis is established later. Neuropsychiatric disorders related to movement disorders There are similarities worth noting between PTSD and tics. As PTSD, the tics involve the thoughts and images of the involuntary reiterative stereotyped phenomenon, in the case of PTSD and simple unresolved movements in the case of tics. In both cases, the neocortical representations are activated by striated or limbic contribution. Tics can be temporarily repressed with conscious effort. However, when the effort is stopped or when the tics are broken through, in spite of an effort to suppression, it is often a rebound in frequency or intensity. A similar phenomenon has been demonstrated with undesirable images in an experimental memory model-PTSD phenomenon by subjects of afflictive film images (Davies MI, Clark DM: Thought suppression produces a rebound effect with analogue post-traumatic intrusions, Behav Res Ther, 36: 571-82, 1998 Jun). There is also a strong association of OCD with movement disorders. OCD is associated with the Tourette syndrome (Tourette syndrome, TS), as well as with several other basal ganglion diseases including Sydenham chorea and Huntington's disease. There is strong evidence of a link between OCD and motor tics. While estimates of the occurrence of OCD in patients with TS vary from 5% to more than 50%, all estimates are significantly greater than the prevalence of OCD in the general population. The clinical characteristics shared between OCD and TS include "discoloration and decrease of symptoms, early age to attack, ego-dystonic behavior (that is, behavior contrary to conscious preferences of the individual), worsening with depression and anxiety, and its occurrence in the same family "(Robertson and Yakely, supra). Genetic studies suggest that in some families, there is a single dominant autosomal gene that can be phenotypically expressed as TS, OCD, or both. TS is most frequently treated with dopamine antagonists and OCD with serotonin reuptake inhibitors (SRIs). However, the addition of dopamine antagonists may increase the therapeutic efficacy of SRIs in OCD, and the addition of SSRIs may increase the efficacy of dopamine antagonists in TS. All of these considerations support the idea that there are overlapping physiological mechanisms for OCD and TS. Tics and OCD can be produced by the CNS effects of an autoimmune reaction to infection with Group A beta-hemolytic streptococci - PANDAS syndrome - Pediatric Autoimmune Disorders Associated with Streptococci (Swedo SE, et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases, Am J Psychiatry, 155: 264-71, 1998 Feb). Similarly, traumatic brain damage can lead to a new simultaneous attack of OCD tics and symptoms (Krauss JK; Jankovic J: Tics secondary to craniocerebral trauma. Mov Disord, 12: 776-82, 1997 Sep). OCD symptoms were compared between patients with blepharospasm, a focal dystonia caused by basal ganglion dysfunction, and hemifacial spasm, a syndrome with superficially similar symptoms, but due to peripheral nerve dysfunction. Blepharospasm patients had OCD symptoms more significantly on a symptom checklist (Broocks, et al .: Higher prevalence of obsessive-compulsive symptoms in patients with blepharospasm than in patients with hemifacial spasm. Am J Psychiatry, 155: 555-7 , 1998 Apr). OCD is not only associated with TS, but the obsessive-compulsive phenomenon shares common clinical features with tics. Both imply repetitive, stereotyped, involuntary phenomena. In the case of OCD, there are resolved thoughts or motor sequences (compulsive rituals); in the case of tics, they are simpler, without resolved movements. Both involve activation of neocortical representations by limbic or striated contributions. As noted above, there are clinical and physiological similarities between tics, OCD obsessions and rituals, and unwanted thoughts and images of PTSD. Although, the pathophysiological, epidemiological and clinical association of tics and OCD is somewhat stronger than those of PTSD with tics, PTSD and OCD may be correlated with tics. Therefore, it was reasoned that useful treatments for tics could help for the undesired phenomenon in PTSD, and that if they are used in PTSD, they could also be used for OCD obsessions and compulsions. A link between movement disorders and somatoform disorders can be made through the correlation between sematoform disorders, PTSD and OCD. A few relevant studies are as follows: 1) Rogers et al. I study the predominance of somatoform disorders in a sample of 654 patients with anxiety disorders. Thirty-six (5.5%) of the subjects had past or current somatoform disorders. Subjects with somatoform disorders were significantly more likely to have histories of post-traumatic stress disorder (22% vs. 8%) (Rogers MR, et al .: Prevalence of somatoform disorders in a large sample of patients with anxiety disorders. 37 (l): 17-22 1996 Jan-Feb). 2) Women with chronic pelvic pain not explained by a thorough gynecological evaluation were compared with controls that were either free of pain, or had pain in some other area of the body. Women with chronic pelvic pain had a much higher ratio of past sexual abuse than those of the other two groups (Collett BJ, et al .: A comparative study of women with chronic pelvic pain, chronic nonpelvic pain and those with no history of pain attending general practitioners Br J obstet Gynaecol, 105 (1): 87-92 1998 Jan). 3) A study of 45 patients with pseudo-attacks (non-epileptic seizures), with diagnosis of pseudo-seizure confirmed by simultaneous video and EEG recording, revealed a 49% prevalence of post-traumatic stress disorder (Bowman ES; Markand ON: Psychodynamics and psychiatric diagnoses of pseudoseizure subjects, Am J Psychiatry, 153 (1): 57-63 1996 Jan). 4) A study of 442 patients with OCD revealed that 12% had a concurrent diagnosis of body dysmorphic disorder. The authors concluded that the two disorders are "strongly related" (Simeon D, et al .: Body dysmorphic disorder in the DSM-IV field trial for obsessive-compulsive disorder Am J Psychiatry, 152 (8): 1207-9 1995 Aug ). As noted above, subsequent studies have shown that SRIs, the mainstay of treatment for OCD, are effective in the treatment of body dysmorphic disorder. 5) Women with chronic pelvic pain unexplained by a gynecological evaluation showed the same abnormality of hypothalamic-pituitary-adrenal regulation as seen in women with PTSD. Compared with normal controls, in both cases the adrenal produces less cortisol in response to ACTH, and cortisol is suppressed with a lower dose of dexamethasone (Heim C et al., Abuse-related posttraumatic stress disorder and alternations of the hypothalamic -pituitary-adrenal axis in women with chronic pelvic pain. psychoso Med. 60 (3): 309-318 1998 May-Jun). 6) A study of 256 college students demonstrated a positive correlation between self-reported nervous habits and tics, their bodily sensations, and their level of anxiety (Woods DW, et al .: Habits, tic, and stuttering.) Prevalence and relationship to anxiety and somatic awareness Behav Modif, 20 (2): 216-25 1996 Apr) While the direction of causality is not clear, the association is compatible with the idea that a common underlying physiological disturbance may predispose individuals to tics and amplification of somatic symptoms. Taken together, studies such as these suggest that trauma can lead to PTSD and various somatoform disorders, and often to a combination of the two. There is a coincidence in symptoms between hypochondriasis, body dysmorphic disorder, and OCD (specifically with obsessions). Similarly, there is a coincidence in the symptoms between tics and OCD (specifically with compulsions). Individuals with hypochondriasis or body dysmorphic disorder have obsessive thoughts about diseases: or about their appearance. The symptoms of tics resemble simple compulsions. In all of these conditions there are thoughts, perceptions or behaviors that are recurrent, stereotyped, unwanted, undesirable or involuntary. In addition, all these associated with increased anxiety.

These characteristics suggest overlapping pathophysiology of several conditions. The coincidence in symptoms and mechanisms between the different disorders suggests that an effective treatment for PTSD, tics, and OCD could also be beneficial for somatoform disorders. Non-Obvious Shooting - from Somatic Pain to Somatization Based on the physiology of pain transmission and modulation one might expect somatic pain to respond to a drug with combined GABA-A agonist and glutamate-NMDA antagonist properties, if the drug dose was enough (Cañavero S, Bonicalzi V: supra). However, the phenomenon of somatization, with its similarities to PTSD, OCD, and tics, and with its putative generation by neural knots of repercussion, average response to doses of such a drug that could not be sufficient to significantly affect the transmission of somatic pain . In fact, the 5 patients treated personally with acamprosate for movement disorders had all had diseases interspersed with pain as a symptom. None had reported analgesic effects of the acamprosate dose (333 to 666 mg) taken several times a day for their movement disorder. Based on the above consideration, it was submitted that drugs with GABA-A agonist effects and NMDA-glutamate antagonists in appropriate proportion, would relieve symptoms of somatoform disorders at non-toxic doses., and at doses not necessarily associated with general analgesia. Of course, the effect of these drugs on symptoms other than pain is not involved in all animal experiments on GABA, glutamate, and spinal pain transmission. Treatment of neuropsychiatric disorders Based on this experience and the previous reasoning, acamprosate was administered to a patient with PTSD (see Case Report 1). The patient enjoyed significant relief of PTSD symptoms, in a dose-related manner, without side effects. The response of PTSD symptoms was not due to a non-specific alteration in the level of mood or anxiety. In fact, the patient experienced relief from flashbacks, traumatic memories, and emotional insensitivity on days when she felt depressed or anxious. Improvements were experienced in the areas of the frequency of repetitive, undesirable thoughts about traumatic events, and psychic insensitivity. In addition, the patient was able to talk more freely about traumatic events and showed a reduction in self-injurious behavior and the severity of his response to fear. In a prior, co-pending, part number serial patent application 09 / 193,892, it was shown that acamprosate, a GABA-A / NMDA-glutamate antagonist, had a marked benefit in the treatment of tics. That benefit was enhanced by the addition of magnesium. The benefit of acamprosate treatment was also enhanced by the addition of an NMDA-glutamate antagonist (e.g., memantine). In another aspect, the benefit of the acamprosate treatment could be improved by the co-administration of another GABA-A agonist. One of ordinary skill in the art will recognize that magnesium, an NMDA antagonist or a GABA-A agonist can be combined not only with acamprosate, but with any agent (or combination of agents) having NMDA antagonist activity or GABA agonist activity. When treating movement disorders, it was also observed that the synergy of GABA-A actions and NMDA actions allow acamprosate, with or without magnesium, to provide significant therapeutic actions at non-toxic doses. In addition, the synergy of the effect was observed in the absence of a corresponding toxicity synergy. It was proposed, by extension, that this synergy of beneficial effects without synergy of toxicity would occur with the combined use of GABA-A agonists and NMDA-glutamate antagonists to treat neuropsychiatric disorders. In the current invention, acamprosate, a GABA receptor agonist that also decreases the post-synaptic response of NMDA-type glutamate receptors that can reduce or ameliorate symptoms associated with PTSD, OCD, sematoform disorders (somatization disorder), is described. , conversion disorder, hypochondriasis, and body dysmorphic disorder), and other neuropsychiatric disorders including depression, mania, and schizophrenia, when these disorders have symptoms involving stereotypical retrospective thoughts, perceptions, and behaviors. An important example is major depression, which is often associated with retrospective scene bending on issues of guilt or pessimism. Alternatively, the acamprosate and the related compound can be used to treat symptoms, for example, thoughts, perceptions or repetitive, involuntary, unwanted or undesirable, stereotyped behaviors, which are associated with a movement disorder. Some examples of movement disorders that may exhibit such symptoms include Tourette's syndrome, focal dystonia, Huntington's disease, Parkinson's disease, Syndenham chorea, systemic lupus erythematosus, and drug-induced movement disorders. According to the theory of the present invention, a GABA-A agonist with concurrent antagonistic effects in the transmission of NMDA-type glutamate reduces the severity of symptoms associated with neuropsychiatric disorders, including PTSD and the extension of OCD and somatoform disorders. Furthermore, it is proposed that acamprosate and other agents both (i) decrease NMDA-type neurotransmission and (ii) increase the neurotransmission of the GABA-A receptor are useful in the treatment of PTSD, OCD, somatoform disorder and other neuropsychiatric disorders. The class of drugs that have simultaneous GABA-A agonism and NMDA antagonism, synergistic at non-toxic doses represent a newer class of therapeutic agents for neuropsychiatric disorders. The novelty of the conception of these drugs as an "advance" in psychopharmacology is affirmed. The advanced principle is that many important neuropsychiatric disorders involve the abnormal activity of polysynaptic neural nodes through the cortex, striatum, and thalamus. The abnormal activity of these knots produces thoughts, perceptions and behaviors that are recurrent, stereotyped, and unwanted, undesirable or involuntary. Limbic structures such as the amygdala and the region marked with anterior circles are part of these circuits, or influence them. The synapse with GABA or glutamate as its main transmitter, are part of these circuits. O, GABA and glutamate modulate traffic to two or more synapses in these circuits. An excess or deficiency in GABA in the limbic system or basal ganglia can contribute to a neuropsychiatric disorder. Due to GABA-A agonism -increasing an inhibitory influence- is combined with NMDA antagonism -by decreasing an excitatory influence- the gain in the circuit is decreased to two or more synapses, leading to a substantial decrease in activity in the circuit as a all. Normal neural traffic does not imply recurrent activity in these cortical-striate-thalamic circuits is affected to a lesser degree which is the activity responsible for the production of symptoms. This is true because normal traffic is not influenced like many synapses. In addition, some of the drugs encompassed by this application may not reduce normal activity to individual synapses as much as reduce excessive activity. The invention described herein has a broad scope, which comprises the use of drugs with a particular combination of actions for a specific therapeutic purpose. It is obvious to one skilled in the art that a variety of different compounds and delivery systems can be employed to personify the invention. The agents can be synthesized with two active portions, one in an NMDA antagonist and the other a GABA-A agonist. Or agents with the desired combination of pharmacodynamic properties can be modified to improve their absorption, pharmacokinetics, or ability to cross the blood-brain barrier. Agents can be released by a variety of delivery systems, to improve the reliability of absorption or convenience of administration.

Acamprosate (N-acetylhomotaurinate calcium) is the calcium salt of N-acetylhomotaurine, a derivative of the amino acid of taurine. (Taurine is aminoethanesulfonic acid, homotaurine is aminopropanesulfonic acid, acetylhomotaurine is N-acetylaminopropanesulfonic acid). It is used clinically in the treatment of abstinent alcoholics to reduce or inhibit their anxiety for alcohol. Acamprosate, which is chemically similar to GABA neurotransmitter inhibitor, is a GABA agonist, particularly to GABA-A receptors. In addition, it reduces the post-synaptic response of NMDA-type glutamate receptors and reduces inflows through the operated voltage channels. (Wilde &Wagstaff, Drugs, 53: 1039-53, 1997). Acamprosate, because of its low toxicity, is a particularly attractive drug for use in treating patients who experience intolerable side effects when treated with currently available medications for neuropsychiatric disorders. In controlled trials for the treatment of alcoholism, 3,338 patients were implicated, acamprosate had no severe medical or neurological side effects. Incidentally, the relationship of the marginalized subject was identical in the group receiving acamprosate treatment and in the group receiving a placebo (Wilde and Wagstaff, Drugs, June, 53 (6): 1038-53, 1996). Many patients experience intolerable side effects of SRIs, which are currently the standard treatment for Acamprosate can be used either as a substitute for SRIs, or to increase the efficacy of SRIs, and allows the use of better tolerated, lower doses. The above hypothesis with respect to a motor control circuit involves GABA (receptors through GABA-A) and glutamate (receptors via NMDA) which imply that any drug that is a GABA-A agonist and a glutamate antagonist of the type NMDA can improve neuropsychiatric disorders. Acamprosate (N-acetylhomotaurinate calcium) is a specific example of such a drug for which direct human evidence of efficacy in the treatment of PTSD is presented. Other examples of such drugs include other salts of N-acetylhomotaurine, and those derived from homotaurine and acetylhomotaurine which have similar effects on GABA-A and NMDA-like glutamate transmission, and prodrugs that are metabolized in the liver, blood, or brain to produce N-acetylhomotaurinate or related compounds with similar pharmacodynamic properties. Accordingly, a preferred embodiment of the present invention provides homotaurine and N-acetylhomotaurine derivatives at effective and non-toxic doses to a patient for the treatment of neuropsychiatric disorders.

Particularly preferred are acamprosate derivatives that are readily absorbed from the gastrointestinal tract. Acamprosate is irregularly absorbed from the Gl tract, in part due to the polar, hydrophilic nature of the acetylhomotaurinate ion. It is well known in the art that certain drug derivatives can be better and safer absorbed because they are more lipophilic. For example, the prepared esters of the acetylhomotaurinate ion would be more lipophilic, and therefore may have greater predictable absorption through the membranes of the intestinal mucosa. If such an ester were non-toxic and would naturally be metabolized in the body, for example, adhered by enzymes in the blood, liver or brain, it could be particularly preferred as a vehicle to safely deliver the acetylhomotaurinate ion to the brain. Furthermore, such derivatives as described above would have, in appropriate doses, equal or greater efficacy in treating any neuropsychiatric disorder of acamprosate response. Alternatively, the drug can be covalently linked to a lipophilic molecule for better absorption. Generally, any pro-drug with improved acamprosate delivery would also be a preferred means of delivery according to the present invention. A particularly preferred form of acamprosate would be an acamprosate derivative with a longer half-life. Such acamprosate derivative would be clinically superior to acamprosate, because it can be taken once a day, instead of three or four times a day, as is necessary when acamprosate is used. An additional approach to lengthening the half-life of acamprosate or a related medicament is to deliver it in a time-release capsule. In another preferred embodiment, a pharmaceutical agent is selected from the group of agents that act as GABA receptor agonists and also acts to decrease the function of the NMDA receptor by an indirect or modulator mechanism such as, in a non-limiting form, calcium acamprosate ( N-acetylhomotaurinate calcium), other salts of N-acetylhomotaurinate (for example, magnesium N-acetylhomotaurinate or lithium N-acetylhomotaurinate), acetylhomotaurine base, other homotaurine derivatives having similar pharmacodynamic actions in GABA and glutamate transmission, and prodrugs that are metabolized in the liver, blood, or brain to produce N-acetylhomotaurinate or compounds related to similar pharmacodynamic actions in GABA and glutamate transmission. In another preferred embodiment, a pharmaceutical agent is selected from the group of agents that have the ability to reduce post-synaptic excitatory potentials that produce glutamate in striated cells, including acamprosate and the range of similar compounds and prodrugs previously described. In other preferred embodiments, a combination of two or more pharmaceutical agents is selected such that the combination acts concurrently to increase GABA transmission (particularly through GABA-A receptors) and to attenuate the transmission of NMDA-type glutamate (e.g. , non-competitive inhibition, or indirect or modulatory effects on NMDA receptors). A fourth embodiment is to combine such compounds or mixtures of compounds with memantine or a similar, non-competitive NMDA receptor blocking agent described in detail below. The combinations can be either mixtures, covalently linked portions with combined action, or prodrugs metabolized in the blood, liver or brain to release each member of the combination. The magnesium ion, which blocks calcium channels, is known to be an antagonist of the glutamate NMDA receptor. If a magnesium or chelate salt is given together with another NMDA antagonist, the action of the latter is improved. In particular, the present invention establishes that magnesium supplementation may increase the action of acamprosate in the treatment of a neuropsychiatric disorder. An effective drug treatment can not only treat PTSD, but you can avoid this if it occurs quickly after stress. Trauma victims can be presumably identified as being particularly at risk for developing PTSD. This includes those with a history of previous trauma in childhood, as well as those with acute stress reactions. For example, a rape victim may be at risk for developing PTSD and an effective dose of acamprosate may be administered to prevent the development of PTSD. In another modality, magnesium supplementation is used in conjunction with a GABA-A agonist in order to delay the PTSD attack in a person at risk, or the attack of another neuropsychiatric disorder in a person identified as being at risk for this. In yet another modality, magnesium supplementation will reduce the symptoms associated with various neuropsychiatric disorders. The present invention teaches the use of an NMDA-agonist GABA antagonist strategy with or without administration of magnesium to treat and prevent neuropsychiatric disorders. According to the present invention, magnesium supplementation will increase the therapeutic effects of other NMDA receptor antagonists and lower regulators (see Case Report 5). In a preferred embodiment, magnesium is administered with acamprosate (calcium N-acetylhomotaurine) to treat neuropsychiatric disorders. In a particularly preferred embodiment, the magnesium salt of N-acetylhomotaurine and the magnesium salts of those N-acetylhomotaurine derivatives that similarly improve GABA transmission and decrease the neurotransmission of NMDA glutamate, are effective treatments of neuropsychiatric disorders. It will be recognized by those skilled in the art that for all conditions whereby calcium N-acetylhomotaurinate is an effective treatment, magnesium N-acetylhomotaurinate, and the magnesium salts of those N-acetylhomotaurine derivatives which have similar effects in GABA neurotransmission and glutamate-NMDA neurotransmission will also be effective treatments. A specific example of such a compound is one that has two active portions, one that is a GABA-A agonist and one that is an NMDA antagonist. In the body, the compound can either remain intact, or it can be metabolized into two compounds, one with the GABA-A agonist activity and the other with NMDA antagonist activity. Alternatively, any magnesium or chelate salt can be administered with any salt of a homotaurine derivative or N-acetylhomotaurine having NMDA antagonist activity and GABA-A agonist, to treat neuropsychiatric disorders. In a non-limiting example, a pill containing the appropriate dose of acamprosate together with the appropriate dose of magnesium can be formulated and administered to a patient with a neuropsychiatric disorder. In other preferred embodiments, an agent having NMDA antagonist activity and GABA agonist activity is combined with the appropriate dose of magnesium in a pill. In yet another preferred embodiment, an NMDA antagonist is combined with a GABA agonist in an appropriate dose of magnesium in the form of a pill. One of ordinary skill in the art will recognize that the administration composition is not limited to a pill, but may also be a syrup, an elixir, a liquid, a tablet, a release time capsule, an aerosol or a transdermal patch. The acamprosate to magnesium ratio can be varied to optimize the therapeutic synergy of the two ingredients. It is proposed that the effective dose ranges will be similar for the treatment of neuropsychiatric disorders such as movement disorders, but some variation may exist and the dose ranges may be determined experimentally by those of ordinary skill in the art. The magnesium N-acetylhomotaurinate (Durlach, supra); 1980), with a ratio of magnesium acetylhomotaurinate of approximately 1:20 by weight, does not optimize the therapeutic effect of the two components for the treatment of movement disorders (see US Patent Applications serial numbers 09 / 006,641 and 09 / 193,892, incorporated herein by reference). A typical therapeutic dose of acetylhomotaurinate, the amount of magnesium is so low to have therapeutically relevant effects on the transmission of glutamate. In my experience, excellent therapeutic results were obtained from combining a dose of 2 grams per day of acamprosate with 1 gram of elemental magnesium, giving as a salt or chelate (see US Patent Application Serial No. 09 / 193,892). This combination gives better relief of TD and tics than 2 grams of acamprosate alone. It has also been shown that a single dose of 300 mg of magnesium will increase the therapeutic effect of a single dose of 666 mg of acamprosate. One of ordinary skill in the art will await the ranges of doses determined to be effective in treating movement disorders to also be effective in treating other neuropsychiatric disorders, since the mechanism of hypotheses of therapeutic action is the same. By allowing for variations in individual response, and variations in intestinal absorption of acamprosate and magnesium, it is stated that the optimal Mg: acetylhomotaurinate ratio for an individual patient for treatment of neuropsychiatric disorders will be in some way between 1: 6 and 1: 1 . Lower magnesium to acamprosate ratios are unlikely to increase the therapeutic effect of acamprosate significantly, and ratios higher than 1: 1 are likely to produce magnesium toxicity (or at least Gl intolerance) at a typical daily dose of acamprosate. grams. Although magnesium N-acetylhomotaurinate may be slightly more effective than calcium N-acetylhomotaurinate for the treatment of neuropsychiatric disorders, in the present application they effectively increase the magnesium content of acamprosate and related compounds by magnesium ion administration (as a salt or chelate) in combination with a N-acetylhomotaurinate salt, because there is a significant benefit to administer a higher magnesium ratio for acamprosate which is present in the magnesium salt of acamprosate. Another aspect of the present invention involves the prevention of neuropsychiatric disorders, including anxiety disorders, psychotic disorders, mood disorders and somatoform disorders, with an agent or combination of agents having NMDA antagonist activity and simultaneous GABA-A agonist activity without co-administration of magnesium. In a preferred embodiment of this aspect of the invention, such NMDA antagonist / GABA-A agonist combinations are used to prevent the development or aggravation of a neuropsychiatric disorder, for example, in a patient exhibiting preliminary symptoms of a neuropsychiatric disorder. In another preferred embodiment of this aspect of the invention, the combined activities of the NMDA antagonist / agonist GABA-A are used to prevent the development of a neuropsychiatric disorder (e.g., PTSD) followed by stress. In a particularly preferred embodiment, agents or activity combinations of agents with NMDA antagonist / GABA-A agonist are administered to a patient at risk to develop a neuropsychiatric disorder, such as PTSD, to avoid complications of substance abuse and somatization. Specifically, the prevention of alcoholism subsequent to extreme stress is particularly desirable. Alcoholism often develops as a complication of PTSD and / or following a traumatic event in personal life. To avoid the development of substance abuse after trauma, the patient who experiences the traumatic event is treated with an agent with NMDA antagonist activity / GABA-A agonist shortly combined after the event of the traumatic event. The value of acamprosate in treating abstinent alcoholics is well known. Nevertheless, the use of acamprosate to avoid alcoholism in people at risk has not been proposed until now. One of ordinary skill in the art will recognize that the present invention is not limited to a method of treating PTSD, OCD and other neuropsychiatric disorders with any agent that reduces the neurotransmission of NMDA-type glutamate and increases GABA neurotransmission through direct effects in GABA and NMDA receptors. The invention also encompasses the use of agents that modify NMDA glutamate and the transmission of GABA in the same direction through indirect effects on receptors (ie, through pre-synaptic effects in neurotransmitter release, allosteric modulation of the receptor site , o-effects in the intracellular response to the link from the transmitter to the receiver), presynaptic effects in the release of the transmitter, inhibition of GABA reincorporation, etc. It will be obvious to a person skilled in the art that a range of derivatives and prodrugs will all be therapeutically effective, as large as having a sufficient effect on the transmission of GABA-A and glutamate-NMDA at non-toxic doses. Any compound or mixture that combines the effects on the transmission of glutamate and GABA are hypothesized to underlie the therapeutic effects of acamprosate are within the scope of the presently claimed invention. No matter how a drug, prodrug or mixture thereof decreases the neurotransmission of glutamate-NMDA and increases the neurotransmission of GABA, it only improves the symptoms associated with neuropsychiatric disorders at tolerable non-toxic doses (for example, of side effects of unacceptable toxicity) . As previously discussed, the inventive treatment can be used to treat any neuropsychiatric disorder that involves as symptoms of thoughts, perceptions or unwanted, undesirable, or repetitive involuntary, stereotyped behaviors. In addition, the inventive treatment can be used to ameliorate or eliminate symptoms that are consequences of such neuropsychiatric disorders, for example, cognitive dysfunction or abnormalities of motivation, mood, or impulse control. The basal ganglia, including the estrado, are a point of intersection of motor, cognitive and emotional circuits. Basal ganglion diseases often involve cognitive, emotional, behavioral, and motivational changes, as well as motor dysfunction. The limbic system, including the amygdala and the region marked with anterior circles can also influence this circuit. The advanced treatments in this invention are effective for the symptoms of various disorders involving the dysfunction of the basal ganglia or the limbic system or circuits through them. It can be expected that these treatments will improve some of the other symptoms that accompany the basal ganglia and disorders of the limbic system. The present invention will now be illustrated by the following non-limiting example: Case Report Administering acamprosate to 33-year-old women with PTSD. This patient has PTSD counting several incidents of sexual abuse in childhood and adolescence. Its symptoms include undesirable images of episodes of abuse (regressions), undesirable thoughts about episodes of abuse (traumatic memories), nightmares, response of increased fright, anxiety, depression, avoidance of the company of men, emotional insensitivity, suicide idea, and self-injury or risky behavior (for example, self-cutting, reckless motoring). The above symptoms were not alleviated by any of the large numbers of medications, including antipsychotic (neuroleptic) drugs, antidepressants, benzodiazepines, and antiepileptic drugs. In March 1998, the patient started acamprosate at a dose of 333 mg three times a day. The dose was gradually increased to 666 mg three times a day. In this dose, the patient had less anxiety, fewer ideas of suicide, minor regressions of traumatic events, less undesirable thoughts of abuse, less psychic insensitivity, and greater ability to talk about the traumatic events that precipitated his PTSD. The additional doses of 666 mg of acamprosate, taken as necessary, relieved psychic tension, despair, the idea of suicide, and psychic insensitivity precipitated by memories of his trauma.

The patient's PTSD symptoms continued to respond to acamprosate treatment for a period of 1 year from March, 1998 to March, 1999. During this time, the gradual dose reductions attempted to see if the medication would still be necessary, and if this was to determine the minimum effective dose. Its symptoms respond to a dose-related manner that was duplicated several times. The response of the specific PTSD symptoms to different doses of acamprosate is now described. The severity of symptoms was related semi-quantitatively, based on a consensus of the physician and the patient regarding the intensity of symptoms during the week prior to the date of assessment. The severity scale of symptoms varies from 0 to ++++, with ++++ being the most severe.

Summary The Case Report demonstrates that acamprosate is effective for the treatment of PTSD at effective and non-toxic doses. The administration of acamaprosate to a patient with PTSD resulted in an impressive response regarding several thoughts, perceptions and recurrent behaviors characteristic of PTSD, and without response in his case to conventional psychiatric medications. The response of patients to acamprosate treatment, coupled with the previously reported case of the efficacy of acamprosate in a patient with a simple tic, provides evidence and suggests that patients with other neuropsychiatric disorders, for example OCD and somatoform disorders, will receive similar benefit of acamprosate or similar agents or combination of agents with NMDA antagonist activity and GABA-A agonist activity.

Claims (60)

1. CLAIMS 1. A method for treating symptoms of anxiety disorders comprising the steps of: administering to a patient with an anxiety disorder an effective non-toxic dose of an agent that increases GABA-A neurotransmission and decreases the neurotransmission of glutamate. NMDA, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day wherein the agent is selected from the group consisting of: calcium N-acetylhomotaurinate, magnesium N-acetylhomotaurinate, lithium N-acetylhomotaurinate, salts of N-acetylhomotaurine, acetylhomotaurine base and acetylhomotaurinate derivatives that improve GABA-A transmission and reduce the transmission of NMDA-type glutamate.
2. 2. The method for avoiding symptoms of anxiety disorders in a patient in need thereof, characterized in that it comprises the steps of: avoiding symptoms of anxiety disorders by administering to the patient an effective and non-toxic dose of an agent that increases GABA- neurotransmission A and glutamate-NMDA neurotransmission decreases, wherein the agent is selected from the group consisting of: calcium N-acetylhomotaurinate, magnesium N-acetylhomotaurinate, lithium N-acetylhomotaurinate, N-acetylhomotaurine salts, acetylhomotaurine base and acetylhomotaurinate derivatives that improve GABA-A transmission and reduce the transmission of glutamate of the NMDa type.
3. The method according to claim 1 or 2, characterized in that such symptoms are selected from the group consisting of repetitive and stereotyped unwanted thoughts; unwanted perceptions retrospective and stereotyped scenes; undesirable reiterative and stereotyped thoughts; undesirable perceptions retrospective and stereotyped scenes; repetitive and stereotyped involuntary movements; repetitive and stereotyped involuntary behaviors; repetitive and stereotyped compulsive movements; and compulsive behaviors retrospective and stereotyped scenes.
4. 4. The method according to claim 1 or 2, characterized in that said anxiety disorder is selected from the group consisting of: post-traumatic stress disorder and obsessive-compulsive disorder.
5. 5. The method according to claim 1 or 2, characterized in that the agent increases the neurotransmission GABA-A and decreases the neurotransmission of glutamate-NMDA with synergy of therapeutic efficacy and without synergy of toxicity.
6. 6. The method according to claim 1 or 2, characterized in that the agent is available in the blood.
7. The method according to claim 1 or 2, characterized in that the agent is available in the brain.
8. The method according to claim 1 or 2, characterized in that the agent is a pro-drug metabolized in a body to release acetylhomotaurinate ion in the body.
9. The method according to claim 8, characterized in that the pro-drug is an acetylhomotaurinate ester or an ester of an acetylhomotaurinate derivative having pharmacodynamic effects on neurotransmission GABA-A and glutamate of the NMDA type similar to those of N -acetylomotaurinate calcium.
10. 10. The method of compliance with the claim 1 or 2, characterized in that the agent is calcium N-acetylhomotaurinate or N-acetylhomotaurinate.
11. 11. The method according to claim 1 or 2, characterized in that the agent comprises a derivative of calcium N-acetylhomotaurinate or a base derivative of N-acetylhomotaurine having pharmacodynamic effects in the transmission of GABA-A or glutamate-NMDA. similar to those of calcium N-acetylhomotaurinate.
12. The method according to claim 11, characterized in that the derivatives have a longer half-life in a patient than the calcium N-acetylhomotaurinate.
13. The method according to claim 11, characterized in that the derivatives are absorbed from a gastrointestinal tract at a rate greater than an absorption rate for calcium N-acetylhomotaurinate.
14. 14. The method according to claim 11, characterized in that known amounts of the derivatives are absorbed from a gastrointestinal tract.
15. 15. The method according to claim 1 or 2, characterized in that the agent comprises two active portions, one which is the GABA-A agonist and another which is the NMDA antagonist.
16. 16. The method of compliance with the claim 1 or 2, characterized in that the agent is metabolized in the body into two compounds, one with GABA-A agonist activity and the other with NMDA agonist activity.
17. 17. The method according to claim 1 or 2, characterized in that the administration step comprises oral administration.
18. 18. The method according to claim 1 or 2, characterized in that the anxiety disorder is related to a deficiency in GABA in the basal ganglia or limbic system.
19. 19. The method according to claim 1 or 2, characterized in that said anxiety disorder is related to an excess of glutamate in the basal ganglia or limbic system.
20. 20. A method for treating symptoms of anxiety disorders comprising the steps of: selecting a first pharmacologically active agent that acts as an agonist of the GABA-A receptor; selecting a second pharmacologically active agent that acts as an antagonist of the glutamate receptor of the NMDA type; and administering such first and second agents to a patient with an anxiety disorder at effective and non-toxic doses, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day.
21. 21. A method for avoiding symptoms of anxiety disorders in a patient in need thereof, characterized in that it comprises the steps of: selecting a pharmacologically active agent that acts as a GABA-A receptor agonist; selecting a pharmacologically active agent that acts as an NMDA-type glutamate receptor antagonist; and avoiding the progression of symptoms of an anxiety disorder by administering first and second agents to the patient with an anxiety disorder at effective and non-toxic doses, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day.
22. 22. The method according to claim 20 or 21, characterized in that the symptoms are selected from the group consisting of reiterative and stereotyped unwanted thoughts; unwanted perceptions retrospective and stereotyped scenes; undesirable, repetitive and stereotyped thoughts; undesirable, repetitive and stereotyped perceptions; repetitive and stereotyped involuntary movements; involuntary behaviors retrospective and stereotyped scenes; repetitive and stereotyped compulsive movements; and compulsive behaviors retrospective and stereotyped scenes.
23. 23. The method according to the claim 20 or 21, characterized in that such an anxiety disorder is selected from the group consisting of post-traumatic stress disorder and obsessive-compulsive disorder.
24. 24. The method according to claim 20 or 21, characterized in that the first and second agents increase GABA-A neurotransmission and decrease the neurotransmission of glutamate-NMDA with synergistic therapeutic efficacy and without toxicity synergy.
25. 25. The method according to claim 20 or 21, characterized in that the step of administering further comprises selecting doses of the first and second agents such that the combination of the first and second doses reduces symptoms of such anxiety disorder to non-toxic doses.
26. 26. The method according to claim 20 or 21, characterized in that in the selection step, the first agent and the second agent are the same agent.
27. 27. The method according to claim 20 or 21, characterized in that such anxiety disorder is related to a deficiency in GABA in the basal ganglia or limbic system.
28. 28. The method according to claim 20 or 21, characterized in that said anxiety disorder is related to an excess of glutamate in the basal ganglia or limbic system.
29. 29. The method of compliance with the claim 20 or 21, characterized in that after the step of selecting a second pharmacologically active agent, the method further comprises selecting a third pharmacologically active agent that is a non-competitive NMDA receptor antagonist., or an ion channel blocker to channels linked to NMDA receptors, and wherein after the step of administering the first and second agents, the method further comprises administering the third active agent.
30. 30. The method according to claim 29, characterized in that in the steps of administering, the third agent is administered in conjunction with the first and second agents.
31. 31. The method according to claim 29 or 30, characterized in that the third agent is an NMDA antagonist.
32. 32. The method according to claim 29 or 30, characterized in that the third agent is an NMDA antagonist and a GABA-A agonist.
33. 33. The method according to claim 29 or 30, characterized in that the third agent is memantine.
34. 34. The method according to claim 29 or 30, characterized in that the third agent is a memantine derivative with pharmacodynamic effects at NMDA receptors similar to those of memantine.
35. 35. The method of compliance with the claim 29 or 30, characterized in that the third agent is magnesium.
36. 36. A method for treating symptoms of anxiety disorders comprising: increasing the therapeutic effects of NMDA receptor antagonists and lower regulators in a patient with an anxiety disorder by administering to said patient an effective dose of magnesium ion.
37. 37. The method according to claim 36, characterized in that the NMDA receptor antagonist is magnesium N-acetylhomotaurine given in an effective and non-toxic dose.
38. 38. The method according to claim 36, characterized in that the NMDA receptor antagonist is the magnesium salt of any N-acetylhomotaurinate derivative that enhances the neurotransmission GABA-A and attenuates the neurotransmission of glutamate-NMDA.
39. 39. The method according to claim 36, characterized in that the NMDA receptor antagonist is the magnesium salt of any N-acetylhomotaurine derivative which is an effective treatment for symptoms of anxiety disorders.
40. 40. The method according to claim 36, characterized in that said anxiety disorder is selected from the group consisting of post-traumatic stress disorder and obsessive-compulsive disorder.
41. 41. A method for treating symptoms of anxiety disorders comprising: administering to a patient a composition in an effective and non-toxic dose comprising: (i) an NMDA receptor antagonist (ii) a GABA-A (iii) ion agonist of magnesium, wherein the GABA-A agonist and the NMDA receptor antagonist are selected from the group consisting of: calcium N-acetylhomotaurinate, magnesium N-acetylhomotaurinate, lithium N-acetylhomotaurinate, N-acetylhomotaurine salts, acetylhomotaurine and derivatives thereof that improve GABA-A transmission and reduce the transmission of glutamate of the NMDA type.
42. 42. The method of compliance with the claim 41, characterized in that said derivative is available in blood.
43. 43. The method according to claim 41, characterized in that said derivative is available in the brain.
44. 44. The method according to claim 41, characterized in that said derivative is a prodrug metabolized in liver, blood, or brain to release acetylhomotaurinate ion.
45. 45. The method according to the claim 41, characterized in that such a derivative is a prodrug metabolized in liver, blood or brain to release an acetylhomotaurinate ion derivative having pharmacodynamic effects in neurotransmission GABA-A and NMDA-glutamate similar to the effects of calcium N-acetylhomotaurinate.
46. 46. The method according to claim 45, characterized in that such a pro-drug comprises an acetylhomotaurinate ester, or an ester of any acetylhomotaurine derivative having pharmacodynamic effects on neurotransmission of GABA-A and NMDA-glutamate similar to that of N -acetylomotaurinate calcium.
47. 47. The method according to claim 41, characterized in that said derivative has a half-life in a patient that is greater than a half-life of calcium N-acetylhomotaurinate.
48. 48. The method according to claim 41, characterized in that said derivative is absorbed from the gastrointestinal tract at a rate that is greater than an absorption rate for calcium N-acetylhomotaurinate.
49. 49. The method of compliance with the claim 41, characterized in that an effective dose of (i) an NMDA receptor antagonist (ii) a GABA-A agonist (iii) a magnesium ion is supplied in the form of a pill, a syrup, an elixir, a liquid, a tablet, a time-release capsule, an aerosol or a transdermal patch.
50. 50. A method for treating symptoms of obsessive-compulsive disorder, comprising: administering to a patient with symptoms of obsessive-compulsive disorder an agent or combination of agents having NMDA-glutamate antagonist activity and GABA-A agonist activity at effective doses and non-toxic, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day wherein the agent or combination of agents is selected from the group consisting of: calcium N-acetylhomotaurinate, magnesium N-acetylhomotaurinate, N-acetylhomotaurinate lithium, salts of N-acetylhomotaurine, acetylhomotaurine base and derivatives thereof that improve transmission GABA-A and reduce the transmission of glutamate of the NMDA type.
51. 51. A method for treating symptoms of post-traumatic stress disorder comprising: administering to a patient with symptoms of post-traumatic stress disorder an agent or combination of agents having NMDA-glutamate antagonist activity and GABA-A agonist activity at effective and non-toxic doses, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day wherein the agent or combination of the agents is selected from the group consisting of: calcium N-acetylhomotaurinate, N-acetylhomotaurinate magnesium, lithium N-acetylhomotaurinate, N-acetylhomotaurine salts, acetylhomotaurine base and derivatives thereof that improve GABA-A transmission and reduce the transmission of NMDA-type glutamate.
52. 52. A method for preventing the progression of symptoms of post-traumatic stress disorder in a patient in need thereof, comprising: administering to a patient an agent or combination of agents having NMDA-glutamate antagonist activity and GABA agonist activity -A at effective and non-toxic doses, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day wherein the agent or combination of agents is selected from the group consisting of: calcium N-acetylhomotaurinate, N magnesium acetylhomotaurinate, lithium N-acetylhomotaurinate, N-acetylhomotaurine salts, homotaurine base and derivatives thereof, which improve GABA-A transmission and reduce the transmission of NMDA type glutamate.
53. 53. A method for preventing the development of symptoms of post-traumatic stress disorder following extreme stress in a patient in need thereof, comprising: administering to the patient an agent or combination of agents having an NMDA-glutamate antagonist activity and GABA-A agonist activity at effective and non-toxic doses, wherein the dose ranges from about 1 gram per day to about 2.6 grams per day wherein the agent or combination of agents is selected from the group consisting of: N-acetylhomotaurinate calcium, magnesium N-acetylhomotaurinate, lithium N-acetylhomotaurinate, N-acetylhomotaurine salts, acetylhomotaurine base and derivatives thereof, which improve GABA-A transmission and reduce NMDA-type glutamate transmission.
54. 54. The method according to any of claims 50, 51, 52 or 53, characterized in that said agent or combination or agents is co-administered with magnesium ion.
55. 55. A method for treating symptoms of anxiety disorders comprising the steps of: administering to a patient with an anxiety disorder an effective non-toxic dose of calcium N-acetylhomotaurinate, wherein the dose ranges from about 1 gram per day at approximately 2.6 grams per day.
56. 56. A method for treating symptoms of post-traumatic stress disorder comprising the steps of: administering to a patient with post-traumatic stress disorder an effective non-toxic dose of calcium N-acetylhomotaurinate, wherein the dose varies from between approximately 1 gram per day to approximately 2.6 grams per day.
57. 57. A method for avoiding symptoms of post-traumatic stress disorder in a patient in need thereof, comprising the steps of: administering to the patient an effective non-toxic dose of calcium N-acetylhomotaurinate, wherein the dose varies from between approximately 1 gram per day to approximately 2.6 grams per day.
58. 58. A method for treating symptoms of obsessive-compulsive disorder comprising the steps of: administering to a patient with obsessive-compulsive disorder an effective non-toxic dose of calcium N-acetylhomotaurinate, wherein the dose varies from about 1 gram per day to approximately 2.6 grams per day.
59. 59. A method for avoiding symptoms of obsessive-compulsive disorder in a patient in need thereof comprising the steps of: administering to the patient an effective and non-toxic dose of calcium N-acetylhomotaurinate, wherein the dose ranges from about 1 gram per day to approximately 26 grams per day.
60. 60. The method according to any of claims 55-59, characterized in that the step of administering further comprises administering an effective dose of magnesium ion.