Treatment of serotonin reuptake inhibitor withdrawal syndrome

Abstract

The present invention relates to a method for treating serotonin reuptake inhibitor withdrawal syndrome comprising administration of a therapeutically effective amount of escitalopram gentisate.

Description

[Technical field]

[0001] Depression is a common illness worldwide, with more than 250 million sufferers. This means that an estimated 1 in 15 adults will be affected in any given year, and 1 in 6 will experience depression at some point in their lives. Depression can become a serious health condition, especially if it persists for a long time and has moderate or severe intensity. It can cause sufferers to suffer greatly and fail to function at work, school, or with their family. In the worst cases, depression can lead to suicide. Nearly 800,000 people die by suicide every year, and suicide remains the second leading cause of death in people aged 15-29. A recent study showed that the diagnosis of major depressive disorder in the United States increased from 6% in 1996 to more than 10% in 2015. The same study showed that only 70% of patients received any antidepressant therapy. [Background technology]

[0002] For over 20 years, the most common treatment for depression has been oral antidepressants such as serotonin reuptake inhibitors. Current estimates are that this drug class accounts for 70-90% of all antidepressant prescriptions in the United States.

[0003] Antidepressants are also one of the most commonly prescribed classes of drugs in Europe and the United States, with the number of prescriptions and duration of use increasing year on year. Between 2000 and 2018, over 7 million UK adults (16% of the adult population) were prescribed an antidepressant in 2017, with over half of these patients estimated to have been taking the drug for more than two years, experiencing a 170% increase in use. Similar figures are seen in the United States, where prevalence increased from 8% of the population in 2002 to almost 13% (37 million adults) by 2014, with around half of these patients taking the drug for at least five years. The average duration of antidepressant use has also more than doubled in the ten years between 2005 and 2015 in both the UK and the US.

[0004] Despite a large increase in the diagnosis of depression, the number of patients prescribed antidepressants, and the duration of their use, it is estimated that one-third of patients taking the drugs for more than two years have no remaining clinical indications justifying their continued administration. Suggestions have therefore been made by both researchers and government-appointed bodies that prescribers should give more consideration to the possibility of discontinuing antidepressant therapy in at least some of their prescribed population.

[0005] However, discontinuation of oral serotonin reuptake inhibitor therapy is accompanied by a variety of clinical symptoms. First identified in 1997, serotonin reuptake inhibitor withdrawal syndrome includes a wide variety of somatic and psychological symptoms, including gastrointestinal complaints of nausea, vomiting, and crampy abdominal pain, flu-like symptoms, and lethargy, excessive sweating or flushing, dizziness, tremors, as well as cognitive impairment such as irritability, anxiety, confusion, and memory loss. The prevalence of the syndrome varies depending on the serotonin reuptake inhibitor being discontinued, but it is estimated to occur in an average of just over half of all cases of drug discontinuation. The syndrome may persist for long periods of time, even after the drug is no longer prescribed. In one study, 87% reported that the syndrome persisted for at least 2 months, 59% for at least 1 year, and 16% for more than 3 years.

[0006] It is understood that the variability in the incidence of symptoms after discontinuation of serotonin reuptake inhibitors is partly explained by differences in the pharmacokinetic profiles of individual drugs within the class. Several factors have been suggested to be relevant, including short plasma half-lives and the presence of active metabolites. Nevertheless, even the approved product monographs for controlled-release antidepressant dosage forms warn that the syndrome may develop upon discontinuation. Summary of the Invention [Problem to be solved by the invention]

[0007] Currently, treatment options for serotonin reuptake inhibitor withdrawal syndrome remain limited. Rechallenge of antidepressants has been shown to successfully resolve most symptoms, but is clearly not a practical option for patients seeking to discontinue taking the medication. Other methods include attempting to switch the patient to a different, preferably less symptomatic, serotonin reuptake inhibitor, or bridging to a non-serotonin reuptake inhibitor antidepressant, before discontinuing therapy. Very often, physicians will attempt to taper the dose of the antidepressant. Studies have shown that a 14-day taper is unsuccessful, and the generally accepted current practice is to taper over an extended period of several months, typically 4-6 months. Recent reports have also suggested that taper may need to be hyperbolic rather than a linear dose reduction. Maintaining patients' compliance with a drug they no longer wish to take remains a significant concern for each of these treatment approaches, and managing dose reductions when they no longer match available commercial doses is a practical problem, leading some researchers to even suggest switching to unregulated combined liquid formulations.

[0008] In light of the underlying conditions and the important public health requirement to reduce unnecessary prescriptions of antidepressants in the general population, there remains a need for practical, simple solutions to reduce the prevalence, duration, and severity of serotonin reuptake inhibitor withdrawal syndrome. [Means for solving the problem]

[0009] The present invention relates to the treatment or prevention of serotonin reuptake inhibitor withdrawal syndrome, which comprises administering to a subject in need thereof a therapeutically effective amount of escitalopram gentisate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In this disclosure, the singular forms "a," "an," and "the" include plural references, and a reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" is a reference to one or more such compounds, and equivalents thereof known to those of skill in the art. As used herein, the term "plurality" means more than one. When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, it is understood that the particular value forms another embodiment by using the antecedent "about." All ranges are inclusive and combinable.

[0011] When values ​​are expressed as approximations, by using the antecedent "about," it will be understood that the particular value forms another embodiment. As used herein, "about X," where X is a numerical value, preferably refers to ±10% of the cited value (including limits). For example, the phrase "about 8" refers to a value of 7.2 to 8.8 (inclusive), and as another x example, the phrase "about 8%" refers to a value of 7.2% to 8.8% (inclusive). When present, all ranges are inclusive and combinable. For example, when a range of "1 to 5" is recited, the recited range should be construed to include ranges such as "1 to 4," "1 to 3," "1 to 2," "1 to 2 and 4 to 5," "1 to 3 and 5," etc. In addition, when a list of alternatives is affirmatively provided, such list also includes embodiments in which any of the alternatives may be excluded. For example, if a range of "1 to 5" is recited, such a description may support a situation in which any of 1, 2, 3, 4, or 5 is excluded; thus, a recitation of "1 to 5" may support "1 and 3 to 5" but not 2, or simply "2 is not included."

[0012] As used herein, the terms "component," "composition," "composition of a compound," "compound," "drug," "pharmacologically active agent," "active agent," "therapeutic agent," "therapy," "treatment," or "agent" are used interchangeably herein to refer to a compound or composition of matter that induces a desired pharmacological and / or physiological effect by local and / or systemic action upon administration to a human subject.

[0013] As used above and throughout this disclosure, the term "effective amount" refers to an amount effective to achieve the desired result in terms of treating the relevant disorder, condition, or side effect at the required dosage and for the required period of time. It will be understood that the effective amount of the components of the present invention will vary from patient to patient, not only with respect to the particular compound, component, or composition selected, the route of administration, and the ability of the component to induce the desired result in the individual, but also with respect to the severity of the disease state or condition to be alleviated, hormone levels, the individual's age, sex, weight, the individual's metabolic rate, the condition of the patient, and the severity of the pathological condition to be treated, concurrent medications or special diets followed by a particular patient, and other factors that a person skilled in the art would recognize, and that the appropriate dosage is determined at the discretion of the attending physician. Dosage regimens can be adjusted to provide improved therapeutic responses. A therapeutically effective amount is also an amount in which any toxic or adverse effects of the component are outweighed by the therapeutically beneficial effects.

[0014] The present invention relates to the treatment or prevention of serotonin reuptake inhibitor withdrawal syndrome, which comprises administering to a subject in need thereof a therapeutically effective amount of escitalopram gentisate.

[0015] As used herein, the term "serotonin reuptake inhibitor withdrawal syndrome" refers to a constellation of symptoms that can occur following cessation of an orally administered serotonin reuptake inhibitor that has been taken continuously for at least one month.

[0016] Symptoms associated with serotonin reuptake inhibitor withdrawal syndrome have been described in published clinical literature, such as Jha (2018) and Warner (2006), and can include general complaints, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, dermatological, neurological, and psychiatric symptoms.

[0017] Common complaints associated with serotonin reuptake inhibitor withdrawal syndrome include chills, malaise, flu-like symptoms, fatigue, lethargy, fever, sweating, blurred vision, abnormal eye movements, eye pain, eye twitching, tinnitus, rhinorrhea, sinus congestion, stuffy nose, and increased salivation.

[0018] Respiratory complaints associated with serotonin reuptake inhibitor withdrawal syndrome include shortness of breath.

[0019] Cardiovascular complaints associated with serotonin reuptake inhibitor withdrawal syndrome include palpitations, tachycardia, and elevated systolic and diastolic blood pressure.

[0020] Gastrointestinal complaints associated with serotonin reuptake inhibitor withdrawal syndrome include nausea, vomiting, diarrhea, abdominal pain, stomach cramps, loss of appetite, and abdominal bloating.

[0021] Serotonin reuptake inhibitor withdrawal musculoskeletal and genitourinary complaints include genital hypersensitivity and premature ejaculation.

[0022] Musculoskeletal complaints associated with serotonin reuptake inhibitor withdrawal syndrome include sore muscles, myalgia, joint pain, and muscle spasms.

[0023] Skin complaints associated with serotonin reuptake inhibitor withdrawal syndrome include pruritus.

[0024] Neurological complaints associated with serotonin reuptake inhibitor withdrawal syndrome include imbalances such as vertigo, dizziness, mild headache, gait unsteadiness, or ataxia; sensory disturbances such as abnormal sensitivity to sound, electric shock sensations, paresthesia, numbness, tinnitus, taste disturbances, or brain zaps; neuromuscular symptoms such as acute dystonia, myoclonus, tremors, agitation, Parkinson's syndrome, or akathisia; and cognitive symptoms such as delirium, memory loss, memory impairment, disorientation, or confusion.

[0025] Psychiatric complaints associated with serotonin reuptake inhibitor withdrawal syndrome include dysphoria, hypomania, depression, crying fits, tearfulness, impulsivity, irritability, irritability, aggression, anger fits, mood swings, problems concentrating, muscle tension, worsening mood such as suicidal or homicidal thoughts, worsening anxiety such as tension, panic, or generalized anxiety, sleep disturbances such as insomnia, hypersomnia, vivid dreams, nightmares, or disrupted circadian rhythms, and perception disturbances such as depersonalization, derealization, hypnotic hallucinations, or unusual visual sensations such as geometric shapes and colors, auditory or visual hallucinations.

[0026] As used herein, the term "treatment of serotonin reuptake inhibitor withdrawal syndrome" refers to the alleviation or reduction of at least one adverse or negative effect of a symptom or complaint associated with serotonin reuptake inhibitor withdrawal syndrome.

[0027] In one embodiment of the present invention, the treatment of serotonin reuptake inhibitor withdrawal syndrome refers to the alleviation or reduction of at least one adverse or negative impact of any of the following general complaints, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, skin, neurological, or psychiatric symptoms associated with serotonin reuptake inhibitor withdrawal syndrome. In another embodiment of the present invention, the treatment of serotonin reuptake inhibitor withdrawal syndrome refers to the alleviation or reduction of the adverse or negative impact of any of the following general complaints, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, skin, neurological, or psychiatric symptoms associated with serotonin reuptake inhibitor withdrawal syndrome. In another embodiment of the present invention, the treatment of serotonin reuptake inhibitor withdrawal syndrome refers to the alleviation or reduction of all adverse or negative impact of any of the following general complaints, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, skin, neurological, or psychiatric symptoms associated with serotonin reuptake inhibitor withdrawal syndrome.

[0028] As used herein, the term "discontinued" or "discontinuation" refers to the abrupt cessation or significant reduction in dose within the previous seven days of an orally administered serotonin reuptake inhibitor that has been taken continuously for at least one month.

[0029] As used herein, the term "escitalopram gentisate" refers to the gentinalate salt of escitalopram, which is described in Patent Application No. WO2019 / 073388, the entirety of which is incorporated herein by reference.

[0030] In one embodiment of the present invention, the escitalopram gentisate is crystalline. In another embodiment of the present invention, the escitalopram gentisate is non-crystalline. In one embodiment of the present invention, the escitalopram gentisate is escitalopram gentisate Form I. In another embodiment of the present invention, the escitalopram gentisate is escitalopram gentisate Form II.

[0031] As used herein, the term "prevention of serotonin reuptake inhibitor withdrawal syndrome" refers to the reduction of at least one adverse or negative effect of any of the common complaints, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, cutaneous, neurological, or psychiatric symptoms associated with serotonin reuptake inhibitor withdrawal syndrome in a subject who has discontinued oral administration of a serotonin reuptake inhibitor but has not yet exhibited any of the complaints or symptoms associated with serotonin reuptake inhibitor withdrawal syndrome. This term applies only during the period in which the subject is administered the escitalopram gentisate of the present invention or up to 28 days after said administration.

[0032] In one embodiment of the present invention, prevention of serotonin reuptake inhibitor withdrawal syndrome refers to a reduction in the adverse or negative impact of at least one of the complaints or symptoms associated with serotonin reuptake inhibitor withdrawal syndrome. In another embodiment, prevention of serotonin reuptake inhibitor withdrawal syndrome refers to a prevention of most of the adverse or negative impact of the complaints or symptoms associated with serotonin reuptake inhibitor withdrawal syndrome. In another embodiment, prevention of serotonin reuptake inhibitor withdrawal syndrome refers to a prevention of all of the adverse or negative impact of the complaints or symptoms associated with serotonin reuptake inhibitor withdrawal syndrome.

[0033] In one embodiment of the present invention, the term "orally administered serotonin reuptake inhibitors" refers to orally administered selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-noradrenaline reuptake inhibitors (SNRIs). Examples of SSRIs include citalopram, escitalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, and pharmaceutically acceptable salts thereof. Examples of SNRIs include duloxetine, venlafaxine, milnacipran, and pharmaceutically acceptable salts thereof.

[0034] In one embodiment of the present invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor prior to administration of a therapeutically effective amount of escitalopram gentisate. In a preferred embodiment, the discontinued orally administered serotonin reuptake inhibitor is selected from the group consisting of SSRIs and SNRIs. In another preferred embodiment, the discontinued orally administered serotonin reuptake inhibitor is selected from the group consisting of citalopram, escitalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, and pharmaceutically acceptable salts thereof. In another preferred embodiment, the discontinued orally administered serotonin reuptake inhibitor is selected from the group consisting of duloxetine, venlafaxine, milnacipran, and pharmaceutically acceptable salts thereof.

[0035] In one embodiment of the present invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor that has been taken continuously for at least one month prior to administration of a therapeutically effective amount of escitalopram gentisate. In another embodiment of the present invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor that has been taken continuously for at least 6 weeks, or at least 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, or 60 months prior to administration of a therapeutically effective amount of escitalopram gentisate. In a preferred embodiment of the present invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor that has been taken continuously for at least 6 weeks prior to administration of a therapeutically effective amount of escitalopram gentisate. In another preferred embodiment of the present invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor that has been taken continuously for at least 6 months prior to administration of a therapeutically effective amount of escitalopram gentisate. In another preferred embodiment of the invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor for at least 12 consecutive months prior to administration of a therapeutically effective amount of escitalopram gentisate. In another preferred embodiment of the invention, the subject has discontinued administration of an orally administered serotonin reuptake inhibitor for at least 24 consecutive months prior to administration of a therapeutically effective amount of escitalopram gentisate.

[0036] In one embodiment of the invention, the treatment or prevention of serotonin reuptake inhibitor withdrawal syndrome comprises administering escitalopram gentisate with an antidepressant other than an SSRI or SNRI. In another embodiment of the invention, the treatment or prevention of serotonin reuptake inhibitor withdrawal syndrome comprises administering escitalopram gentisate as the only antidepressant. Examples of antidepressants other than SSRIs or SNRIs include tricyclic antidepressants such as amitriptyline, imipramine, and desipramine; tetracyclic antidepressants such as maprotiline, mianserin, and mirtazapine; noradrenaline dopamine reuptake inhibitors such as bupropion; serotonin partial agonist reuptake inhibitors such as vilazodone and vortioxetine; serotonin antagonists and reuptake inhibitors such as trazodone and nefazodone; NMDA receptor antagonists such as ketamine, esketamine, dextromethorphan, dextrolphan, and domethadone; noradrenaline reuptake inhibitors such as reboxetine; and other agents such as pregabalin and agomelatine.

[0037] In one embodiment of the present invention, the administration of escitalopram gentisate comprises the administration of a sustained release injectable pharmaceutical dosage form comprising escitalopram gentisate. In a preferred embodiment of the present invention, the sustained release injectable pharmaceutical dosage form comprising escitalopram gentisate is administered subcutaneously. In another preferred embodiment of the present invention, the sustained release injectable pharmaceutical dosage form comprising escitalopram gentisate is administered intramuscularly.

[0038] As used herein, the term "sustained release injectable pharmaceutical dosage form" refers to an injectable dosage form that provides a sustained release of escitalopram into the bloodstream over a period of preferably at least 21 days.

[0039] The pharmaceutical dosage forms of the present invention include dosage forms suitable for human use without excessive toxic side effects. Dosage forms within the scope of the present invention include the active pharmaceutical ingredient escitalopram gentisate and at least one pharma-ceutically acceptable carrier or excipient. Examples of pharmaceutical dosage forms of the present invention include, for example, microcapsules, nanocapsules, microspheres, nanospheres, microparticles, nanoparticles, polymer-drug conjugates, micelles, liposomes, hydrogels, and other in situ forming depots or implants. The dosage forms can be formulated using biodegradable polymers or other suitable materials using methods known in the art.

[0040] Examples of biodegradable polymers useful in preparing the dosage forms of the present disclosure include poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly-1-lactic acid, poly-dlactic acid, poly(glycolic acid), copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactones), polyorthiesters, poly(glycolic acid-caprolactones), poly(amino acids), polyesteramides, polyanhydrides, polyphosphazines, poly(alkylene alkylates), biodegradable polyurethanes, polyvinylpyrrolidones, polyalkanoic acids, polyethylene glycols, copolymers of polyethylene glycol and polyformesters, albumin, chitosan, casein, waxes, or blends or copolymers thereof.

[0041] Examples of platform technologies that are useful in preparing the sustained release pharmaceutical dosage forms of the present disclosure include those from Novartis (see, e.g., WO2010 / 018159), Alkermes (see, e.g., WO2001 / 91720), Allergan (see, e.g., WO2013 / 112434), Reckitt Benckiser (see, e.g., WO2009 / 091737), Icon Bioscience (see, e.g., WO2013 / 036309), Flamel Technologies (see, e.g., WO2012 / 080986), QLT (see, e.g., WO2008 / 153611), Rovi Pharmaceuticals (see, e.g., WO2011 / 151356), Dong-A (see, e.g., WO2008 / 130158), Durect (see, e.g., WO2004 / 052336), NuPathe (see, e.g., WO2005 / 070332), Ascendis Pharma (see, e.g., WO2011 / 042453), Endo (see, e.g., WO2013 / 063125), Delpor (see, e.g., WO2010 / 105093), PolyActiva (see, e.g., WO2010 / 040188), Flexion Therapeutics (see, e.g., WO2012 / 019009), pSivida (see, e.g., WO2005 / 002625), Camurus (see, e.g., WO2005 / 117830), Bind Therapeutics (see, e.g., WO2010 / 075072), Zogenix (see, e.g., WO2007 / 041410), Ingell (WO2011 / 083086), Foresee Pharmaceuticals (see, e.g., WO2008 / 008363), Medincell (see, e.g., WO2012 / 090070), MapiPharma (see, e.g., WO2011 / 080733), DelSiTech (see, e.g., WO2008 / 104635), OctoPlus (see, e.g., WO2005 / 087201), Nanomi (see, e.g., WO2005 / 115599), Peptron (see, e.g., WO2008 / 117927), GP Pharm (see, e.g., WO2009 / 068708), Pharmathen (see, e.g., WO2014 / 202214), Titan Pharmaceuticals (see, e.g., WO2007 / 139744), Tolmar (see, e.g., WO2009 / 148580), Heron and those associated with Intarcia Therapeutics (see, e.g., US2014 / 323517), and Intarcia Therapeutics (see, e.g., WO2005 / 048952), the disclosures of which are incorporated herein by reference in their entireties. Methods for formulating the active ingredient or a pharma- ceutically acceptable salt thereof into a dosage form suitable for use in the present methods are described, for example, in Hu et al., IJPSR, 2012; vol. 3(9): 2888-2896; Hoffman, Adv. Drug. Del. Rev. 54 (2002) 3-12; AlTahami et al. Recent Patents on Drug Del. & Formulation 2007, 1 65-71, Pattni et al. Chem. Rev. 2015 May 26, and Wright and Burgess (ed.) Long Acting Injections and Implants (2012), the disclosures of which are incorporated herein by reference in their entireties.

[0042] In one embodiment of the present invention, administration of a sustained release injectable pharmaceutical dosage form comprising escitalopram gentisate provides for the release of a therapeutically effective amount of escitalopram into the bloodstream.

[0043] In one embodiment of the invention, a therapeutically effective amount of escitalopram in the bloodstream is provided by administration of a single dose of escitalopram gentisate. In another embodiment of the invention, a therapeutically effective amount of escitalopram in the bloodstream is provided by administration of multiple doses of escitalopram gentisate. In one embodiment of the invention, a therapeutically effective amount of escitalopram in the bloodstream is provided by multiple doses of escitalopram gentisate administered at least 14 days apart from each other. In another embodiment of the invention, a therapeutically effective amount of escitalopram in the bloodstream is provided by multiple doses of escitalopram gentisate administered at least 28 days apart from each other.

[0044] In one embodiment of the invention, the multiple doses of escitalopram gentisate include 5 or less doses of escitalopram gentisate. In another embodiment of the invention, the multiple doses of escitalopram gentisate include 4 or less doses of escitalopram gentisate. In another embodiment of the invention, the multiple doses of escitalopram gentisate include 3 or less doses of escitalopram gentisate. In another embodiment of the invention, the multiple doses of escitalopram gentisate include 2 or less doses of escitalopram gentisate.

[0045] As used herein, the term "dose of escitalopram gentisate" shall refer to any single or multiple individual administrations of escitalopram gentisate within a six hour period.

[0046] In one embodiment of the present invention, administration of escitalopram gentisate provides a therapeutically effective amount of escitalopram in the bloodstream after the cessation of orally administered serotonin reuptake inhibitor.In one embodiment of the present invention, the therapeutically effective amount of escitalopram is sufficient to treat depression for a period of at least 14 days.In another embodiment of the present invention, the therapeutically effective amount of escitalopram is sufficient to treat depression for a period of at least 28 days.

[0047] In one embodiment of the invention, following administration of escitalopram gentisate, the plasma level of escitalopram increases until it reaches a maximum plasma level, which then gradually decreases over time. In one embodiment of the invention, the plasma level of escitalopram is maintained at a maximum value by administration of one or more further doses of escitalopram gentisate before gradually decreasing over time.

[0048] In one embodiment of the present invention, administration of escitalopram gentisate provides a therapeutically effective amount of escitalopram in the bloodstream, which gradually decreases over time until it is no longer traceable by standard analytical methods. In one embodiment of the present invention, plasma escitalopram levels gradually decrease over a 14-day period following administration of escitalopram gentisate. In another embodiment of the present invention, plasma escitalopram levels gradually decrease over a 28-day period following administration of escitalopram gentisate. In another embodiment of the present invention, plasma escitalopram levels gradually decrease over a 35-day period following administration of escitalopram gentisate. In another embodiment of the present invention, plasma escitalopram levels gradually decrease over a 42-day period following administration of escitalopram gentisate. In another embodiment of the present invention, plasma escitalopram levels gradually decrease over a 49-day period following administration of escitalopram gentisate. In another embodiment of the invention, the plasma escitalopram levels are gradually decreased over a period of 56 days after administration of escitalopram gentisate. In another embodiment of the invention, the plasma escitalopram levels are gradually decreased over a period of 63 days after administration of escitalopram gentisate. In another embodiment of the invention, the plasma escitalopram levels are gradually decreased over a period of 70 days after administration of escitalopram gentisate. In another embodiment of the invention, the plasma escitalopram levels are gradually decreased over a period of 77 days after administration of escitalopram gentisate. In another embodiment of the invention, the plasma escitalopram levels are gradually decreased over a period of 84 days after administration of escitalopram gentisate. In another embodiment of the invention, the plasma escitalopram levels are gradually decreased over a period of 4 months after administration of escitalopram gentisate. In another embodiment of the invention, plasma escitalopram levels gradually decrease over a period of 5 months following administration of escitalopram gentisate.

[0049] In one embodiment of the invention, the time until plasma escitalopram levels are no longer traceable by standard analytical methods is at least 14 days, at least 28 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 63 days, at least 70 days, at least 77 days, at least 84 days, at least 4 months, or at least 5 months after administration of the single or final dose of escitalopram gentisate.

[0050] In one embodiment of the invention, the dose of escitalopram gentisate is the same with each administration. In another embodiment of the invention, the dose of escitalopram gentisate is lower with each subsequent administration.

[0051] In one embodiment of the invention, the administered dose of escitalopram gentisate comprises 600 mg or less of escitalopram. In another embodiment of the invention, the administered dose of escitalopram gentisate comprises 550 mg or less of escitalopram. In another embodiment of the invention, the administered dose of escitalopram gentisate comprises 500 mg or less of escitalopram. In another embodiment of the invention, the administered dose of escitalopram gentisate comprises 450 mg or less of escitalopram. In another embodiment of the invention, the administered dose of escitalopram gentisate comprises 400 mg or less of escitalopram. In another embodiment of the invention, the administered dose of escitalopram gentisate comprises 350 mg or less of escitalopram. In another embodiment of the invention, the administered dose of escitalopram gentisate comprises 300 mg or less of escitalopram. In another embodiment of the present invention, the dose of escitalopram gentisate administered comprises 250 mg or less of escitalopram. In another embodiment of the present invention, the dose of escitalopram gentisate administered comprises 200 mg or less of escitalopram. In another embodiment of the present invention, the dose of escitalopram gentisate administered comprises 150 mg or less of escitalopram. In another embodiment of the present invention, the dose of escitalopram gentisate administered comprises 100 mg or less of escitalopram. In another embodiment of the present invention, the dose of escitalopram gentisate administered comprises 75 mg or less of escitalopram. In another embodiment of the present invention, the dose of escitalopram gentisate administered comprises 50 mg or less of escitalopram. As used herein, the term "mg of escitalopram" refers to the amount of mg of escitalopram free base equivalent measured within the dosage form of escitalopram gentisate. For example, "100 mg of escitalopram" refers to the equivalent of 100 mg of escitalopram free base based on approximately 147.5 mg of escitalopram gentisate.

[0052] In one embodiment of the invention, the subject's plasma levels of escitalopram are elevated to a steady state of about 20 ng / ml during the period following the first administration of escitalopram gentisate.

[0053] As used herein, the term "steady state" or "steady state plasma levels" refers to consistent plasma levels over a period of at least three days.

[0054] In one embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 3 days after administration of escitalopram gentisate. In another embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 7 days after administration of escitalopram gentisate. In another embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 14 days after administration of escitalopram gentisate. In another embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 21 days after administration of escitalopram gentisate.

[0055] In one embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 3 days after injection of escitalopram gentisate. In another embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 7 days after injection of escitalopram gentisate. In another embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 14 days after injection of escitalopram gentisate. In another embodiment of the invention, the subject maintains a steady state plasma level of escitalopram of about 20 ng / ml for at least 21 days after injection of escitalopram gentisate.

[0056] In one embodiment of the invention, administration of escitalopram gentisate results in a linear decrease in the plasma level of escitalopram over time. In another embodiment of the invention, administration of escitalopram gentisate results in a hyperbolic decrease in the plasma level of escitalopram over time. In one embodiment of the invention, administration of escitalopram gentisate results in a linear decrease in the plasma level of escitalopram over time, followed by a hyperbolic decrease. In one embodiment of the invention, the decrease in the plasma level of escitalopram over time occurs after a single dose of escitalopram gentisate. In another embodiment of the invention, the decrease in the plasma level of escitalopram occurs after multiple doses of escitalopram gentisate.

[0057] In one embodiment of the invention, administration of escitalopram gentisate results in a decrease in plasma levels of escitalopram over a period of up to 5 months. In one embodiment of the invention, administration of escitalopram gentisate results in plasma levels of escitalopram decreasing from either a maximum and / or steady state plasma concentration of about 20 ng / ml to levels untraceable by standard analytical methods after 5 months.

[0058] In one embodiment of the invention, one month after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 16 ng / ml, two months after about 12 ng / ml, three months after about 8 ng / ml, and four months after about 4 ng / ml. In another embodiment of the invention, 19 days after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 9 ng / ml, 38 days after about 5 ng / ml, 56 days after about 3 ng / ml, 75 days after about 2 ng / ml, 113 days after about 1 ng / ml, and 130 days after which the plasma level of escitalopram will be less than 1 ng / ml. In another embodiment of the invention, after 19 days of either a maximum plasma concentration and / or a steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 10 ng / ml, after 38 days about 6 ng / ml, after 56 days about 4 ng / ml, after 75 days about 3 ng / ml, after 94 days about 2 ng / ml, after 113 days about 1 ng / ml and after 130 days the plasma level of escitalopram will be less than 1 ng / ml.

[0059] In one embodiment of the invention, administration of escitalopram gentisate results in a decrease in plasma levels of escitalopram over a period of up to four months. In one embodiment of the invention, administration of escitalopram gentisate results in plasma levels of escitalopram decreasing from either a maximum and / or steady state plasma concentration of about 20 ng / ml to levels untraceable by standard analytical methods after four months.

[0060] In one embodiment of the invention, one month after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 15 ng / ml, two months after about 10 ng / ml, and three months after about 5 ng / ml. In another embodiment of the invention, 15 days after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 9 ng / ml, 30 days after about 5 ng / ml, 45 days after about 3 ng / ml, 60 days after about 2 ng / ml, 90 days after about 1 ng / ml, and 105 days after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be less than 1 ng / ml. In another embodiment of the invention, 15 days after either a maximum plasma concentration and / or a steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 10 ng / ml, after 30 days about 6 ng / ml, after 45 days about 4 ng / ml, after 60 days about 3 ng / ml, after 75 days about 2 ng / ml, after 90 days about 1 ng / ml, and after 105 days the plasma level of escitalopram will be less than 1 ng / ml.

[0061] In one embodiment of the invention, administration of escitalopram gentisate results in a decrease in plasma levels of escitalopram over a period of up to three months. In one embodiment of the invention, administration of escitalopram gentisate provides plasma levels of escitalopram that decrease from either a maximum and / or steady state plasma concentration of about 20 ng / ml to levels untraceable by standard analytical methods after three months.

[0062] In one embodiment of the invention, one month after either a maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 13.3 ng / ml, and two months after about 6.7 ng / ml. In another embodiment of the invention, 11 days after either a maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 9 ng / ml, 23 days after about 5 ng / ml, 34 days after about 3 ng / ml, 45 days after about 2 ng / ml, 68 days after about 1 ng / ml, and 79 days after the plasma level of escitalopram will be less than 1 ng / ml. In another embodiment of the invention, 11 days after either a maximum plasma concentration and / or a steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 10 ng / ml, after 23 days about 6 ng / ml, after 34 days about 4 ng / ml, after 45 days about 3 ng / ml, after 56 days about 2 ng / ml, after 68 days about 1 ng / ml and by 79 days the plasma level of escitalopram will be less than 1 ng / ml.

[0063] In one embodiment of the invention, administration of escitalopram gentisate results in a decrease in plasma levels of escitalopram over a period of up to two months. In one embodiment of the invention, administration of escitalopram gentisate results in plasma levels of escitalopram that decrease from either a maximum and / or steady state plasma concentration of about 20 ng / ml to levels untraceable by standard analytical methods after two months.

[0064] In one embodiment of the invention, two weeks after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 15 ng / ml, one month after about 10 ng / ml, and six weeks after about 5 ng / ml. In another embodiment of the invention, eight days after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 9 ng / ml, 15 days after about 5 ng / ml, 23 days after about 3 ng / ml, 30 days after about 2 ng / ml, 45 days after about 1 ng / ml, and 53 days after any maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be less than 1 ng / ml. In another embodiment of the invention, after 8 days of either a maximum plasma concentration and / or a steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 10 ng / ml, after 15 days about 6 ng / ml, after 23 days about 4 ng / ml, after 30 days about 3 ng / ml, after 38 days about 2 ng / ml, after 45 days about 1 ng / ml and after 53 days the plasma level of escitalopram will be less than 1 ng / ml.

[0065] In one embodiment of the invention, administration of escitalopram gentisate results in a decrease in plasma levels of escitalopram over a period of up to one month. In one embodiment of the invention, administration of escitalopram gentisate results in plasma levels of escitalopram decreasing from either a maximum and / or steady state plasma concentration of about 20 ng / ml to levels untraceable by standard analytical methods after one month.

[0066] In one embodiment of the invention, one week after either a maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 15 ng / ml, two weeks after about 10 ng / ml, and three months after about 5 ng / ml. In another embodiment of the invention, four days after either a maximum and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 9 ng / ml, eight days after about 5 ng / ml, eleven days after about 3 ng / ml, fifteen days after about 2 ng / ml, twenty-three days after about 1 ng / ml, and twenty-six days after which the plasma level of escitalopram will be less than 1 ng / ml. In another embodiment of the invention, after 4 days of a maximum plasma concentration and / or steady state plasma concentration of about 20 ng / ml, the plasma level of escitalopram will be about 10 ng / ml, after 8 days about 6 ng / ml, after 11 days about 4 ng / ml, after 15 days about 3 ng / ml, after 19 days about 2 ng / ml, after 23 days about 1 ng / ml, and after 26 days the plasma level of escitalopram will be less than 1 ng / ml.

[0067] In one embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing symptoms for less than 6 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing less than 50% of symptoms for less than 6 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing any of the symptoms for less than 6 months after the first administration of escitalopram gentisate.

[0068] In one embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing symptoms for less than 5 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing less than 50% of symptoms for less than 5 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing any of symptoms for less than 5 months after the first administration of escitalopram gentisate.

[0069] In one embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing symptoms for less than 4 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing less than 50% of symptoms for less than 4 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing any of symptoms for less than 4 months after the first administration of escitalopram gentisate.

[0070] In one embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing symptoms for less than 3 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing less than 50% of symptoms for less than 3 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing any of symptoms for less than 3 months after the first administration of escitalopram gentisate.

[0071] In one embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing symptoms for less than 2 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing less than 50% of symptoms for less than 2 months after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing any of symptoms for less than 2 months after the first administration of escitalopram gentisate.

[0072] In one embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing symptoms for less than one month after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing less than 50% of symptoms for less than one month after the first administration of escitalopram gentisate. In another embodiment of the present invention, treating serotonin reuptake inhibitor withdrawal syndrome comprises the subject experiencing any of symptoms for less than one month after the first administration of escitalopram gentisate.

[0073] The present invention will be better understood by reference to the following examples, although those skilled in the art will readily appreciate that the specific experiments detailed are merely illustrative of the invention as more fully described in the claims that follow. EXAMPLES

[0074] Example 1: Preparation of escitalopram base from escitalopram oxalate salt Escitalopram oxalate (40 g) and deionized water (170 ml) were introduced into a 250 ml jacketed glass reactor equipped with a mechanical stirrer, a circulating oil bath, and a thermometer. While the mixture was stirred, 45 ml of ether was added while maintaining the jacket temperature at 25°C throughout the isolation procedure. The pH of the mixture was adjusted to 9.0-9.5 by addition of 25% NH4OH. The stirrer was stopped to allow the mixture to settle. Two liquid phases and a solid precipitate were formed. The resulting mixture was filtered and the resulting solid cake was washed with 40 ml of ether. The filtrate and the ether washes were then reintroduced into the reactor. The organic and aqueous phases were separated and collected in different containers. The aqueous phase was reintroduced into the reactor and extracted with 50 ml of ether. After settling, the aqueous phase was discarded. The two organic extracts were mixed in the reactor and washed twice with 25 ml of water. The organic solution was evaporated in a rotary evaporator under vacuum while maintaining the bath temperature at 70° C. until complete evaporation of the solvent occurred. The resulting residue, 30.1 g of a clear, colorless oil (hot), was transferred to an amber glass vial.

[0075] Example 2: Preparation of escitalopram gentisate form I Two hundred microliters (μl) of a clear solution of 100 mg / mL of escitalopram free base in methanol was added to a 4 mL vial. The methanol was evaporated by removing the cap of the vial. The remaining material was dried at 60°C and dried in vacuum for 3-6 hours, after which 500 μl of 0.125 M gentic acid in methanol was added to the vial. The methanol was evaporated again by removing the cap of the vial. The material was dried at 60°C and further dried in vacuum for 3-5 hours. 250 μl of isopropanol was added to the dried material in the vial. A magnetic stirrer was placed in the vial and the mixture was stirred. The solution was sonicated or the stirrer was moved with a spatula whenever the stirrer was stopped by the viscous material at the bottom of the vial. The vial was sonicated when a whitish solid was identified as stuck to the side of the vial. Stirring was continued for 24-28 hours until the solution became a thick slurry. The slurry was filtered and the resulting solid was dried at 60° C. followed by vacuum drying overnight. A sample was subjected to X-ray powder diffraction (XRPD) and identified as escitalopram gentisate Form I.

[0076] Example 3: Preparation of a sustained release injectable dosage form of escitalopram gentisate A drug solution is prepared by dissolving 400 g of escitalopram gentisate in 1267 g of benzyl alcohol to form a 24 wt% drug solution. A polymer solution is formed by dissolving 600 g of MEDISORBS 7525 DL polymer in 3000 g of ethyl acetate to form a 16.7 wt% polymer solution. The drug solution and polymer solution are combined to form a first discontinuous phase. A second continuous phase is prepared by preparing 30 liters of a 1% PVA solution, where the PVA acts as an emulsifier. To this is added 2086 g of ethyl acetate to form a 6.5 wt% ethyl acetate solution.

[0077] The two phases are combined using a static mixer, such as a 1 / 2" Kenics static mixer available from Chemineer, Inc., North Andover, MA. A total flow rate of 3 L / min generally provides a particulate size distribution with a mass median diameter (MMD) in the range of about 80-90a. The ratio of continuous to discontinuous phase is 5:1 (v / v). The length of the static mixer can vary from about 9 inches to about 88 inches. The quench liquid is a 2.5% solution of ethyl acetate and water for injection (WFI) at 5-10°C. The volume of the quench liquid is 0.25 L / g batch size. The quench step is carried out over about 4 hours with agitation of the particulates in the quench tank.

[0078] After the quench step is completed, the microparticles are transferred to a collection, dehydration, and drying device. The microparticles are rinsed using 17 liters of chilled (about 5° C.) 25% ethanol solution. The microparticles are dried and then reslurried in a reslurry tank using a 25% ethanol solution (extraction medium) maintained at a temperature lower than the Tg (glass transition temperature) of the microparticles. The microparticles are then returned to the quench tank and washed with another extraction medium (25% ethanol solution) maintained at a temperature higher than the Tg of the microparticles for at least 6 hours. The Tg of the microparticles is about 18° C. (about room temperature), and the temperature of the extraction medium in the quench tank is greater than about 18° C., preferably 25±1° C. The microparticles are returned to the collection, dehydration, and drying device for dehydration and final drying. Drying continues for a period of more than about 16 hours.

[0079] Example 4: Treatment and prevention of serotonin reuptake inhibitor withdrawal syndrome with escitalopram gentisate A sample population of 300 adult subjects who have been administered an oral serotonin reuptake inhibitor for at least one continuous month period but are now being advised to discontinue therapy will be identified and randomized into two groups, Group A (n=100) and Group B (n=200). All patients will be screened at baseline and subjects who exhibit symptoms or signs that may be associated with serotonin reuptake inhibitor withdrawal syndrome despite being administered an oral serotonin reuptake inhibitor will be excluded from the study.

[0080] On Day -1, all subjects receive their final dose of orally administered serotonin reuptake inhibitor.On Day 0, subjects in Group A receive an extended release injectable form of escitalopram gentisate containing 600 mg of escitalopram.

[0081] All subjects are screened for symptoms or signs that may be related to serotonin reuptake inhibitor withdrawal syndrome on days 1, 2, 3, 4, 5, 6, 7, 14, 28, 35, 42, 49, 56, 63, 70, 77, 84, 100, 120, and 150. Subjects in group B who exhibit symptoms or signs that may be related to serotonin reuptake inhibitor withdrawal syndrome at any stage from days 1 to 7 are randomized into two groups (groups B1 and B2), with group B1 receiving a sustained release injectable form of escitalopram gentisate containing 600 mg of escitalopram on the day the syndrome is confirmed to be occurring, and group B receiving a placebo injection. Two subsequent injections of 400 mg and 200 mg of escitalopram will be administered to groups A and B1 on days 30 and 60, respectively, while group B2 will receive placebo injections on days 30 and 60.

[0082] The primary endpoint of this study is the reduction in signs and symptoms of serotonin reuptake inhibitor withdrawal syndrome compared to placebo when escitalopram gentisate is administered any time between days 0 and 7 following cessation of an orally administered serotonin reuptake inhibitor.

[0083] Those skilled in the art will understand that many changes and modifications can be made to the preferred embodiments of the present disclosure, and that such changes and modifications can be made without departing from the spirit of the present disclosure. It is therefore intended that the appended claims cover all such equivalent variations that fall within the true spirit and scope of the present disclosure.

Claims

1. A sustained-release injectable pharmaceutical formulation containing escitalopram for the treatment or prevention of serotonin reuptake inhibitor withdrawal syndrome.

2. The sustained-release injectable pharmaceutical formulation according to claim 1, wherein escitalopram gentisate is administered to a subject who has discontinued the administration of an orally administered SSRI or SNRI.

3. The sustained-release injectable pharmaceutical formulation according to claim 2, wherein the discontinued orally administered SSRI or SNRI is an SSRI selected from the group consisting of citalopram, escitalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, and pharmaceutically acceptable salts thereof, or an SNRI selected from the group consisting of duloxetine, venlafaxine, milnacipran, and pharmaceutically acceptable salts thereof.

4. The sustained-release injectable pharmaceutical formulation according to claim 2, wherein, prior to discontinuation, the subject has been continuously orally administering the SSRI or SNRI for a period of at least 6 weeks.

5. The sustained-release injectable pharmaceutical formulation according to claim 4, wherein the period is at least 6 months.

6. The sustained-release injectable pharmaceutical formulation according to claim 4, wherein the period is at least 12 months.

7. The sustained-release injectable pharmaceutical formulation according to claim 4, wherein the period is at least 24 months.

8. The sustained-release injectable pharmaceutical formulation according to claim 2, wherein the escitalopram gentisate is the only antidepressant administered to the subject.

9. The sustained-release injectable pharmaceutical formulation according to claim 1, which is administered subcutaneously or intramuscularly to a subject.

10. A sustained-release injectable pharmaceutical dosage form according to any one of claims 1 to 9, administered as a single dose of escitalopram gentisate.

11. A sustained-release injectable pharmaceutical dosage form according to any one of claims 1 to 9, administered as multiple doses of escitalopram gentisate.

12. The sustained-release injectable pharmaceutical dosage form according to claim 11, wherein the dosages are administered at least 14 days apart from each other, or at least 28 days apart from each other.

13. The sustained-release injectable pharmaceutical dosage form according to claim 12, wherein the multiple administrations include 5 or fewer separate administrations of escitalopram gentisate.

14. The sustained-release injectable pharmaceutical dosage form according to claim 12, wherein the multiple administrations include 3 or fewer separate administrations of escitalopram gentisate.

15. The sustained-release injectable pharmaceutical dosage form according to claim 11, wherein the dosages of escitalopram gentisate administered are the same for each administration.

16. The sustained-release injectable pharmaceutical dosage form according to claim 11, wherein the dosages of escitalopram gentisate administered decrease for each administration.

17. The sustained-release injectable pharmaceutical dosage form according to any one of claims 1 to 9, wherein the subject is administered 600 mg or less of escitalopram, 500 mg or less of escitalopram, or 400 mg or less of escitalopram.

18. Treatment of serotonin reuptake inhibitor discontinuation syndrome includes treatment of related common complaints, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, skin, nerve, or mental symptoms, in the sustained-release injectable pharmaceutical dosage form according to claim 1.