Field of the invention

The present invention relates to novel uses of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt thereof in the treatment of signs and symptoms of post-CO VID-19 syndrome or ongoing symptomatic COVID-19.

Background of the invention

Since the WHO declaration of COVID-19 as a global pandemic in March 2020, it is estimated that almost 600 million people have tested positive for the virus globally [World Health Organization. WHO coronavirus disease (COVID-19) dashboard; August 2022], Consensus exists that the true infection rate is considerably higher, with estimates of approximately 5-10- fold greater. A significant percentage of individuals who have recovered from COVID-19 infection present with unabating, non-specific, distressing and functionally impairing symptoms (post-CO VID-19 syndrome). Commonly reported symptoms include, but are not limited to, cognitive impairment (e.g., “brain fog”), fatigue, apathy, depression, anxiety, insomnia, anergia and loss of appetite (Nalbandian, A. et. al.; Nat. Med. (2021), 27, 601-615; Post-acute COVID- 19 Syndrome; E. Maxwell, National Institute for Health Research Centre for Engagement and Dissemination, 2020, Living with COVID 19). Studies suggest that the phenomenology of post- CO VID- 19 syndrome is subserved by disturbance in immune-inflammatory systems (Hasichaolu et. al. BioMed Research International, 2020, Article ID 7570981, Newell, K. et. al. Curr. Opin. Immunol. (2022) 77, 102228). Working definitions of COVID-19, including ongoing symptomatic COVID-19 and post-COVID-19 syndrome, are proposed by the UK National Institutes for Health and Care Excellence (NICE guideline December 2020: CO VID 19 rapid guideline: managing the long-term effects of COVID-19 (NG188)). Currently, no treatment is identified as safe and effective for post-COVID-19 syndrome.

A candidate treatment for post-COVID-19 syndrome would preferably be capable of improving measures of cognitive function (i.e., objective and subjective), motivation and energy, as well as reducing fatigue. The candidate treatment would preferably target biological systems subserving circadian rhythms, as well as reward and reinforcement brain mechanisms. The profile of the candidate treatment would preferably have effect on inflammatory cytokines and cellular systems.

Vortioxetine [l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine] is a multimodal antidepressant that works through modulation of receptor activity and serotonin transporter inhibition. Vortioxetine has been approved for the treatment of major depression globally in more than 80 countries, including the United States (FDA 2013) and European Countries (European Commission 2013). l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine (vortioxetine) is thought to work through a combination of two pharmacological modes of action: reuptake inhibition and receptor activity. In vitro studies indicate that l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine is a 5-HT3 and 5-HT7 receptor antagonist, 5-HTIB receptor partial agonist, 5-HTIA receptor agonist and inhibitor of the 5-HT transporter. In vivo nonclinical studies have demonstrated that l-[2- (2,4-dimethyl-phenylsulfanyl)phenyl]piperazine enhances levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound. Preliminary in vitro and in vivo studies suggest that vortioxetine exerts anti-inflammatory and immunomodulatory effects on human monocytes/macrophages and in mice, systems known to be activated in subjects with post CO VID-19 syndrome (Talmon, T. et. al., Br. J. Pharmacol. (2018), 175, 113-124; Tomaz, V., et. al.; J. Affect. Disord., (2020), 268, 188-200). l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and its use in the treatment of central nervous system (CNS) diseases were first disclosed in the International patent application published as WO 02/029232. Later patent applications (WO 2007/144005; WO 2008/113359; WO 2009/062517) have disclosed crystalline salts of the compound, manufacturing processes, and further therapeutic uses of the compound.

In the clinical development program, vortioxetine was efficacious, safe, and well tolerated in adults and the elderly with Major Depressive Disorder (MDD), in short-term treatment and long-term maintenance treatment. The approved therapeutic dose range for vortioxetine in adults is 5 to 20 mg/day.

Vortioxetine is established as pro-cognitive, as evidenced by significant improvement on both subjective and objective measures and it also improves general functioning in patients with MDD (Christensen MC. et. al., J. Affect. Disord. (2018), 227, 787-94; McIntyre R. S. et. al. J. Clin. Psychiatry (2017), 78, 15-21). Vortioxetine is documented to improve anticipatory and consummatory measures of reward function/anhedonia in patients with MDD (Cao B, et al., Front Psychiatry. (2019), 10, 17). Furthermore, vortioxetine has demonstrated significant improvement on measures of motivation and energy, is not associated with emotional blunting and has preliminary evidence of improving sleep behaviour and circadian rhythms in patients with MDD (Fagiolini A. et. al. J. Affect: Disord. (2021), 283, 472-9, Cao B., et. al. J. Psychopharmacol. (2019), 33, 1388-94).

Given the important implications post-COVID-19 syndrome may have on patients, it is important to be able to provide treatments which reduce for example cognitive impairment, depressed mood (depression), anxiety, fatigue and anhedonia in persons with post-COVID-19 syndrome or ongoing symptomatic COVID-19.

Summary of the invention

The present inventors hypothesize that l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt will be effective in the treatment of signs and symptoms of post-COVID-19 syndrome in a subject with post-COVID-19 syndrome or ongoing symptomatic COVID-19, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.

Thus, in one embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic COVID-19 or post-COVID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In one embodiment, the invention provides a method for the treatment of signs and symptoms of ongoing symptomatic C OVID- 19 or post-COVID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia, the method comprising the administration of a therapeutically effective amount of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In one embodiment, the invention provides l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of signs and symptoms of ongoing symptomatic COVID-19 or post-COVID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia.

Detailed description of the invention

The molecular structure of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine [vortioxetine] is shown below

In the present context, l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof is referred to as Compound I. A particular salt, e.g. the hydrobromide salt is referred to as Compound I HBr.

In one embodiment, said pharmaceutically acceptable salts are acid addition salts of acids that are non-toxic. Said salts include salts made from organic acids, such as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Said salts may also be made from inorganic salts, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Particular mention is made of salts made from methanesulfonic acid, maleic acid, fumaric acid, meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphorous acid and nitric acid. Distinct mention is made of the hydrobromide salt. Hence, in one embodiment, the invention provides the use of the hydrobromide salt of l-[2-(2,4-dimethylphenylsulphanyl)- phenyl]piperazine.

Oral dosage forms, and in particular tablets, are often preferred by the patients and the medical practitioner due to the ease of administration and the consequent better compliance. For tablets, it is preferable that the active ingredients are crystalline. In one embodiment, the invention relates to the use of Compound I in a crystalline form. The crystallinity of Compound I is evidenced by the XRDP shown in e.g WO 2007/144005.

As evidenced by the data provided in WO 2007/144005 (see example 4a-f) the hydrobromide salt of l-[2-(2,4-dimethylphenylsulphanyl)-phenyl]piperazine (Compound I HBr) may exist in several forms, i.e. it is polymorphic. The polymorphic forms have different properties. The beta form Compound I HBr (as defined in WO 2007/144005) is the more stable as demonstrated by the higher DSC melting point and the lower solubility. Moreover, the beta form has an attractive combination of low hygroscopicity and solubility, which makes this compound particularly suited for making tablets. Hence, in one embodiment, the invention provides the use of the hydrobromide salt of l-[2-(2,4-dimethylphenylsulphanyl)- phenyl]piperazine with XRDP reflections at approximately 6.89, 9.73, 13,78 and 14.62 (°20) (± 0.1), such as at approximately 6.89, 8.48, 9.73, 13.78, 14.62 and 24.73 (°20) (± 0.1).

Alternatively, if Compound I is provided in an oral drop formulation, other salts characterised by higher solubility may be preferred. When a compound is administered as an oral drop formulation, a few drops of a concentrated, liquid formulation of said drug is measured out and added to a glass of water, juice or the like that the patient drinks. As an example, the antidepressant cipramil is provided as an oral drop formulation at 40 mg/ml. The DL lactate salt of Compound I has been found to have a high solubility and therefore to be particularly suited for oral drop formulations. Thus, Vortioxetine is available in some countries as an oral drop formulation at 20 mg/mL. Hence, in one embodiment, the invention provides the use of the DL- lactate salt of l-[2-(2,4-dimethylphenylsulphanyl)-phenyl]piperazine. Compound I is typically administered in daily doses of 1-100 mg, such as 2- 40 mg, such as 2, 5, 10, 15, 20, 25, 30, 35 mg. A daily dose may involve once daily dosing, or dosing two or more times daily.

Compound I is conveniently administered as a pharmaceutical composition which may be prepared by conventional methods in the art. Particular mentioning is made of tablets, which may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymers, microcrystalline cellulose, sodium starch glycolate, corn starch, mannitol, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

Oral drop formulations typically comprise, in addition to the active ingredient, excipients selected from solvent, buffer, surfactant, surface tension modifier, viscosity modifier, preservative, antioxidant, colourants, tastes masker, and flavour.

The pharmaceutical compositions which may be used in this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, liquids etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.

Conveniently, Compound I is administered in unit dosage form containing said compound in an amount of about 1 to 50 mg, such as 5, 10, 15 or 20 mg. Tablets comprising Compound I may conveniently be prepared by wet granulation. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried. Compound I is typically mixed with lactose monohydrate, corn starch and copovidone in a high shear mixer together with water. Following formation of granulates, these granulates may be sieved in a sieve with a suitable sieve size, and dried. The resulting, dried granulates are then mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate, following which the tablets are pressed. Alternatively, wet granulation of Compound I may be achieved using mannitol, corn starch and copovidone, which granulates are mixed with microcrystalline cellulose, sodium starch glycolate and magnesium stearate before tablets are pressed. Alternatively, wet granulation of Compound I may be achieved by using anhydrous calcium hydrogen phosphate, corn starch and copovidone, which granulates are mixed with microcrystalline cellulose, sodium starch glycolate (type A), talc and magnesium stearate before tablets are pressed. Copovidone is a PVP-VA copolymer. Alternatively, tablets comprising Compound I may be obtained by mixing Compound I, mannitol and microcrystalline cellulose in a fluid bed granulation dryer onto which mixture an aqueous solution of hydroxypropyl cellulose is sprayed to give a granulated powder. The obtained granulates are then mixed with microcrystalline cellulose, sodium starch glycolate and magnesium stearate. The obtained mixture can subsequently be pressed into tablets. Typically, the tablets are coated with a suitable coating material.

In one embodiment the invention provides l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic CO VID- 19 or post-COVID- 19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia, and wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt.

In one embodiment the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the use above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.

In one embodiment the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15 or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl] piperazine.

In one embodiment the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine.

In one embodiment the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops.

In one embodiment the invention provides l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof according to the uses above, wherein said subject is human.

In one embodiment the invention provides a method for the treatment of signs and symptoms of ongoing symptomatic CO VID- 19 or post-COVID- 19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia, the method comprising the administration of a therapeutically effective amount of 1- [2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment the invention provides the use of l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]- piperazine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of signs and symptoms of ongoing symptomatic COVID-19 or post-CO VID-19 syndrome in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic CO VID-19 or post-COVID- 19 syndrome in a subject with ongoing symptomatic COVID-19 or post-COVID- 19 syndrome, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of post-COVID-19 syndrome in a subject with post-COVID-19 syndrome, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of ongoing symptomatic CO VID- 19 in a subject with ongoing symptomatic COVID-19, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said signs and symptoms continue for more than 4 weeks, such as more than 5 weeks, such as more than 6 weeks, such as more than 7 weeks, such as more than 8 weeks, such as more than 9 weeks, such as more than 10 weeks, such as more than 11 weeks following the onset of an infection consistent with COVID-19. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms of an infection consistent with CO VID-19 infection in a subject, wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of signs and symptoms that develop during or after an infection consistent with COVID-19 in a subject, wherein said signs and symptoms continue for more than 4 weeks, such as more than 5 weeks, such as more than 6 weeks, such as more than 7 weeks, such as more than 8 weeks, such as more than 9 weeks, such as more than 10 weeks, such as more than 11 weeks, such as more than 12 weeks following the onset of an infection consistent with COVID-19, and wherein said signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In an embodiment, the invention relates to l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine or a pharmaceutically acceptable salt thereof for use in the treatment of long term signs and symptoms of COVED- 19 infection in a subject, wherein said long term signs and symptoms are selected from cognitive impairment, depression, anxiety, fatigue and anhedonia. In an embodiment said long term signs and symptoms continue for more than 4 weeks, such as more than 5 weeks, such as more than 6 weeks, such as more than 7 weeks, such as more than 8 weeks, such as more than 9 weeks, such as more than 10 weeks, such as more than 11 weeks, such as more than 12 weeks following the onset of said COVID-19 infection. In an embodiment said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide salt, lactic acid salt and pyroglutamate salt. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 1-50 mg l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4- dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a unit dose of 5mg, lOmg, 15mg or 20mg l-[2-(2,4-dimethylphenylsulfanyl)- phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg/day, lOmg/day, 15mg/day or 20mg/day of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. In an embodiment l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof is administered as oral tablets or oral drops. In an embodiment said subject is human.

In some embodiments the baseline-to-endpoint change in Digit Symbol Substitution Test (DSST) score is an increase of about 12 points, such as 11 points, such as 10 points, such as 9 points, such as 8 points, such as about 6 points, after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Trails Making Test (TMT)-A score is a decrease of about 6 seconds, such as 7 seconds, such as 8 seconds, such as 9 seconds, such as 10 seconds, such as 11 seconds, such as about 12 seconds, after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Trails Making Test (TMT)-B score is a decrease of about 16 seconds, such as 18 seconds, such as 19 seconds, such as 20 seconds, such as 21 seconds, such as about 22 seconds, after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Rey's auditory verbal learning test (RAVLT) score is an increase by 5, such as by 4, such as by 3 words (acquisition) and an increase by 1, such as by 2, such as by 3 words (delayed recall), after 8 weeks of administration. In some embodiments the baseline-to-endpoint change in the Perceived Deficits Questionnaire, 20-item (PDQ-20) score is a reduction in score of about 14, such as 13, such as 12, such as 11, such as 10, such as about 8, after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Fatigue Severity Scale (FSS) is a reduction of about 3 points, such as 4 points, such as 5 points, such as 6 points, such as 7 points, such as about 8 points, after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Snaith Hamilton Pleasure Rating Scale (SHAPS) is a decrease of about 2 points, such as 3 points, such as about 4 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Patient Health Questionnaire, 9- item (PHQ-9) score is a reduction of about 5 points, such as 6 points, such as 7 points, such as 8 points, such as about 9 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Generalized Anxiety Scale, 7-item (GAD-7) is a decrease by about 3 points, such as 4 points, such as 5 points, such as 6 points, such as about 7 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the World Health Organization Wellbeing Scale, 5-item (WHO-5) is an increase of about 1 point, such as about 2 points, such as about 3 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the EuroQol, 5-dimension, 5-level (EQ-5D-5L) score is an increase of about 18, such as 20, such as 21, such as 22, such as 23, such as 24, such as about 25 after 8 weeks of administration. In some embodiments the baseline-to-endpoint change in the Sheehan Disability Scale (SDS) is a reduction of about 6 points, such as 7 points, such as 8 points, such as 9 points, such as about 10 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint reduction in the Post-Covid Functional Scale (PCFS) corresponds to a statistically significant improvement after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the fMRI and Monetary Incentive Delay (MID) Task is a statistically significant change in brain activation after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Stanford Expectations of Treatment Scale (SETS) is an improvement in positive and/or in negative expectancy of more than 1 point, such as of 2 points, such as of 3 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the Behavioural Activation Scale (BAS) is an improvement of 3 points, such as 4 points, such as 5 points, such as 6 points after 8 weeks of administration.

In some embodiments the baseline-to-endpoint change in the International Physical Activity Questionnaire (IPAQ) score is an improvement of about 4 points, such as 5 points, such as 6 points, such as about 7 points after 8 weeks of administration.

Definitions The Digit Symbol Substitution Test (DSST) was initiated over a century ago as an experimental tool to understand human associative learning. Its clinical utility, owing to its brevity and high discriminant validity, was first recognized in the 1940s, and now the DSST is among the most commonly used tests in clinical neuropsychology. The DSST is a paper-and- pencil cognitive test presented on a single sheet of paper that requires a subject to match symbols to numbers according to a key located on the top of the page. The subject copies the symbol into spaces below a row of numbers. The DSST is perhaps the most commonly used test in all of neuropsychology, owing to several inherent properties: brevity, reliability, and the minimal impact of language, culture, and education on test performance. DSST offers a practical and effective method to monitor cognitive functions over time in clinical practice.

Trails Making Test (TMT)-A/B: The Trail Making Test is commonly used as a diagnostic tool in clinical settings. Poor performance is known to be associated with many types of brain impairment. The test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. The test can be used to assess change in cognitive function.

Perceived Deficits Questionnaire, (PDQ) The Perceived Deficits Questionnaire -- Depression (PDQ-D) is a brief patient-rated scale to assess subjective cognitive dysfunction in people with depression. The PDQ-D is a 20-item questionnaire that generates a total score and 4 subscale scores (attention/concentration, retrospective memory, prospective memory, and planning/organization). A 5-item version (PDQ-D-5) is also available.

The PDQ-D was originally developed as a scale for use in patients with multiple sclerosis. It has since been adapted and validated for use in patients with major depressive disorder. The test can be used to assess change in subjective cognitive functioning.

Fatigue Severity Scale (FSS) The Fatigue Severity Scale is a 9-item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle in patients with a variety of disorders. It was originally devised for people with Multiple Sclerosis or systemic lupus erythematosus. The test can be used to assess change in severity and impact of fatigue. Snaith Hamilton Pleasure Rating Scale (SHAPS): The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-administered, paper-and-pencil questionnaire with 14 items assessing four domains of pleasure response/hedonic experience: interest/pass-times, social interaction, sensory experience, and food/drink. The test can be used to assess change in four domains of pleasure response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink.

Patient Health Questionnaire, 9-item (PHQ-9) is an instrument that is widely used in diagnosing and determining the severity of depression. The PHQ-9 asks patients to rate, on a four-point scale ranging from “not at all” to “most days,” the frequency with which they have experienced certain depression symptoms m the preceding 2 weeks. The test can be used to assess change across self-rated depressive symptoms.

Generalized Anxiety Scale, 7-item (GAD-7) The Generalised Anxiety Disorder Assessment (GAD-7) is a seven-item instrument that is used to measure or assess the severity of generalised anxiety disorder (GAD). Each item asks the individual to rate the severity of his or her symptoms over the past two weeks. The test can be used to assess change across self-rated general anxiety symptoms.

World Health Organization Well being Scale, 5-item (WHO-5): The World Health Organisation- Five Well-Being Index (WHO-5) is a short self-reported measure of current mental wellbeing. The test can be used to assess change in subjective well-being.

Sheehan Disability Scale (SDS): The SDS (Table 1) is a five-item, self-rated questionnaire designed to measure the extent to which a patient's disability due to an illness or health problem interferes with work/school, social life/leisure activities, and family life/home responsibilities. The test can be used to assess change in functional impairment due to disability.

Rey’s auditory verbal learning test (RAVLT): The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological assessment designed to evaluate verbal memory in patients.

The RAVLT can be used to evaluate the nature and severity of memory dysfunction and to track changes in memory function over time. The test can be used to assess change in verbal memory.

EuroQuol, 5-dimension, 5-level (EQ-5D-5L) The EQ-5D-5L is a generic health status measure developed by the EuroQol Group for measurement of quality of daily life, providing descriptions of five dimensions of health status: mobility, self-care, usual activities, pain/ discomfort and anxiety/depression. The test can be used to assess change in quality of daily life across 5 dimensions (mobility, capacity for self-care, conduct of usual activities, pain/discomfort and anxiety/depression).

Post-Covid Functional Scale (PCFS): A patient-reported outcome measure to evaluate the consequences of COVID-19 and their effect on functional status]. The PCFS Scale can be used both at the time of hospital discharge, and to monitor functional status post discharge. The scale has been designed to cover the entire range of functional limitations. The test can be used to assess change in functional status over time following COVID-19 infection. fMRI and Monetary Incentive Delay (MID) Task: MID is a tool for studying the different stages of reward-based learning, from reward anticipation to its delivery.

Stanford Expectations of Treatment Scale (SETS) may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.

Montgomery- Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

Columbia-Suicide Severity Rating Scale (CSSRS) is a measure used to identify and assess individuals at risk for suicide. Behavioral Activation Scale (BAS) Behavioral Activation Scale (BAS) is a 24-item self-report questionnaire designed to measure two motivational systems: the behavioral inhibition system (BIS), which corresponds to motivation to avoid aversive outcomes, and the behavioral activation system (BAS), which corresponds to motivation to approach goal-oriented outcomes.

Borg Rating of Perceived Exertion Scale (RPE) is a way of measuring physical activity intensity level. It is based on the physical sensations a person experiences during physical activity, including increased heart rate, increased respiration or breathing rate, increased sweating, and muscle fatigue.

International Physical Activity Questionnaire (IPAQ) is a 27-item self-reported measure of physical activity for use with individual adult patients.

The CogState Identification Test measures attention using a choice reaction time paradigm. The outcome measure is speed of performance.

The CogState Detection Test measures processing speed using a simple reaction time paradigm. The outcome measure is speed of performance.

The CogState DSST is a processing speed test that is based on the well-established digit symbol coding paradigm. The outcome measure is total number of correct responses in matching the symbols with the appropriate digits.

The CogState One Card Learning Test measures visual memory using a pattern separation paradigm. Outcome measures is accuracy of performance.

The term “Acute COVID- 19” as used herein means signs and symptoms of COVID- 19 for up to 4 weeks following an infection consistent with COVID-19.

The term “Ongoing symptomatic COVID-19” as used herein means signs and symptoms of

CO VID-19 that develop during or after an infection consistent with COVID-19, and continue from 4 to 12 weeks following an infection consistent with COVID-19 (e.g. continue from 4 to 12 weeks after the start of acute COVID 19). The term ‘Subacute COVID-19’ is also intended to indicate signs and symptoms of CO VID-19 from 4 to 12 weeks following an infection consistent with COVID-19, such as from 4 to 12 weeks following the onset of an infection consistent with CO VID- 19.

The term "post-CO VID 19 syndrome " as used herein means: signs and symptoms that develop during or after an infection consistent with COVID- 19, and continue for more than 12 weeks following an infection consistent with COVID-19, (e.g. continue 12 weeks or more after the start of acute COVID 19), and are not explained by an alternative diagnosis. The term ‘chronic COVID-19’ is also intended to indicate signs and symptoms of COVID-19 extending beyond 12 weeks following an infection consistent with COVID-19, such as 12 weeks following the onset of an infection consistent with COVID- 19.

An infection consistent with COVID- 19 may be established or confirmed for example by a documented history of SARS-CoV-2 infection with typical symptoms and/or a positive SARS-CoV-2 test (PCR, antigen or antibody) at some point during the course of illness or (in the case of antibodies) also after the acute course of illness.

The onset or start of an infection consistent with COVID-19 may for example be at the onset or start of the typical symptoms of an infection consistent with COVID-19 and/or upon receipt of a positive SARS-CoV-2 test (PCR, antigen or antibody).

In addition to the definitions above, “long CO VID” or “long COVID-19” may be used to describe signs and symptoms that continue or develop after acute CO VID-19. It includes both “ongoing symptomatic COVID-19” (from 4 to 12 weeks after the start of acute COVID 19) and “post-CO VID-19 syndrome” (12 weeks or more after the start of acute COVID 19). The definitions of the above terms are suggested by the NICE guidelines (NICE guideline December 2020: COVID 19 rapid guideline: managing the long-term effects of COVID-19 (NG188)).

‘Signs and symptoms’ of ‘Ongoing symptomatic COVID-19’ may for example be cognitive impairment (e.g. “brain fog”), fatigue, apathy, depression, anxiety, anhedonia, insomnia, anergia, loss of appetite, dyspnea, cough, headaches, and/or chest pain.

‘Signs and symptoms’ of post-CO VID 19 syndrome may for example be cognitive impairment (e.g. “brain fog”), fatigue, apathy, depression, anxiety, anhedonia, insomnia, anergia, loss of appetite, dyspnea, cough, headaches and chest pain.

‘Cognitive deficits’, ‘cognitive disturbances’ or ‘cognitive impairment’ as used herein, as a sign and symptom of post-COVID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID include a decline in cognitive functions or cognitive domains, e.g. working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving e.g. executive function, speed of processing and/or social cognition. In particular, cognitive deficits or cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts and/or difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts. Furthermore, it includes “brain fog”. The terms "cognitive deficits", “cognitive disturbances” and "cognitive impairment" are intended to indicate the same and are used interchangeably.

‘Depression’ as used herein, as a sign and symptom of post-COVID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID, may be characterized by depressive symptoms as defined by DSM-5, e.g. depressed mood, loss of interest/pleasure, weight loss or gain, insomnia or hypersomnia, fatigue or loss of energy, feeling worthless or excessive/inappropriate guilt, and/or decreased concentration. The symptoms may be measured by e.g. MADRS and/or PHQ-9. ’Anhedonia’ as used herein, as a sign and symptom of post-CO VID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID, may be characterized for example by a loss of interest and lack of reactivity to pleasurable stimuli.

’Anxiety’ as used herein, as a sign and symptom of post-COVID-19 syndrome, ongoing symptomatic COVID-19 or long CO VID, may be characterized by symptoms defined by DSM- 5, such as the presence of excessive anxiety and worry, edginess or restlessness, fatigue, impaired concentration, irritability and/or difficulty in sleeping. The symptoms of GAD may be measured by e.g. GAD-7.

A "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as "a therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

The term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being. All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase "the compound" is to be understood as referring to various compounds used in the invention or particular described aspect, unless otherwise indicated.

Unless otherwise indicated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by "about," where appropriate).

The description herein of any aspect or aspect of the invention using terms such as “comprising”, “having,” “including,” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

Examples

Hypotheses

Herein, we hypothesize that vortioxetine (10-20 mg) will be more effective than placebo in the treatment of cognitive impairment in persons with post-COVID-19. Furthermore, we hypothesize that vortioxetine (10-20 mg) will be more effective than placebo in the treatment of depression, anxiety, fatigue and/or anhedonia in persons with post-COVID-19 syndrome. Example 1

The effect of vortioxetine in the treatment of cognitive impairment is investigated in a randomized, double-blinded, placebo-controlled clinical trial in persons with post-CO VID- 19 syndrome. Furthermore, the effect of vortioxetine in the treatment of depression, anxiety, fatigue /or anhedonia in persons with post-COVID-19 syndrome is investigated.

Approximately 200 subjects are enrolled in a placebo-controlled clinical trial, i.e., approximately 100 subjects are allocated to vortioxetine (10-20 mg) and approximately. 100 subjects are allocated to placebo.

Study Design

Eight-week, randomized, double-blinded, placebo-controlled clinical trial:

Eight- week intervention (i.e., weeks 0-8)

Two-week drug discontinuation and safety follow-up period (i.e., weeks 8-10)

Primary Endpoint: Week 8

Participants receiving vortioxetine will be provided 10 mg/day on days 1-14 of the treatment period, andwill be titrated to 20 mg/day at the start of week 3 (day 15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will be 20 mg/day, unless adjudicated otherwise by a study clinician.

Outcomes

Primary Outcome:

Baseline-to-endpoint (i.e., Week 8) change in Digit Symbol Substitution Test (DSST)

Secondary Outcomes: Baseline-to-endpoint change in:

Trails Making Test (TMT)-A/B

Rey's auditory verbal learning test (RAVLT)

Perceived Deficits Questionnaire, 20-item (PDQ-20)

Fatigue Severity Scale (FSS)

Snaith Hamilton Pleasure Rating Scale (SHAPS)

Patient Health Questionnaire, 9-item (PHQ-9)

Generalized Anxiety Scale, 7-item (GAD-7)

World Health Organization Wellbeing Scale, 5-item (WHO-5)

EuroQol, 5-dimension, 5-level (EQ-5D-5L)

Sheehan Disability Scale (SDS)

Post-Covid Functional Scale (PCFS) fMRI and Monetary Incentive Delay (MID) Task

Stanford Expectations of Treatment Scale (SETS)

Montgomery- Asberg Depression Rating Scale (MADRS)

Columbia-Suicide Severity Rating Scale (CSSRS)

Behavioural Activation Scale (BAS)

Borg Rating of Perceived Exertion Scale (RPE)

International Physical Activity Questionnaire (IPAQ)

CogState Online Cognitive Battery [ Time Frame: Weeks 0-8 ]

The CogState Online Cognitive Battery employed in the present trial will consist of four tests:

Domain: Executive Function, Operation: Digit Symbol substitution test (CogState DSST)

Domain: Attention, Operation: Operation: Choice Reaction Time (2 CogState tests: CogState Detection Test, CogState Identification Test)

Domain: Memory, Operation: Visual Learning (CogState One Card Learning Test) Safety outcomes:

Spontaneously reported adverse events

Laboratory (including but not limited to CBC, TSH, electrolytes)

Study Population

Inclusion criteria

Ages 18 - 65

Meets NICE-defined post-COVID-19 syndrome:

NICE Definition: Signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis.

To ensure the above criteria is met, participants will only be included in the study if they meet all eligibility criteria more than 12 weeks from their confirmed and documented positive polymerase chain reaction (PCR) SARS-CoV-2 test, antigen or antibody test.

Documented history of SARS-CoV-2 infection with typical symptoms, and requiring positive SARS-CoV-2 test (PCR, antigen or antibody) at some point during the course or (in the case of antibodies) also after the acute course of illness.

Subjective cognitive complaints as detected by the Perceived Deficits Questionnaire (PDQ)-5. Ability to provide written informed consent.

Exclusion Criteria

Current symptoms are fully explained by major depressive disorder or bipolar disorder.

Pre-existing conditions that may cause cognitive impairment, or symptoms similar to those seen in post-COVID-19 syndrome (e.g., major neurocognitive disorder, schizophrenia, chronic fatigue syndrome [CFS]/ encephalitis meningitis [EM]), as assessed by Mini International Neuropsychiatric Interview (MINI) 7.0.2.

Inability to follow study procedures.

Known intolerance to vortioxetine and/or prior trial of vortioxetine with demonstrated inefficacy.

Not currently taking any other antidepressant in the past 4 weeks.

Current alcohol or substance use disorder.

Inability to provide consent.

Current alcohol and/or substance use disorder as confirmed by the M.I.N.I 7.0.2.

Presence of comorbid psychiatric disorder that is a primary focus of clinical concern as confirmed by the M.I.N.I. 7.0.2.

Medications approved and/or employed off-label for cognitive dysfunction(e.g., psychostimulants).

Any medication for a general medical disorder that, in the opinion of the investigator, may affect cognitive function.

Use of benzodiazepines within 12 hours of cognitive assessments.

Consumption of alcohol within 8 hours of cognitive assessments.

Physical, cognitive, or language impairments sufficient to adversely affect data derived from cognitive assessments.

Diagnosed reading disability or dyslexia.

Clinically significant learning disorder by history.

Electroconvulsive therapy (ECT) in the last 6 months.

History of moderate or severe head trauma (e.g., loss of consciousness for >1 hour), other neurological disorders, or unstable systemic medical diseases that in the opinion of the investigator are likely to affect the central nervous system.

Pregnant and/or breastfeeding.

Received investigational agents as part of a separate study within 30 days of the screening visit.

Actively suicidal/presence of suicidal ideation or evaluated as being at suicide risk (as per clinical judgment using the Columbia-Suicide Severity Rating Scale).

Currently receiving treatment with Monoamine Oxidase Inhibitors (MAOIs) antidepressants, antibiotics such as linezolid, or intravenous methylene blue.

Previous hypersensitivity reaction to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with vortioxetine.

Serotonin syndrome.

Abnormal bleeding.

Previous history of mania/hypomania.

Angle closure glaucoma.

Hyponatremia.

Moderate hepatic impairment.

History of seizures and epilepsy.

Presence of any unstable medical conditions.

Study Visits

Pre-Screen

Participants will be pre-screened via telephone, email, or an online form to determine if they meet above noted inclusion and exclusion criteria.

Screening Visit (Visit 0)

Once participants provide written, informed consent, they will undergo a comprehensive assessment to determine eligibility during the screening visit. Details of assessments completed are included in Table 1.

Baseline (Visit 1)

Participants will undergo the various assessments listed in Table 1. In addition, participants will have their blood drawn and may be invited to participate in an optional fMRI scan (see details below). Participants will also be assessed by a study physician and provided a prescription for vortioxetine. Some physician visits may be conducted remotely/ online through a secure platform.

Laboratory Assessment: Participants will be asked to fast for 8 hours prior to their baseline (visit 1) and week 8 (visit 4). Participants will have blood drawn for standard clinical parameters. These include glucose, insulin, electrolytes, liver and kidney function tests, lipids, CBC, inflammatory markers (e.g.CRP, ESR), albumin and protein. Participants will also have their blood drawn for various exploratory secondary analyses (e.g. cytokines). Approximately 20 mL of blood will be drawn in 4-5 blood tubes. Two of these tubes will include lavender tubes with EDTA for exploratory analyses. jMRI: A subset of participants may be offered the opportunity to have an fMRI scan completed for secondary, exploratory purposes. This is optional and not the primary focus of the study. Participants may still participate in the study and decide not to participate in this component. During the imaging, participants will be asked to complete a cognitive task (Monetary Incentive Delay).

Week 2 (Visit 2): Participants will complete items listed in Table 1, Week 2 (Visit 2).

Week 4 (Visit 3): Participants will complete items listed in Table 1, Week 4 (Visit 3).

This visit may be completed remotely/online.

Week 8 (Visit 4): Participants will complete items listed in Week 8 (Visit 4) will be completed. The study physician will also discuss transition of care (see below) and/or medication continuation. Participants willalso have their blood drawn and may be asked to participate in the optional fMRI scan.

Optional Post-Study (Week 10): Clinical visit with physician if patient discontinuing with medication andas needed. If a participant chooses to continue with the medication, he/she will be asked to follow up with his/her most responsible physician (MRP) for ongoing care and this post-study visit would not be needed.

Table 1. Study schedule with assessments

Abbreviations: ^a : BAS: Behavioural Activation Scale; CSSRS: Columbia-Suicide Severity Rating Scale; DSST: Digit Symbol Substitution Test; EQ-5D-5L: 5-Level EQ-5D version; fMRI: functional magnetic resonance imaging; FSS: Fatigue Severity Scale; GAD-7: Generalized Anxiety Disorder, 7-item; IPAQ: International Physical Activity Questionnaire; MADRS: Montgomery -Asberg Depression Rating Scale; MID: Monetary Incentive Delay; M I N I: MiniInternational Neuropsychiatric Interview; MoCA: Montreal Cognitive Assessment; PCFS: Post-Covid Functional Scale; PDQ-20: Perceived Deficits Questionnaire, 20-item; PHQ-9: Patient Health Questionnaire, 9-item; RAVLT: Rey's auditory verbal learning test; RPE: Borg Rating of Perceived Exertion Scale; SDS: Sheehan Disability Scale; SETS: Stanford Expectations of Treatment Scale; SHAPS: Snaith-Hamilton Pleasure Scale; TMT-A/B: Trails Making Test-A/B; WHO-5: World Health Organization Well-Being Index, 5-item.

*Visit 3 (Week 4) - Visit may be completed online/remotely.