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WO2025065271A1 - Méthodes et dispositifs de traitement de la dépression - Google Patents

Méthodes et dispositifs de traitement de la dépression Download PDF

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Publication number
WO2025065271A1
WO2025065271A1 PCT/CN2023/121712 CN2023121712W WO2025065271A1 WO 2025065271 A1 WO2025065271 A1 WO 2025065271A1 CN 2023121712 W CN2023121712 W CN 2023121712W WO 2025065271 A1 WO2025065271 A1 WO 2025065271A1
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Prior art keywords
nmdar
module
subject
lhb
drug delivery
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Inventor
Hailan HU
Min Chen
Shuangshuang MA
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Liangzhu Laboratory
Zhejiang University ZJU
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Liangzhu Laboratory
Zhejiang University ZJU
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Priority to PCT/CN2023/121712 priority Critical patent/WO2025065271A1/fr
Publication of WO2025065271A1 publication Critical patent/WO2025065271A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest, and it is estimated that around 3.8%of the population, or 280 million people, experience depression worldwide.
  • medications developed for treating depression e.g. selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, etc.
  • NMDA N-methyl-D-aspartate
  • the present disclosure provides methods for increasing the duration of the therapeutic effects (i.e. antidepression effect) of an NMDAR pore blocker (e.g. ketamine) administered to a subject with depression, therapeutic regimens, pharmaceutical combinations, and implantable drug delivery systems that are capable of efficiently delivering such drugs with durable therapeutic effects.
  • an NMDAR pore blocker e.g. ketamine
  • FIGS. 1A-1L show results that single injection of ketamine causes sustained antidepressant effects and prolonged suppression of LHb bursting activity.
  • FIG. 1A Brain concentration of ketamine after a single i.p. injection of ketamine in CRS mice, as measured by LC-MS/MS. Behavioral effects at different time points, as measured in (FIGS. 1B and 1C) and FIGS. 2A-2D, are marked. Dotted line indicates the half-life of ketamine, which is about 13 min.
  • FIGS. 1B and 1C Behavioral effects at 1 h and 24 h after a single i.p. injection of ketamine in CRS mice in the FST (FIG. 1B) and the SPT (FIG. 1C) .
  • FIG. 1D Experimental paradigm for LHb slice recording after i.p. injection of ketamine (10 mg kg -1 ) in CRS mice.
  • FIG. 1E Representative traces showing spontaneous activity of three LHb neuron types, burst-firing, tonic-firing and silent.
  • FIG. 1F Pie charts illustrating the percent abundance of the three types of LHb neurons in CRS mice at different time points after saline or ketamine i.p. injection.
  • FIG. 1G Experimental paradigm for in vivo recording after a single injection of ketamine (i.p., 10 mg kg -1 ) in CRS mice.
  • FIG. 1H Illustration of in vivo single-unit recording in the LHb.
  • FIG. 1I An example recording site stained with DAPI.
  • White dotted lines demarcate MHb and LHb.
  • White arrows indicate the electrode tracks.
  • Scale bar 100 ⁇ m.
  • LHb lateral habenula.
  • MHb medial habenula.
  • FIG. 1J Example traces showing in vivo neuronal activity recorded in CRS mice before, 1 h and 24 h after saline (green, left) or ketamine (blue, right) administration. Bursts (pink shades) are identified by the ISI method (see Methods) .
  • FIGs. 1K and 1L Bar graphs illustrating the bursting spike frequency (FIG. 1K) and bursts per minute (FIG.
  • FIGS. 2A-2D show results that single injection of ketamine no longer causes antidepressant effects on day 3 or day 7, related to FIGS. 1A-1L.
  • FIG. 2A Schematic of LC-MS/MS (left) and experimental paradigm for behavioral tests (right) after i.p. injection of 10 mg kg -1 ketamine.
  • FIG. 2B Plasma concentration of ketamine after a single i.p injection of ketamine in CRS mice, as measured by LC-MS/MS. Dotted line indicates the half-life of ketamine.
  • FIGS. 2C and 2D Behavioral effects at 3 d and 7 d after a single i.p. injection of ketamine in CRS mice in the FST (FIG. 2C) and the SPT (FIG. 2D) .
  • Sal saline.
  • Ket ketamine. NS, not significant.
  • FIGS. 3A-3K show results that single injection of ketamine causes prolonged suppression of LHb bursting activity, related to FIGS. 1A-1L.
  • FIG. 3A Pie charts illustrating the percent abundance of the three types of LHb neurons in mice.
  • FIG. 3B Pie charts illustrating the percent abundance of the three types of LHb neurons in CRS mice 3 d after saline or ketamine i.p. injection.
  • FIGS. 3C and 3D Bar graphs illustrating the bursting spike frequency (number of bursting spikes per second, FIG. 3C) and bursts per min (number of bursts per minute, FIG. 3D) in CRS mice at different time points after saline or ketamine i.p. injection.
  • FIG. 3C Bar graphs illustrating the bursting spike frequency (number of bursting spikes per second, FIG. 3C) and bursts per min (number of bursts per minute, FIG. 3D) in CRS mice at different time points after
  • FIG. 3E Percentage of blockade of bursting spike frequency or bursts per min at each time point calculated as (saline value -ketamine value) /saline value.
  • FIG. 3F Recording sites of electrodes in LHb. Black lines indicate location of habenula, green dots indicate recording sites of saline group, blue dots indicate recording sites of ketamine group.
  • FIG. 3G Example traces showing in vivo neuronal activity recorded in CRS mice 3 d after saline (green, top) or ketamine (blue, bottom) administration. Bursts (pink shades) are identified by the ISI method (see Methods) .
  • FIGS. 3H and 3I Bar graphs illustrating the bursting spike frequency (FIG.
  • FIGS. 3J and 3K Percentage of blockade of bursting spike frequency (FIG. 3J) and bursts per minute (FIG. 3K) at each time point calculated as (baseline value -value of each time point) /baseline value. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; NS, not significant.
  • FIGS. 4A-4D show results that ketamine preferentially inhibits LHb neurons with high bursting spike frequency, related to FIGS. 1A-1L.
  • FIG. 4A Histogram distribution of baseline bursting spike frequency of all recorded LHb units. Pie graph showing percentage of neurons with baseline bursting spike frequency larger than 2 Hz.
  • FIGS. 4B and 4C Top: Scatter plots of the bursting spike frequency of recorded LHb units at baseline state plotted against bursting spike frequency at 0-5 min, 5-10 min, 20-30 min and 1 h after i.p. injection of saline (FIG. 4B) or ketamine (FIG. 4C) .
  • FIG. 4D Percentage of LHb neurons inhibited by either saline (green) or ketamine (blue) in the “ ⁇ 2 Hz” and “> 2Hz” (baseline bursting spike frequency) groups. Numbers in each box are percentages of inhibited neurons. Note that a significantly larger fraction of neurons is inhibited by ketamine in the “> 2 Hz group” .
  • FIGS. 5A-5R show results that single injection of ketamine in CRS mice causes prolonged inhibition of NMDAR currents in LHb.
  • FIG. 5A Experimental paradigm for slice recording after i.p. injection of ketamine (10 mg kg -1 ) in CRS mice.
  • FIG. 5B Schematic of the whole-cell recording of evoked synaptic responses in sagittal LHb slices.
  • FIGS. 5C and 5I Example traces of evoked AMPAR-eEPSCs (–70 mV, measured at the peak) and NMDAR-eEPSCs (+40 mV, measured at 35 ms after stimulation, dotted line) in LHb neurons in presence of picrotoxin (PTX) at 1 h (FIG.
  • PTX picrotoxin
  • FIGS. 5C and 5I Ratios of NMDAR-eEPSCs and AMPAR-eEPSCs (recorded at 1.5 mA stimulation intensity) at 1 h (FIG. 5D) and 24 h (FIG. 5J) after i.p. injection of saline or ketamine in CRS mice.
  • FIGS. 5E, 5G, 5K and 5M Stimulus-response (input-output) curves of NMDAR-eEPSCs (FIGS. 5E and 5K) and AMPAR-eEPSCs (FIGS.
  • FIGS. 5G and 5M Bar graphs of NMDAR-eEPSCs (FIGS. 5F and 5L) and AMPAR-eEPSCs (FIGS. 5H and 5N) recorded at 1.5 mA stimulation intensity at 1 h (FIGS. 5F and 5H) and 24 h (FIGS. 5L and 5N) after i.p. injection of saline or ketamine in CRS mice.
  • FIGS. 5F, 5H, 5L and 5N Bar graphs of NMDAR-eEPSCs (FIGS. 5F and 5L) and AMPAR-eEPSCs (FIGS. 5H and 5N) recorded at 1.5 mA stimulation intensity at 1 h (FIGS. 5F and 5H) and 24 h (FIGS. 5L and 5N) after i.p. injection of saline or ketamine in CRS mice.
  • FIGS. 5F, 5H, 5L and 5N Bar graphs of NMDAR-eEPSCs (FIGS. 5F
  • FIGS. 5P and 5R Stimulus-response (input-output) curves of NMDAR-eEPSCs (isolated by application of PTX and NBQX under voltage clamp at +40 mV) of LHb neurons at 1 h (FIG. 5P) and 24 h (FIG. 5R) after i.p. injection of saline or ketamine in CRS mice.
  • FIGS. 6A-6G show results that single injection of ketamine in CRS mice causes prolonged inhibition of NMDAR currents in LHb, related to FIGS. 5A-5R.
  • FIGS. 6A Left: example traces of LHb eEPSCs evoked at +40mV in presence of PTX (black) , PTX + NBQX (blue) or PTX + NBQX + AP5 (red) in ACSF.
  • Right Amplitudes of eEPSCs measured at 35 ms after stimulation onset.
  • FIGS. 6B-6C Bar graphs showing percentage of NMDAR-eEPSCs smaller or larger than 10 pA at 1 h (FIG. 6B) and 24 h (FIG. 6C) after treatment.
  • FIGS. 6D-6F Bar graphs of ratios of NMDAR-eEPSCs and AMPAR-eEPSCs (FIG. 6D) , NMDAR-eEPSCs (FIG.
  • FIG. 6E Percentage of blockade of NMDAR-eEPSCs at each time point calculated as (saline value -ketamine value) /saline value. *P ⁇ 0.05; ****P ⁇ 0.0001; NS, not significant.
  • FIGS. 7A-7M demonstrate the prolonged blockade of LHb NMDARs after ketamine wash off.
  • FIG. 7A NMDAR-eEPSCs (normalized by baseline) during incubation and wash-out of vehicle, memantine (100 ⁇ M) , or ketamine (100 ⁇ M) .
  • NMDAR-eEPSCs are isolated by application of PTX and NBQX in Mg 2+ free ACSF under voltage clamp at -70 mV.
  • FIG. 7B Bar graphs showing NMDAR-eEPSCs at the end of the 10 min perfusion period (left) and at 50-60 min (right) .
  • Mem memantine.
  • Ket ketamine.
  • FIG. 7A NMDAR-eEPSCs (normalized by baseline) during incubation and wash-out of vehicle, memantine (100 ⁇ M) , or ketamine (100 ⁇ M) .
  • NMDAR-eEPSCs are isolated by application of PTX and
  • FIG. 7C Experimental paradigm for behavioral testing after local bilateral infusion of ketamine (100 mM, 0.1 ⁇ l each side) or memantine (100 mM, 0.1 ⁇ l each side) into the LHb in CRS mice.
  • FIG. 7D Illustration of bilateral implantation of cannulae in the LHb of CRS mice. Hippo, hippocampus. MHb: medial habenula. LHb: lateral habenula. White dashed lines demarcate MHb and LHb. Scale bar, 500 ⁇ m.
  • FIG. 7E Infusion sites of drugs verified by cholera toxin subunit B (CTB) .
  • CTB cholera toxin subunit B
  • FIGS. 7I-7L Behavioral effects at 24 h (FIG. 7I, FIG. 7J) and 7 d (FIG. 7K, FIG. 7L) after local bilateral infusion of ketamine into the LHb in CRS mice in the FST (FIG. 7I, FIG. 7K) and SPT (FIG. 7J, FIG. 7L) .
  • FIG. 7M Behavioral effects at 14 d after local bilateral infusion of ketamine into the LHb in CRS mice in the FST. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; NS, not significant.
  • FIGS. 8A-8C show the input resistance of recorded neurons, related to FIG. 7A. Input resistance of recorded neurons during baseline, wash-in (at 10 min) and wash-out (at 50 min) periods in ket- (FIG. 8A) , mem- (FIG. 8B) and vehicle- (FIG. 8C) treated groups. NS, not significant.
  • FIGS. 9A-9E demonstrate the recovery of LHb NMDAR-eEPSCs after washout of ketamine in presence of endocytosis blocker Dyngo-4a, related to FIG. 7A and FIG. 10A.
  • FIG. 9A Dyngo-4a successfully blocks LFS (1Hz, 15min) -induced, endocytosis-based long-term depression of NMDAR-eEPSCs in hippocampal CA1 neurons.
  • NMDAR-eEPSCs are isolated by application of PTX and NBQX in Mg 2+ free ACSF under voltage clamp at -70 mV. In the Dyngo-4a group, 30 ⁇ M Dyngo-4a is additionally added in ACSF throughout the recording.
  • FIGS. 9C and 9E Bar graphs showing NMDAR-eEPSCs at the end of the 10 min perfusion period (left) and at 50-60 min (right) .
  • Ket ketamine.
  • the data of vehicle group in (FIG. 9B) was from the data of ket-group in FIG. 7A and the date of vehicle group in (FIG. 9D) was from the data of “no stim” group in FIG. 10A. NS, not significant.
  • FIGS. 10A-10B show results that neural activity untraps ketamine from NMDARs.
  • FIG. 10A Top left: a “kick-off” protocol used to untrap ketamine, including five 3-spairings of presynaptic stimulation (1 Hz) with postsynaptic depolarization (to +10 mV) delivered over a 5 min period.
  • “Kick-off” two blocks of “kick-off” activity given after ketamine wash-out.
  • Pre alone two blocks of presynaptic stimulation alone without postsynaptic depolarization given after ketamine wash-out.
  • Top right Input resistance of recorded neurons during baseline, wash-in (at 10 min) and wash-out (at 50 min) periods in three different conditions.
  • FIG. 10B Bar graphs showing NMDAR-eEPSCs at 50-60 min. **P ⁇ 0.01; NS, not significant.
  • FIGS. 11A-11D show the potential reverse correlation between the level of initial NMDAR blockade and the level of recovery.
  • FIG. 11A NMDAR-eEPSCs (normalized by baseline) during incubation and wash-out of ketamine (10 ⁇ M or 100 ⁇ M) .
  • NMDAR-eEPSCs are isolated by application of PTX and NBQX in Mg 2+ free ACSF under voltage clamp at -70 mV. Bin is 1 min. Each line represents one recorded cell. The red line shows an example cell with no recovery and the green line shows an example cell with 29 %recovery. The black line is the average of all recorded cells.
  • FIG. 11B Illustration of the calculation of maximal blockade, blockade at 50-60 min and recovery percentage.
  • the maximal blockade is averaged by the 10-min values during maximal blockade period (there is some variation among individuals, but mostly between 0 min to 20 min) .
  • Recovery percentage is calculated as: maximal blockade –blockade at 50-60 min.
  • FIG. 11C Bar graph showing the maximal blockade and blockade at 50-60 min of each cell after ketamine perfusion. Each color represents one recorded cell.
  • FIG. 11D Recovery percentage plots against maximal blockade of LHb-NMDAR-eEPSCs. Each color represents one recorded cell.
  • FIG. 12 shows that “Kick off” protocol does not induce NMDAR-LTP.
  • NMDAR-eEPSCs normalized by baseline after kick off protocol.
  • NMDAR-eEPSCs are isolated by application of PTX and NBQX in Mg 2+ free ACSF under voltage clamp at -70 mV.
  • FIGS. 13A-13L show results that activation of LHb input pathway at different ambient ketamine levels regulates ketamine’s sustained antidepressant effects bidirectionally.
  • FIG. 13A Schematic of viral construct, viral injection in the LH and optic fiber implantation in the LHb of CRS mice.
  • FIG. 13B An example showing bilateral viral injection sites in the LH (top) and viral expression in axon terminals in the LHb as well as canular sites for optic fiber implantation (bottom) .
  • LH lateral hypothalamus.
  • EP entopeduncular nucleus.
  • LHb lateral habenula. Scale bar, 200 ⁇ m.
  • FIG. 13A Schematic of viral construct, viral injection in the LH and optic fiber implantation in the LHb of CRS mice.
  • FIG. 13B An example showing bilateral viral injection sites in the LH (top) and viral expression in axon terminals in the LHb as well as canular sites for optic fiber implantation (bottom)
  • FIG. 13C RTPA induced by constant stimulation (635 nm, 40 Hz, 2 ms pulse) of the LH-LHb axon terminals. Left, representative heat maps; Right, percentage of time spent in light-stimulated chamber.
  • FIG. 13D Equation of dynamic equilibrium for the ketamine-NMDAR interaction. K d : dissociation constant.
  • FIG. 13E When ambient ketamine level is lower than K d , the interaction between ketamine and NMDAR favors more unbinding.
  • FIG. 13F Experimental paradigm for stimulating LH-LHb terminals at low ambient ketamine level to untrap ketamine from NMDARs. After CRS, RTPA is conducted to confirm the effectiveness of LH-LHb stimulation.
  • FIG. 13G NMDAR-eEPSCs of LHb neurons recorded at 24 h after ketamine or saline injection from experiment in (FIG. 13F) .
  • FIG. 13H Behavioral effects (FST) at 24 h after ketamine or saline injection from experiment in (FIG. 13F) .
  • FIG. 13G NMDAR-eEPSCs of LHb neurons recorded at 24 h after ketamine or saline injection from experiment in (FIG. 13F) .
  • FIG. 13H Behavioral effects (FST) at 24 h after ketamine or saline injection from experiment in (FIG. 13F) .
  • FIG. 13I When ambient ketamine level is higher than K d , the interaction between ketamine and NMDAR favors mores binding.
  • FIG. 13J Experimental paradigm for stimulating LH-LHb terminals at high ambient ketamine level to trap more ketamine into NMDARs. Immediately after a single injection of ketamine (i.p., 5 mg kg -1 ) , optical stimulation of LH-LHb terminals (635 nm, 40 Hz, 2 ms pulse, 3 min) is delivered, when ketamine’s plasma concentration is above 6 ⁇ M. Electrophysiological recording or behavioral testing are conducted 24 h later. FIG.
  • FIG. 13K NMDAR-eEPSCs of LHb neurons recorded at 24 h after ketamine or saline injection from experiment in (FIG. 13J) .
  • FIG. 13L Behavioral effects (FST) at 24 h after ketamine or saline injection from experiment in (FIG. 13J) .
  • FIGS. 14A-14G show that 40 Hz LH-LHb stimulation induces LHb burst firing and kicks off trapped ketamine in vivo.
  • FIG. 14A Schematic of viral construct, viral injection in the LH of CRS mice.
  • FIG. 14B Experimental paradigm.
  • FIG. 14C Schematic of whole-cell recording of LHb neurons in vitro and representative trace showing burst firing elicited by pulsed light stimulation (635 nm, 40 Hz, 2 ms pulse, 0.5 mW) of LH terminals in LHb brain slices.
  • FIG. 14D Experimental paradigm for electrophysiological recording immediately after optical stimulation in CRS mice.
  • FIG. 15 show the brain concentration of ketamine after a single i.p injection of 5 mg kg -1 ketamine in CRS mice, as measured by LC-MS/MS. As noted by the dotted line, the half-life of ketamine is 13 mins.
  • FIG. 16 illustrates a block diagram of a drug delivery system according to various embodiments. Blocks boxed with dotted lines represent optional features according to certain embodiments.
  • the present disclosure substantially provides methods for improving, or more specifically increasing the duration of, the therapeutic effects (i.e. antidepression effect) of an NMDAR pore blocker that is administered to a subject in need thereof (e.g. patients with depression, etc. ) , therapeutic regimens and pharmaceutical combinations, and implantable drug delivery systems that are capable of efficiently delivering such drugs with durable therapeutic effects.
  • the term "subject” refers to a mammal that is susceptible to depression, which may include a human subject, but may also include other primates (e.g. monkeys, apes, etc. ) rodents (e.g. mouse, rat, etc. ) , or other species of mammals;
  • the term “N-methyl-D-aspartate receptor (NMDAR) refers to the ionotropic glutamate receptor present on the cell membranes of neurons in the brain of a subject, whose activation relies on the binding of agonistic ligands (e.g. glutamate, glycine and NMDA, etc.
  • NMDAR pore blocker or “NMDAR channel blocker” , refers to a class of compounds that can block the ion channel (i.e.
  • NMDAR which optionally comprises one or more of ketamine, memantine, dextromethorphan (AXS-05) , dizocilpine, amantadine, lanicemine, D-methadone, etc., or pharmaceutically acceptable derivatives thereof;
  • pharmaceutically acceptable means that a molecular entity or a composition is generally believed to be physiologically tolerable and does not typically produce intolerable adverse effects (e.g. toxicity, etc. ) when administered to a subject;
  • derivative refers to any pharmaceutically acceptable salt, solvate, or prodrug of a compound which, upon administration, is capable of providing (directly or indirectly) the compound or an active metabolite or residue thereof.
  • a method for increasing the duration of the therapeutic effect of NMDAR pore blocker comprising at least one of: (1) prior to, or within a first time period after, administering the NMDAR pore blocker or a pharmaceutically acceptable salt thereof to the subject, carrying out a first procedure such that ion channels of a greater proportion of the NMDAR molecules in the lateral habenula (LHb) of the subject are opened to be thereby accessible to molecules of the NMDAR pore blocker compared to when the first procedure is absent; or (2) after administering the NMDAR pore blocker or a pharmaceutically acceptable salt thereof to the subject, carrying out a second procedure such that untrapping of the molecules of the NMDAR pore blocker from the NMDAR is prevented or reduced.
  • LHb lateral habenula
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent consisting either of a cationic form of the agent in combination with a suitable anion, or of an anionic form of the agent in combination with a suitable cation.
  • the pharmaceutically acceptable salts for each of the NMDAR pore blockers listed above are well-known to artisans working in the field.
  • the pharmaceutically acceptable salts of ketamine include: (R, S)-ketamine hydrochloride, (R, R) -ketamine hydrochloride, (S, S) -ketamine hydrochloride, ketamine derivatives hydrochloride, etc.
  • the first time period is the plasma elimination half-time of the NMDAR pore blocker in the recipient subject.
  • the NMDAR pore blocker is ketamine, memantine, dextromethorphan (AXS-05) , dizocilpine, amantadine, lanicemine or D-methadone
  • the first time period is approximately 3 hours, 60 hours, 29.5 hours, 16 hours, 9 hours and 33 hours, respectively.
  • catheter refers to a thin tube made of a biocompatible material that is inserted or embedded in the body and intended for local drug delivery at a region of interest; optionally the catheter may further comprise a sensing module that is capable of detecting certain physiological or physicochemical parameters (e.g. temperature, pH, concentration of certain molecules, etc. ) .
  • a catheter When a catheter is employed, it can be arranged such that its drug delivery outlet is disposed within, or in the proximity of, the LHb of the subject.
  • the catheter may be directly utilized for drug delivery, but optionally may be further operably connected to a distally arranged reservoir, such as an Ommaya reservoir (Zubair A et al. 2023; Liu HG et al. 2021) , which can be disposed beneath a scalp or elsewhere of the subject and allows for the repeated filling of the injectable contents (i.e. formulations of the NMDAR pore blocker) .
  • a distally arranged reservoir such as an Ommaya reservoir (Zubair A et al. 2023; Liu HG et al. 2021) , which can be disposed beneath a scalp or elsewhere of the subject and allows for the repeated filling of the injectable contents (i.e. formulations of the NMDAR pore blocker) .
  • the term "controllable implantable device” refers to a drug delivery device implanted within the body and designed to realize a controllable drug delivery following a preset program or upon receiving an external instruction. When a controll
  • the implantable device may be wholly embedded within, or in a proximity of, the LHb of the subject.
  • the implantable device may have Ommaya reservoir-like configuration, comprising a catheter module and a reservoir module that are distally arranged in the body.
  • the catheter module has a drug delivery outlet that is arranged within, or in the proximity of, the LHb of the subject, and is further operably connected the reservoir module accommodates the NMDAR pore blocker.
  • the phrase "ion channels of a greater proportion of the NMDAR molecules in the lateral habenula (LHb) of the subject are opened to be thereby accessible to molecules of the NMDAR pore blocker compared to when the first procedure is absent" in (1) means that the proportion of the NMDAR molecules in the LHb that are opened in the presence of the first procedure is at least 20% (e.g. 20%, 40%, 60%, 80%, 100%, etc.
  • the phrase "untrapping of the molecules of the NMDAR pore blocker from the NMDAR is prevented or reduced" in (2) means that in the presence of the second procedure, the number of the NMDAR pore blocker molecules previously trapped in the pores of the NMDAR in the LHb that are untrapped or displaced thereoff is zero ( “prevented” ) or smaller ( “reduced” ) than compared to otherwise (i.e. in the absence of the second procedure) .
  • each of the first and second procedures may comprise behavioral (or psychological) , pharmaceutical (or chemical) , physical measures or any of their combinations.
  • the first procedure may comprise a first behavioral measure, which may include applying an aversive stimulus to the subject.
  • aversive stimulus refers to a noxious or unpleasant stimulus or occurrence intended to elicit aversion, avoidance, and/or withdrawal responses from a subject, which may be realized by negative reinforcement or positive punishment.
  • An aversive stimulus may comprise a stressor, which can be a chemical or biological agent, an environmental condition, an external stimulus or an event that cause stress to an individual or that individual might consider demanding, challenging and/or threatening.
  • applying an aversive stimulus may include providing one or more unpleasant cues (e.g.
  • a human subject may be provided with a virtual reality (VR) device, TV, a computer monitor or a projector, that displays images, sounds or videos, or may be forced in a specially designed environment (e.g. a room with horror or disturbing scenes or on a special device such as a maze, etc. ) , that can arouse unpleasant, horrified, painful, and/or aversive feelings, and/or recall bad memories/experiences to the subject.
  • VR virtual reality
  • a rodent subject may be treated for restrained stress, forced swimming, tail suspension, air puff, social attack, bitter taste, olfactory cue (fox urine, 2, 5-Dihydro-2, 4, 5-trimethylthiazoline (TMT) , ect. ) , sleep deprivation, water deprivation, footshock, noise, or looming visual stimulus.
  • TMT 5-trimethylthiazoline
  • the first procedure may comprise a first chemical measure, comprising providing at least one priming agent to the subject.
  • the term "priming agent” as used herein refers to a chemical/biological agent that is capable of facilitating pores/channels of the NMDAR molecules in the LHb to open to thereby become more accessible to the NMDAR pore blocker (s) compared to when the priming agent is absent.
  • the at least one priming agent may comprise an NMDAR agonist, which may be of any of the following classes: (1) aspartate or derivatives (e.g. D-aspartate, NMDA, L-aspartate, etc. ) ; (2) glutamate or derivatives (e.g.
  • the at least one priming agent may be systemically or locally delivered.
  • the first procedure may comprise a a first physical measure capable of at least one of: (a) increasing the permeability of brain-blood barrier in a brain of the subject so as to increase a local concentration of the molecules of the NMDAR pore blocker in the LHb; or (b) stimulating the activity of the NMDAR in the LHb.
  • a a first physical measure capable of at least one of: (a) increasing the permeability of brain-blood barrier in a brain of the subject so as to increase a local concentration of the molecules of the NMDAR pore blocker in the LHb; or (b) stimulating the activity of the NMDAR in the LHb.
  • focused ultrasound can be utilized to thereby provide an acoustic measure to increase the permeability of brain-blood barrier in the LHb of the subject. Focused ultrasound-mediated blood brain barrier has been applied for localized delivery of drugs, genes or other therapeutical agents in the treatment of other central nervous system diseases (Gorick CM et al. 2022 and Wang J et al
  • a surgical measure can also be applied to realize (a) as described above, whereas a first electrophysical measure, by means of an electrode or an implantable device capable of electrically stimulating the activity of the NMDAR in the LHb can be applied to realize (b) as described above.
  • the second procedure comprises a second behavioral measure, which includes providing an environment to the subject such that the subject is capable of obtaining pleasant feelings (e.g. by providing one or more visual, auditory, haptic, olfactory, and/or gustatory cues that can arouse pleasant feelings) and/or avoiding negative emotional episodes.
  • the providing one or more such pleasant cues can be by any means, such as by means of a VR device.
  • the second procedure comprises a second chemical measure, comprising providing at least one enhancing agent to the subject.
  • enhancing agent refers to chemical/biological agent that is capable of enhancing the therapeutic effects of NMDAR pore blocker (s) as described above compared to when the agent is absent, and as such the enhancing agent may work by antagonizing the NMDAR activity and/or by suppressing the neuronal activity in the LHb of the subject.
  • the at least one enhancing agent comprises at least one first reagent, each capable of antagonizing the NMDAR activity, and selected from one of the following classes: (1) NMDAR open channel blocker (e.g.
  • NMDAR competitive antagonist e.g.
  • antagonist-2-amino-7-phosphonoheptanoic acid AP7
  • antagonist 2-amino-5-phosphonopentanoic acid AP5
  • 4- [ (2E) -3-Phosphono-2-propenyl] -2-piperazinecarboxylicacid CPPene
  • CPC agonist-1-aminocyclopropanecarboxylic acid
  • ACPC rapastinel
  • D-cycloserine Ro 25-6981
  • (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol CP-101606
  • ifenprodil rislenemdaz hydrochloride
  • MK-0657 ifenprodil, rislenemdaz hydrochloride
  • the at least one enhancing agent comprises at least one second reagent, each capable of suppressing the neuronal activity in the LHb of the subject, selected from one of the following classes: (1) Gamma-aminobutyric acid type A receptor (GABAaR) agonists (e.g. Muscimol, etc. ) ; (2) ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) antagonists (e.g.
  • GABAaR Gamma-aminobutyric acid type A receptor
  • AMPAR ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor
  • NBQX 3-dihydroxy-6-nitro-7-sulfamoyl-benzo
  • CNQX 6-cyano-7-Nitroquinoxaline-2, 3-dione
  • sodium channel blockers e.g. tetrodotoxin (TTX) , etc.
  • the second procedure comprises a second physical measure capable of suppressing the activity of the NMDAR in the LHb, which can comprise a second electrophysical measure by means of an electrode or an implantable device capable of electrically suppressing the activity of the NMDAR in the LHb.
  • a therapeutic regimen for treating a subject with depression comprising: (1) administering an NMDAR pore blocker or a pharmaceutically acceptable salt thereof to the subject; and (2) prior to, or within a first time period after, administering an NMDAR pore blocker or a pharmaceutically acceptable salt thereof to the subject, carrying out a first procedure such that ion channels of a greater proportion of the NMDAR molecules in a lateral habenula (LHb) of the subject are opened to be thereby accessible to molecules of the NMDAR pore blocker compared to when the first procedure is absent.
  • LHb lateral habenula
  • the administering of the NMDAR pore blocker or a pharmaceutically acceptable salt thereof comprises systemic administration, and the first time period is the plasma elimination half-time of the NMDAR pore blocker.
  • the administering of the NMDAR pore blocker or a pharmaceutically acceptable salt thereof comprises local administration, which can be by means of a controllable implantable device or by means of a catheter.
  • the first procedure comprises a first behavioral measure, which comprises applying an aversive stimulus, e.g. providing one or more unpleasant cues (including visual, auditory, haptic, olfactory, gustatory cues or any combination thereof) , to the subject.
  • the first procedure comprises a first chemical measure, comprising providing at least one priming agent to the subject, wherein each of the at least one priming agent is capable of opening pores of the NMDAR molecules in the LHb.
  • the first procedure comprises a first physical measure capable of at least one of: (a) increasing the permeability of brain-blood barrier in a brain of the subject so as to increase a local concentration of the molecules of the NMDAR pore blocker in the LHb; or (b) stimulating the activity of the NMDAR in the LHb.
  • a first physical measure capable of at least one of: (a) increasing the permeability of brain-blood barrier in a brain of the subject so as to increase a local concentration of the molecules of the NMDAR pore blocker in the LHb; or (b) stimulating the activity of the NMDAR in the LHb.
  • the therapeutic regimen as described above further comprises: (3) after administering the NMDAR pore blocker or a pharmaceutically acceptable salt thereof to the subject, carrying out a second procedure such that untrapping of the NMDAR pore blocker molecules from the NMDAR is prevented or reduced.
  • the second procedure comprises a second behavioral measure, comprising providing an environment to the subject such that the subject is capable of obtaining pleasant feelings and/or avoiding negative emotional episodes.
  • the second procedure comprises a second chemical measure, comprising providing at least one enhancing agent to the subject.
  • the second procedure comprises a second physical measure capable of suppressing the activity of the NMDAR in the LHb.
  • a pharmaceutical combination for treating a subject with depression comprising: (1) at least one NMDAR pore blocker or a pharmaceutically acceptable salt thereof; and one or both of: (2) at least one priming agent, each capable of opening pores of the NMDAR molecules in the LHb; or (3) at least one enhancing agent, each capable of suppressing neuronal activity in the LHb.
  • the different embodiments for the NMDAR pore blocker, the priming agent, and the enhancing agent can reference the first aspect of the disclosure as described above.
  • the present disclosure further provides a drug delivery system, which is capable of realizing a controlled local release of an NMDAR pore blocker within a lateral habenula (LHb) of a subject.
  • a drug delivery system which is capable of realizing a controlled local release of an NMDAR pore blocker within a lateral habenula (LHb) of a subject.
  • FIG. 16 illustrates a block diagram of a drug delivery system according to some embodiments of the disclosure.
  • the drug delivery system 001 comprises an implantable unit 1000, and optionally further comprises an external control unit 2000, and/or an external power unit 3000.
  • the implantable unit 1000 is wholly or partially embedded within, or in the proximity of the LHb region in the brain of the subject, which can be implanted via surgery, and is configured to realize a controllable or programmable in vivo local drug delivery.
  • the implantable unit 1000 can be designed to substantially comprise a miniaturized multi-module microdevice actuating the passive or on-demand in vivo drug release, which can be realized by means of a microchip and/or a microelectromechanical systems (MEMS) .
  • MEMS microelectromechanical systems
  • module refers to an assembly of functionally inter-connected hardware components (i.e. structural, electronic, mechanical, and/or MEMS components) that is designed to carry out a specific functionality, and may optionally also comprise software programs that control these hardware components to operate.
  • hardware components i.e. structural, electronic, mechanical, and/or MEMS components
  • the implantable unit 1000 comprises a first reservoir module 400, a dispensing module 300, a control module 200 and a power source module 100.
  • the first reservoir module 400 accommodates a pharmaceutically acceptable formulation of the NMDAR pore blocker.
  • the dispensing module 300 is operably coupled to the first reservoir module 400, and is configured, upon receiving a first activation command from the control module 200, to dispense the NMDAR pore blocker out of the first reservoir module 400.
  • the control module 200 is communicatively coupled to the dispensing module 300 and is configured to control the dispensing module 300 for activation.
  • the power source module 100 is electrically connected, and configured to provide power to the dispensing module 300 and the control module 200 respectively.
  • the dispensing mechanism by which the dispensing module dispenses the NMDAR pore blocker out of the first reservoir module can be by means of a microchip (Hilt JZ et al. 2005; Stevenson CL et al. 2012) , a micropump (Lo R et al. 2009; Joshitha C et al. 2017) , a microvalve (Nafea M et al. 2018) , a microprobe (Spieth S et al. 2014) , a microneedle (Kim YC et al. 2012) , a cantilever (Cheong HR et al. 2018) , or a shape memory alloy (Reynaerts D et al. 1997; Ali MSM et al. 2011) .
  • the disclosures of these above cited references are incorporated herein by reference in their entireties.
  • a pharmaceutically acceptable formulation refers to a formulation of a therapeutically active agent that is suitable for storage in a chosen medical device, delivery by a chosen route of administration, and is generally tolerated by the subject and exhibits an acceptable toxicity profile when administered at an appropriate dose.
  • a pharmaceutically acceptable formulation may comprise a therapeutically active agent and one or more pharmaceutically acceptable excipients (i.e. substances formulated alongside with the therapeutically active agent for storage, pharmacokinetic, pharmacodynamic, or other considerations) , and/or one or more pharmaceutically acceptable carriers (i.e. substances formulated alongside with the therapeutically active agent for efficient drug delivery consideration; e.g. liposome) .
  • the pharmaceutical acceptable formulation of ketamine contained in the first reservoir module of the implantable unit of the drug delivery system disclosed herein may be a liquid injectable solution comprising ketamine hydrochloride diluted in sterile water, 0.9%sodium chloride, or 5%dextrose.
  • the pharmaceutical acceptable formulation of the therapeutically active agent may be physically (i.e. via different packages) or mechanistically (i.e. dispensed from one single package) divided into a plurality of dosage forms, each containing one single dose.
  • the first reservoir module 400 in the implantable unit 1000 comprises a plurality of reservoirs, each accommodating one therapeutically effective dose of the NMDAR pore blocker, and the plurality of reservoirs can be arranged in an array or in a matrix.
  • the dispensing module 300 is configured, upon receiving the first activation command from the control module 200, to dispense the NMDAR pore blocker out of the plurality of reservoirs in the first reservoir module 400, one per time.
  • Each reservoir is provided with a capping membrane made of a biocompatible composition
  • the dispensing module 300 comprises a dispensing mechanism configured to break the capping membrane so as to allow the one therapeutically effective dose of the NMDAR pore blocker to be released out of the each of the plurality of reservoirs.
  • the drug delivery system 001 can realize a precise local release of the NMDAR pore blocker (i.e. therapeutically active agent) to the LHb region of the subject in a controllable and repeated manner.
  • the dispensing mechanism comprises an electrothermal activation mechanism
  • the capping membrane has a biocompatible and heat-responsive composition such as titanium (Ti) , platinum (Pt) or gold (Au) , etc.
  • the dispensing mechanism comprises an electrochemical activation mechanism
  • the capping membrane can have a composition of gold (Au) .
  • Au gold
  • the first reservoir module 400 in the implantable unit 1000 comprises one single reservoir
  • the dispensing module 300 is configured, upon receiving the first activation command from the control module 200, to operate on the first reservoir module 400 such that the NMDAR pore blocker is released out of the one single reservoir, one therapeutically effective dose per time.
  • a micropump e.g. infusion type, peristaltic type, thermopneumatic type, osmotic type, or positive displacement type; disclosed in Lo R et al. 2009; Sheybani R et al. 2015; Meng E et al. 2012; Au AK et al.
  • the implantable unit 1000 may further comprise a second reservoir module 420 accommodating a pharmaceutically acceptable formulation of a priming agent.
  • the dispensing module 300 is further operably coupled to the second reservoir module 420, and is further configured, upon receiving a second activation command from the control module 200, to dispense the priming agent out of the second reservoir module 420.
  • control module 200 is configured to control the dispensing module 300 to sequentially dispense the priming agent out of the second reservoir module 420 (so as to maximally open the pores of the NMDAR protein complexes in the LHb region for better access by the NMDAR pore blocker molecules) and dispense the NMDAR pore blocker out of the first reservoir module 400 (so as to locally provide the NMDAR pore blocker molecules to achieve the anti-depression effects on the recipient subject) .
  • the implantable unit 1000 may further comprise a third reservoir module 440 accommodating a pharmaceutically acceptable formulation of an enhancing agent.
  • the dispensing module 300 is further operably coupled to the third reservoir module 440, and is further configured, upon receiving a third activation command from the control module 200, to dispense the enhancing agent out of the third reservoir module 440.
  • the control module 200 is configured to control the dispensing module 300 to sequentially dispense the NMDAR pore blocker out of the first reservoir module 400 (so as to locally provide the NMDAR pore blocker molecules to achieve the anti-depression effects) and dispense the enhancing agent out of the third reservoir module 440 (so as to increase the duration of the therapeutic effects of the NMDAR pore blocker molecules) .
  • the implantable unit 1000 comprise all of the first, second and third reservoir modules 400, 420 and 440 as described above, and the control module 200 is configured to control the dispensing module 300 to sequentially dispense the priming agent out of the second reservoir module 420 (so as to maximally open the pores of the NMDAR protein complexes in the LHb region) , dispense the NMDAR pore blocker molecules out of the first reservoir module 400 (so as to locally provide the NMDAR pore blocker molecules) , and dispense the enhancing agent out of the third reservoir module 440 (so as to increase the duration of the therapeutic effects of the NMDAR pore blocker molecules) .
  • each of the second or third reservoir module 420 and 440 may exist as one single reservoir or may be divided into a plurality of reservoirs, each containing one therapeutically effective dose of the priming agent or enhancing agent, and the dispensing module 300 is further provided with a corresponding dispensing mechanism to thereby realize a controllable delivery of the priming agent and/or the enhancing agent.
  • Relevant description can reference to the description of the first reservoir module 400 provided above.
  • the implantable unit 1000 may further comprise a catheter module 500 with a drug delivery outlet arranged within, or in the proximity of, the LHb of the subject, and the catheter module 500 is distally and operably connected to the first reservoir module 400 (optionally also to the second reservoir module 420, and/or to the third reservoir module 440) .
  • the first, second and/or reservoir module 400, 420 and 440, along with other modules of the implantable unit 1000 i.e. the power source module 100, the control module 200, and the dispensing module 300
  • the implantable unit 1000 may be arranged in a distal position relative to the drug delivery outlet of the catheter module 500, such as beneath a scalp of the subject.
  • the configuration of this embodiment of the implantable unit 1000 is similar to the Ommaya reservoir (Zubair A et al. 2023; Liu HG et al. 2021) .
  • This distributed arrangement has multiple advantages.
  • the power source module 100 is close to the body surface, it allows for convenient battery replacement if a non-rechargeable battery is employed, or allows for optimized wireless energy transmission if a power receiver for wireless energy transmission is employed.
  • the power source module 100 comprises a first energy sub-module capable of storing energy, which can be a supercapacitor (Sheng H et al. 2021; Rita AA et al. 2021; US20150287544A1) or a battery (Bock DC et al. 2012; Yang SY et al. 2021) .
  • the battery can preferably include high-capacity, high-energy-density and long-lasting battery. Examples can include lithium batteries (e.g.
  • the drug delivery system 001 comprises an energy-storage device that can directly provide power source to other functional modules (i.e. the control module 200 and the dispensing module 300) .
  • the power source module 100 comprises a second energy sub-module capable of receiving power wirelessly from an external source, e.g. via electromagnetic waves or ultrasonic waves.
  • the drug delivery system 001 disclosed herein can be configured to realize a wireless power transfer/transmission (WPT; disclosed in Khan SR et al. 2020) , by which the implantable unit 1000 embedded in the recipient subject's brain can wireless receive power from outside, such as from a corresponding external power unit 3000 (see below for more details) .
  • WPT wireless power transfer/transmission
  • the power source module 100 comprises a third energy sub-module capable of harvesting energy from body of the subject, e.g. electrochemically (e.g. biofuel cells that can self-generate energy by glucose oxidation, disclosed in Zebda A et al. 2013; and Maity D et al. 2023) , thermoelectrically (e.g. thermoelectric energy generators providing solid-state energy by converting temperature differences into usable electricity; Janes T et al. 2021) , or piezoelectrically (e.g. energy generators providing energy harvested from heartbeats, blood flow or breathing; Jiang D et al. 2020) .
  • electrochemically e.g. biofuel cells that can self-generate energy by glucose oxidation, disclosed in Zebda A et al. 2013; and Maity D et al. 2023
  • thermoelectrically e.g. thermoelectric energy generators providing solid-state energy by converting temperature differences into usable electricity
  • the drug delivery system 001 further comprises an external power unit 3000 configured to wirelessly transfer energy to the power source module 100 in the implantable unit 1000.
  • the wireless energy transfer is by means of electromagnetic energy transfer (i.e. via the electromagnetic waves)
  • the power source module 100 in the implantable unit 1000 may comprise a power receiver
  • the external power unit 3000 may correspondingly comprise a power transmitter
  • the power receiver and the transmitter substantially form a pair of coupling antennas allowing the energy to be wirelessly transmitted from the external power unit 3000 to the implantable unit 1000, i.e. realizing the wireless power transmission (WPT) .
  • WPT wireless power transmission
  • the WPT comprises electromagnetic power transfer, which can further comprise one or more of a near-field ( ⁇ 100 mm) , a mid-field (100-500 mm; disclosed in Poon A et al. 2007) , or a far-field (>500 mm; disclosed in Huang FJ et al. 2011) WPT, each realized by a corresponding power transmitter-power receiver pair.
  • the WPT comprises a near-field WPT, which further optionally comprise at least one of an inductive coupling WPT (disclosed in Manoufali M et al. 2018; Feng P et al. 2018) , a capacitive coupling WPT (disclosed in Takhti M et al.
  • the wireless energy transfer is by means of ultrasonic energy transfer (i.e. via the ultrasonic waves)
  • the power receiver in the power source module 100 in the implantable unit 1000 and the power transmitter of the external power unit 3000 may both comprise a piezoelectric material, with the power transmitter electrically excited to generate the ultrasound, and the power receiver converting the ultrasound into electrical energy.
  • ultrasonic energy transfer can transmit energy in a range of a few mm up to about 100 mm (Agarwal K et al.
  • control module 200 is programmed to periodically send activation commands to the dispensing module 300 to thereby activate the dispensing module 300 for the delivery of the NMDAR pore blocker from the first reservoir module 400, and optionally of the priming agent from the second reservoir module 420, and/or of the enhancing agent from the third reservoir module 440 according to a program stored in the control module 200.
  • the program can be modified.
  • the drug delivery system further comprises an external control unit 2000, which is communicatively coupled, and configured to send control instructions, to the control module 200 of the implantable unit 1000, and the control module 200 is further configured, upon receiving one control instruction from the external control unit 2000, to send a corresponding activation command to the dispensing module 3000.
  • the external control unit 2000 is communicatively coupled to the implantable unit 1000 by means of a corresponding pair of antennas, one arranged on the external control unit 2000 and the other one on the implantable unit 1000.
  • the implantable unit 1000 there is only one-way communication between the implantable unit 1000 and the external control unit 2000, i.e., the control module 200 of the implantable unit 1000 is configured to only receive control instructions from the external control unit 2000, and as such, the antenna in the control module 200 can be configured only as a signal receiver, whereas the antenna in the external control unit 2000 is configured as a signal transmitter.
  • the external control module 2000 may further comprise a user interface allowing the subject or a doctor to manually prescribe the control instructions (e.g. instructions to deliver the NMDAR pore blocker) .
  • the external control module 2000 may be a mobile phone or an exclusive device.
  • the control module 200 may be configured to optionally transmit the state information that is collected from a sensing module 600 to the external control unit 2000 to thereby realize a data telemetry.
  • the antenna in each of the control module 200 and the external control unit 2000 is configured both as a signal receiver and a signal transmitter.
  • the sensing module 600 may optionally comprise an electrode for detecting the electrophysiological state of the LHb neurons, and/or may optionally comprise a sensor (e.g.
  • the external control module 2000 may similarly comprise a user interface allowing the subject or a doctor to manually prescribe the control instructions and allowing the state information collected by the sensing module 600 to be displayed to the subject or the doctor.
  • the external control module 2000 may be further communicatively connected to a cloud so as to upload the state information of the subject to the cloud for centralized processing.
  • there is no manual prescription and the external control module 2000 or the cloud server that communicatively connected to the external control module 2000 may, based on the state information collected from the sensing module 600, automatically make the prescription.
  • the external control module 2000 may send the control instruction to the control module 200 of the implantable unit 1000 to activate the sequential local drug delivery of the priming agent, the NMDAR pore blocker and the enhancing agent, so as to effectively control depression.
  • the implantable unit 1000 can be manufactured by fabricating the various components on a common platform (e.g. a printed circuit board (PCB) substrate or a silicon substrate) using sophisticated microelectronic integrated circuits technology, such as photolithography, etching, and bonding.
  • a common platform e.g. a printed circuit board (PCB) substrate or a silicon substrate
  • microelectronic integrated circuits technology such as photolithography, etching, and bonding.
  • ketamine as one NMDAR pore blocker.
  • Two remarkable characteristics of ketamine that make it attractive as a new antidepressant treatment are its rapid onset, and sustained activity.
  • a single intravenous infusion of a sub-anesthetic dose of ketamine in depressed patients produces antidepressant and anti-suicidal responses as quickly as an hour, and the effects can last for days (Berman RM et al. 2000) .
  • Regarding the rapid onset of ketamine’s actions much progress has been made in understanding its mechanism.
  • One recent study found that ketamine instantly blocks NMDAR-dependent bursting activity in the lateral habenula (LHb) Yang Y et al.
  • LHb inhibits the downstream aminergic reward center (Matsumoto M et al. 2007) and is hyperactive in the depressive state (Cerniauskas I et al. 2019) . Consequently, ketamine’s rapid blockade of LHb bursting can potentially disinhibit the downstream dopaminergic and serotonergic neurons to quickly improve mood (Yang Y et al. 2018) .
  • Ketamine’s elimination half-life is only approximately 3 h in humans (Clements JA et al. 1982) and 13 min in mice (Maxwell CR et al. 2006) , yet, its antidepressant activities can last for 3 ⁇ 14 d in humans (Berman RM et al. 2000; Newport DJ et al. 2015) and for at least 24 h in mouse models of depression (Maeng S et al. 2008; Autry AE et al. 2011) . This is in dramatic contrast to ketamine’s anesthetic effects, which quickly wear off in a few hours (White PF et al.
  • ketamine’s sustained effects were attributed to long-term plastic mechanisms (Maeng S et al. 2008; Autry AE et al. 2011) , especially new spine formation (Li N et al. 2010) or the ketamine metabolite (2R, 6R) -hydroxynorketamine (HNK) (Zanos P et al. 2016) .
  • ketamine-induced spine growth in mice cannot be detected until 12 hours post treatment (Moda-Sava RN et al. 2019) , and the half-life of (2R, 6R) -HNK is still less than 30 minutes (Zanos P et al. 2019) , not much longer than that of ketamine.
  • mice Male adult (8–16 weeks of age) C57BL/6 mice (SLAC or Shanghai Jihui) were used. Mice were group-housed four per cage under a 12-h light-dark cycle (light on from 7 a.m. to 7 p.m. ) with free access to food and water ad libitum. All animal studies and experimental procedures were approved by the Animal Care and Use Committee of the animal facility at Zhejiang University.
  • Chronic restraint stress (CRS) . Mice were subjected to chronic-restraint stress by placement in 50-ml conical tubes with holes for air flow for 2–4 h per day for 14 consecutive days (Yang Y et al. 2018) .
  • AAV2/9-hSyn-ChrimsonR-tdTomato-WPRE-SV40-pA (titre: 2.27 ⁇ 10 13 v. g. ml -1 , 1:10 dilution, 0.1-0.2 ⁇ l bilateral into LH, Taitool)
  • AAV2/9-hSyn-mCherry-WPRE-pA (titre: 1.53 ⁇ 10 13 v.g. ml -1 , 1: 10 dilution, 0.1-0.2 ⁇ l bilateral into LH, Taitool) were aliquoted and stored at -80 °C until use.
  • mice were deeply anaesthetized by 1%sodium pentobarbital (100 mg kg -1 body weight, Sigma) and placed in a stereotactic frame (RWD Instruments) .
  • the virus was bilaterally injected into the LH (0.1-0.2 ⁇ l) (AP, -0.82 mm from bregma; ML, ⁇ 1.08 mm; DV, -4.90 mm from the dura) using a pulled glass capillary with a pressure microinjector (Picospritzer III, Parker) at a rate of 0.1 ⁇ l min -1 .
  • the injection needle was withdrawn 10 min after the end of the injection.
  • Optical fibers (200 ⁇ m width) were implanted above LHb (AP, -1.72 mm from bregma; ML, ⁇ 1.14 mm; DV, -2.40 mm from the dura) at a 15° angle in the ML direction. After surgery, mice recovered from anaesthesia on a heat pad. Mice were euthanized after all experiments to verify the sites of viral injection and optical fiber implantation. Brain sections were cut at 60 ⁇ m thickness (Leica CM1950) and counterstained with DAPI or Hoechst. Fluorescent image acquisition was performed with the Olympus VS120 virtual microscopy slide scanning system. Only data from mice with correct injections sites were used.
  • Forced swim test (FST) . Forced swim test were used to model behavioral despair, as previous study (Yang Y et al. 2018) . Mice were individually placed in a cylinder (12 cm diameter, 25 cm height) of water (23-25 °C) and swam for 6 min. The test was performed in normal light conditions (30-35 lux) . Water depth was set to prevent animals from touching the bottom with their tails or hind limbs. Animal behaviors were videotaped from the side. The immobile duration during the 2-6 min test was counted offline by an observer blinded to animal treatment. The immobile duration was defined as the time when animals remained floating or motionless with only movements necessary for keeping balance in the water.
  • Sucrose preference test was used to model anhedonia or inability to feel pleasure, as previous study (Yang Y et al. 2018) . Mice were single housed and habituated with two bottles of water for 2 days, followed by two bottles of 2%sucrose for another 2 days. Then after a 24 h water deprivation, animals were exposed to one bottle of 2%sucrose and one bottle of water for 2 h in the dark phase. Bottle positions were switched 1 h after test started. Total consumption of each fluid was measured and sucrose preference was defined as the average of sucrose consumption ratios during the first and second hours. The sucrose consumption ratio was calculated by dividing the total consumption of sucrose by the total consumption of both water and sucrose.
  • RTPA Real-time place aversion
  • a double guide cannulae (centre-to-centre distance 1 mm, RWD) was placed, and inserted bilaterally into the LHb (AP, -1.80 mm from bregma; ML, ⁇ 0.50 mm; DV, -2.65 mm from the dura) of mice.
  • LHb LHb
  • ML ⁇ 0.50 mm
  • DV -2.65 mm from the dura
  • a double dummy cannulae (RWD) secured with a dust cap, was inserted into the guide cannula to prevent clogging during the recovery period.
  • mice had recovered for at least 7 days drugs were microinjected with a double injector cannula, while mice were anaesthetized with isoflurane (RWD) on an anaesthetic machine.
  • Behavioral tests were performed 1 h or 24 h after memantine infusion and 24 h, 7 d or 14 d after ketamine infusion.
  • 0.2 ⁇ l CTB-488 Invitrogen was injected to each side of the LHb after all behavioral tests. Mice were then euthanized 30 min after CTB injection for immunostaining. Brain slices were counterstained with Hoechst before mounting on the slides. Fluorescent image acquisition was performed with the Olympus VS120 virtual microscopy slide scanning system. Only data from mice with correctly sited injections were used.
  • mice Male mice were anaesthetized by isoflurane and subsequently decapitated 2 min, 5 min, 10 min, 30 min, 1 h, 4 h and 24 h after ketamine administration (i.p. ) .
  • Blood was collected in EDTA-containing (30 mg ml -1 ) tubes and centrifuged at 2000rpm for 10 min (4 °C) .
  • Plasma was collected and stored at -80 °C until analysis.
  • Whole brain tissues (about 0.4-0.5 g) were immediately collected in the EP tubes. The tissues were immediately frozen in liquid nitrogen and stored at -80 °C until analysis.
  • the mobile phase consisted of 0.1%formic acid buffer as component A and acetonitrile as component B at a flow rate of 0.35 ml/min, temporized at 10 °C (injection volume: ketamine 10 ⁇ l) .
  • a linear gradient was run as follows: 0-0.5 min, 10%B; 0.5-1.5 min, from 10%B increased to 90%B; 1.5-2.5 min, 90%B; 2.5-2.51 min, from 90%B decreased to 10%B; 2.51-3.5 min, 10%B.
  • the MS/MS analysis was performed using waters TQ-Smicro. Positive electrospray ionization data were acquired using multiple reaction monitoring (MRM) using the following transitions for (R, S) -ketamine studies: 238.096 ⁇ 124.987.
  • LHb brain slices were made from mice expressing ChrimsonR (Chuong et al. 2014) in the LH, a 635 nm, 40 Hz, 0.5 mW, 2 ms duration pulsed (4 pulses) red light was delivered to activate LH-LHb axon terminals.
  • a 635 nm red light was bilaterally delivered into the LHb through optical fibers at 40 Hz, 2 ms pulse, 250 ⁇ W by laser (Inper) when mice entered the stimulated-side chamber.
  • mice were anaesthetized by 1%sodium pentobarbital (100 mg kg -1 body weight, Sigma) , and then perfused with 20 ml ice-cold ACSF (oxygenated with 95%O 2 + 5%CO 2 ) containing (mM) : 125 NaCl, 2.5 KCl, 25 NaHCO 3 , 1.25 NaH 2 PO 4 , 1 MgCl 2 , 2 CaCl 2 and 25 glucose, with 1 mM pyruvate added. The brain was removed as quickly as possible after decapitation and put into chilled and oxygenated ACSF.
  • ACSF oxygenated with 95%O 2 + 5%CO 2
  • Coronal (for spontaneous neuronal activity recording) or sagittal (for eEPSCs recording) slices containing the LHb or hippocampal CA1 were sliced into 300 ⁇ m sections in cold ACSF using the Leica VT1200S vibratome and then transferred to ASCF at 32 °C for incubation and recovery. ACSF was continuously gassed with 95%O 2 and 5%CO 2 . Slices were allowed to recover for at least 1 h before recording. CRS mice and mice both went through an FST at least 1 day before brain slice recording and we only used the CRS animals that showed high immobile duration (>120 s) and the animals that showed low immobile duration ( ⁇ 120 s) in the FST for slice recording.
  • the external ACSF solution containing (mM) 125 NaCl, 2.5 KCl, 25 NaHCO 3 , 1.25 NaH 2 PO 4 , 1 MgCl 2 , 2 CaCl 2 and 25 glucose.
  • Cells were visualized with infrared optics on an upright microscope (BX51WI, Olympus) .
  • a MultiClamp 700B amplifier controlled by DigiData 1550 digitizer and pCLAMP10 software were used for electrophysiology (Axon Instruments) .
  • the series resistance and capacitance were compensated automatically after a stable Gigaseal was formed. Recordings were typically performed between 3 and 10 min after the break-in.
  • LHb neurons show three modes of spontaneous activity at resting conditions.
  • Silent cells showed no spike activity during recording.
  • Tonic cells spontaneously generated tonic trains of action potentials.
  • Burst cells spontaneously generated clusters of spikes with an initially high but progressively declining intra-burst firing frequency in each burst. After membrane potential stabilized, 3 minutes of data were collected to calculate bursting spike frequency and bursts per min. Bursting spike frequency was calculated as the spike number of bursting spikes per second. Bursts per min was calculated as the number of bursts per minute.
  • Percentage of blockade (average value of saline group –value of ketamine group) / average value of saline group*100%
  • Evoked EPSCs were recorded under voltage clamp at -70 mV or + 40 mV in sagittal LHb slices by stimulating the input stria medullaris fiber in a modified extracellular ACSF solution with GABA A R blocker picrotoxin (PTX, 100 ⁇ M, TOCRIS) .
  • Stimulation pulse (0.25-1.50 mA; 0.2 ms; step by 0.25 mA) were delivered every 6-10 s.
  • Cells were first held at -70 mV to record electrically evoked fast AMPAR-mediated currents (AMPAR-eEPSCs) .
  • NMDAR-eEPSCs AMPAR-and slower NMDAR-mediated currents
  • AMPAR-eEPSCs AMPAR-and slower NMDAR-mediated currents
  • More than three traces were averaged at each stimulation intensity and holding potential.
  • AMPAR-eEPSCs were determined by the peak current amplitude at -70 mV.
  • NMDAR-eEPSCs were determined by the current amplitude 35 ms after stimulation onset at + 40 mV.
  • NMDA/AMPA ratios were determined by dividing the NMDAR-eEPSCs by the AMPAR-eEPSCs at 1.5 mA stimulation intensity.
  • the percentages of neurons with > 10 pA NMDAR-eEPSCs were calculated at 1.5 mA stimulation intensity.
  • AMPARs in the LHb mostly lack the GluR2 subunit, and consequently AMPAR-eEPSCs show strong inward rectification and fast decay (Cerniauskas I et al. 2017) , much faster than NMDAR-eEPSCs.
  • mixed NMDAR-and AMPAR-eEPSCs were recorded at + 40 mV with ACSF containing PTX (100 ⁇ M, TOCRIS) . 10 ⁇ M NBQX (AMPAR blocker, Sigma) was then perfused into the recording solution to block AMPAR currents.
  • NMDAR blocker (NMDAR blocker, Sigma) was further added and perfused into the recording solution to block NMDAR currents.
  • the current amplitude detected at 35 ms at +40 mV was significantly blocked by AP5, but showed no difference in the presence or absence of NBQX, suggesting that AMPAR-eEPSCs have mostly decayed by 35 ms (FIG. 6A) .
  • the pure NMDAR-eEPSCs in LHb neurons 1 h or 24 h after ketamine i.p. injection were recorded at + 40 mV by pharmacological isolation method (with NBQX and PTX in recording ACSF to block AMPARs and GABA A Rs respectively) .
  • NMDAR-eEPSCs were calculated by the peak amplitude at this recording condition.
  • evoked NMDAR-eEPSCs were recorded under voltage clamp at -70 mV in a modified extracellular ACSF solution with NBQX (10 ⁇ M, Sigma) to block AMPARs and PTX (100 ⁇ M, TOCRIS) to block GABARs. Recordings were made in ACSF containing no added Mg 2+ to reduce the Mg 2+ blockade of NMDARs. Stimulation intensity (0.1 ⁇ 0.3 ms, 0.1 ⁇ 5 mA) was adjusted for each cell to produce adequate responses. LHb neurons with an NMDAR-eEPSCs less than 10 pA were not used in the wash-out experiments. Stimulation pulses were delivered every 10 s.
  • NMDAR-eEPSCs were normalized by the baseline before drugs application.
  • the normalized NMDAR-eEPSCs at the end of drug perfusion (at 10 min) were calculated to show the degrees of drug blockade (FIG. 7B) and the averaged normalized NMDAR-eEPSCs at 50-60 min to show the degrees of responses recovery (FIGS. 7B and 10B) .
  • Amount of blockade was calculated in a 10-min bin and the maximal one was taken as the maximal blockade. Note that due to trapping effect, the maximal blockade could occur after the end of the 10 min wash-in period (FIGS. 11A-11D) . The percentage of recovery was calculated as: maximal blockade -blockade at 50-60 min (FIGS. 11A-11D) .
  • the input resistance during recording was monitored by 20 mV potential injection.
  • Dyngo-4a (ApexBio) was additionally added to the recording ACSF in LFS-induced LTD of NMDAR experiments and washout experiments (Dankovich TM et al. 2021) .
  • Dyngo-4a (ApexBio) was additionally added to the recording ACSF in LFS-induced LTD of NMDAR experiments and washout experiments (Dankovich TM et al. 2021) .
  • in vitro “kick off” experiments 10 min after ketamine washout, two “kick off” sessions (pairing presynaptic 1 Hz electrically stimulation with 3 s postsynaptic depolarization to +10 mV, 3 s pairing per min, 5 min per session, 30 spikes total) with 4 min interval were performed to cells in the “kick off” group.
  • Spontaneous spiking activity and wideband electronic signals were recorded by a neural recording system (Plexon Inc. ) and digitized at 40 kHz with a gain of 1000 ⁇ .
  • Spontaneous spiking signals were band-pass filtered between 300 and 6000 Hz.
  • Common median reference (CMR) was assigned as a digital reference. The amplitude threshold for the spike capture was adjusted for each unit according to the signal-to-noise ratio.
  • Spontaneous spiking signals of the mice were recorded for 10 min after habituation in their home cages as the baseline. Spiking signals were continuously recorded for 1 h after ketamine treatment (10 mg kg -1 , i.p. ) with headstage un-removed.
  • Paired statistical method was used for the 0-1 h data. For data collected at 24 h or 3 d after ketamine treatment, since animals need to return to homecage for rest, headstage was removed and remounted. Once the headstage is removed and remounted, there is some probability of slight shift of the recording electrode, and the number of units may also change. Therefore, we defined the units before and after the headstage reset as different units and used an unpaired statistical method for the 24 h and 3 d data. The electrodes were lowered in steps of 62.5 ⁇ m after each recording session, followed by at least a 3-day recovery. If mice received a second ketamine injection, at least a one-week interval was introduced before the next recording session. The CRS animals showing high immobile duration (>120 s) in the FST were used in in vivo recording. The positions of the electrodes were verified at the end of all experiments and only data from mice with correct electrode positions were used.
  • ⁇ and ⁇ were the mean and the standard deviation (SD) of all the 100 s-bin values during the baseline period (i.e., 10 min before drug injection) .
  • Example 1 Sustained behavioral effects of ketamine
  • Depressive-like behaviors were measured by both the forced swim test (FST) , which models behavioral despair, and the sucrose preference test (SPT) , which models anhedonia or the inability to feel pleasure.
  • FST forced swim test
  • SPT sucrose preference test
  • LHb neurons are intrinsically active and can be categorized into silent, tonic firing and burst firing types (FIG. 1E) .
  • the proportion of bursting neurons was significantly higher in CRS mice compared with mice (Yang Y et al. 2018) (FIG. 1F, FIG. 3A) .
  • the percentage of bursting neurons dropped from 40%in saline group to 13%in ketamine group (P ⁇ 0.0001, Chi-square test; FIG. 1F) .
  • NMDAR-eEPSCs of the ketamine group showed strongly reduced amplitudes across a range of stimulation intensities compared to the saline group (FIG. 5E) .
  • the levels of NMDAR-eEPSC inhibition (see Methods for calculation) in the LHb at 1 h, 24 h and 3 d after ketamine injection were 81.5 ⁇ 4.4 %, 55.0 ⁇ 11.3 %, and -1.2 ⁇ 25.8%, respectively (FIG. 6G) , again, paralleling the time course of ketamine’s behavioral effects.
  • FIG. 6G To further confirm the persistent blockade of NMDAR by ketamine, we pharmacologically isolated the pure NMDAR-eEPSCs in the LHb of CRS mice in the presence of both GABA A R blocker picrotoxin (PTX) and AMPAR blocker NBQX. The pharmacologically isolated NMDAR-eEPSCs also showed a significant blockade at 24 h after ketamine i.p. injection (FIGS. 5O-5R) .
  • NMDAR-eEPSCs were pharmacologically isolated at -70 mV (in the absence of magnesium to remove magnesium blockade of NMDARs, see Methods, FIG. 7A) .
  • ketamine 100 ⁇ M
  • memantine 100 ⁇ M
  • the memantine-blocked NMDAR-eEPSCs quickly recovered, and by 50 min, only 19.9 ⁇ 18.2%reduction remained (FIG. 7B) .
  • the ketamine-blocked NMDAR-eEPSCs continued to be blocked after ketamine washout, and by 50 min, the reduction of NMDAR-eEPSCs currents was still as large as 82.7 ⁇ 4.7% (FIG.
  • Dyngo-4a an NMDAR endocytosis inhibitor, which could effectively suppress low-frequency stimulation (LFS) -induced endocytosis of hippocampal NMDAR-eEPSCs (FIG. 9A) (Montgomery, J. M., 2005) .
  • LFS low-frequency stimulation
  • FIG. 9A shows that LHb NMDAR-eEPSCs still did not recover after either 100 uM or 10 uM ketamine washout (FIGS. 9B-9E) , suggesting that the persistent suppression of NMDAR-eEPSCs in the LHb after ketamine washout is not due to endocytosis.
  • the post-synaptic NMDARs are shown to be transiently exposed to glutamate for only 1 ⁇ 2 ms (Clements JD et al. 1992) , and the duration of channel open time is less than 10 ms (Buck DP et al. 2000) .
  • ketamine Another factor that could possibly contribute to ketamine’s extended action time in vivo is delayed diffusion (Katz B et al. 1973) . Unlike transmitters which have transporter-based clearance mechanism, ketamine could likely rebind to unbound NMDARs receptors multiple times as it is released and diffuses out of the synaptic clefts or extracellular spaces where astrocytic endfeet tightly wrap around neurons (Cui Y et al. 2018) . Given the difference in wash off experiments between memantine and ketamine (FIGS. 7A-7M) , such lateral diffusion seems unlikely to be the major explanation for the sustained effects, but may nevertheless contribute to the extended action time.
  • the apparent k off of ketamine in vivo can be much longer than the previously measured in-solution k off . Therefore once bound, a significant amount of ketamine is trapped, isolating it from metabolic degradation and sustaining its antidepressant effects.
  • NMDAR inhibitors have distinct inhibition mechanisms (e.g. competitive binding, allosteric binding vs. pore trapping) (Lodge D et al. 1990; Traynelis SF et al. 2010) , pharmacokinetic and pharmacodynamic features. As illustrated in this study, even an NMDAR inhibitor that shares similar trapping mechanism and similar binding affinity as ketamine but a faster off rate –memantine (Parsons CG et al. 1995) –can have less optimal and less lasting antidepressant effects (Gideons ES et al. 2014; Zarate CA et al. 2006) (FIGS. 7A-7M) . These results demonstrate that the unique pharmaceutical features of ketamine are critical for its antidepressant effects, and optimization of these properties is a promising new direction for developing new antidepressant treatments.

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Abstract

La divulgation concerne une méthode pour améliorer les effets antidépresseurs d'un bloqueur de pore du récepteur NMDAR, comprenant : (1) la mise en œuvre, avant l'administration de l'inhibiteur de pore du récepteur NMDAR ou dans un délai d'une demi-vie plasmatique après celle-ci, de mesures comportementales, pharmaceutiques ou physiques visant à permettre l'ouverture des canaux ioniques d'une plus grande proportion des molécules du récepteur NMDAR dans l'habénula latérale (LHb); et éventuellement, (2) la mise en œuvre, après l'administration de l'inhibiteur de pore du récepteur NMDAR, de mesures comportementales, pharmaceutiques ou physiques visant à empêcher ou à réduire le détachement des molécules du récepteur NMDAR de l'inhibiteur de pore du récepteur NMDAR. La divulgation concerne également des régimes thérapeutiques et des combinaisons pharmaceutiques permettant de traiter efficacement la dépression. La divulgation concerne en outre un système d'administration de médicament comprenant une unité implantable permettant une administration régulable, répétée, précise et in vivo d'un bloqueur des pores du récepteur NMDAR et d'un agent d'amorçage et/ou d'amélioration dans la région LHb du cerveau d'un sujet pour ainsi obtenir des effets thérapeutiques améliorés.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006121560A2 (fr) * 2005-04-06 2006-11-16 Adamas Pharmaceuticals, Inc. Procedes et compositions pour le traitement des pathologies associees au systeme nerveux central
WO2012070034A1 (fr) * 2010-11-26 2012-05-31 University Of The Witwatersrand, Johannesburg Dispositif d'administration de médicament
WO2015171770A1 (fr) * 2014-05-06 2015-11-12 Northwestern University Combinaisons de composés modulant nmdar
US20150342947A1 (en) * 2014-05-30 2015-12-03 West Virginia University Ketamine or dextromethorphan formulations and methods of use
US20170258779A1 (en) * 2014-07-31 2017-09-14 Ru-Band Lu Combination therapy for bipolar disorder
WO2018205935A1 (fr) * 2017-05-09 2018-11-15 浙江大学 Méthode de traitement de la dépression, et composition pharmaceutique
CN108853510A (zh) * 2017-05-09 2018-11-23 浙江大学 Nmdar抑制剂和t型钙离子通道抑制剂的组合对抑郁症的治疗和药物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006121560A2 (fr) * 2005-04-06 2006-11-16 Adamas Pharmaceuticals, Inc. Procedes et compositions pour le traitement des pathologies associees au systeme nerveux central
WO2012070034A1 (fr) * 2010-11-26 2012-05-31 University Of The Witwatersrand, Johannesburg Dispositif d'administration de médicament
WO2015171770A1 (fr) * 2014-05-06 2015-11-12 Northwestern University Combinaisons de composés modulant nmdar
US20150342947A1 (en) * 2014-05-30 2015-12-03 West Virginia University Ketamine or dextromethorphan formulations and methods of use
US20170258779A1 (en) * 2014-07-31 2017-09-14 Ru-Band Lu Combination therapy for bipolar disorder
WO2018205935A1 (fr) * 2017-05-09 2018-11-15 浙江大学 Méthode de traitement de la dépression, et composition pharmaceutique
CN108853510A (zh) * 2017-05-09 2018-11-23 浙江大学 Nmdar抑制剂和t型钙离子通道抑制剂的组合对抑郁症的治疗和药物

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