Out of the Pipeline

Intranasal esketamine

Gregory W. Mattingly, MD, and Richard H. Anderson, MD, PhD

reatment-resistant depression (TRD) is Table 1 This glutamatergic a common clinical struggle that prac- Fast facts about intranasal agent is approved Tticing clinicians address on a daily esketamine as an adjunctive basis. Major depressive disorder affects Brand name: Spravato therapy for nearly 1 in 5 Americans at some point in Class: N-methyl-d-aspartate receptor patients with their life and, by definition, impairs social antagonist treatment-resistant and occupational functioning. Historic treat- Indication: Adjunctive therapy for adults with ments have focused on the monoamine treatment-resistant depression depression theories of depression—modulating the Approval date: March 5, 2019 monoamines serotonin, norepinephrine, Availability date: March 18, 2019 and/or dopamine. Limitations of currently Manufacturer: Janssen Pharmaceuticals, Inc., Titusville, NJ available antidepressants include delayed Dosing forms: 28 mg per intranasal device onset of effect and low remission rates. To further complicate the matter, numerous Recommended dosage for treatment- resistant depression studies have shown that with each subse- • Induction phase. Weeks 1 to 4: quent antidepressant trial, patients have a Day 1 starting dose 56 mg (2 devices). decreasing likelihood of responding to sub- Subsequent doses 56 or 84 mg (2 or 3 sequent antidepressant treatment options. devices) twice weekly For example, in the classic STAR*D trial, by • Maintenance phase. Weeks 5 to 8: Once weekly, either 56 or 84 mg per session. the time a patient had not responded to the Weeks 9 and after: Weekly or bi-weekly at first 2 antidepressant options, the chance that 56 mg or 84 mg per session they would respond to a third or fourth anti- • Long-term treatment. Weekly, bi-weekly, depressant had decreased to approximately or once monthly at 56 or 84 mg per session 15% per antidepressant treatment course.1 Source: Reference 2 To address the need for new treatments for patients with TRD, on March 5, 2019 the FDA-approved intranasal esketamine Dr. Mattingly is Associate Clinical Professor, Washington University (brand name: Spravato) (Table 12) follow- School of Medicine, and President, Midwest Research Group, St. Louis, ing the evaluation of its efficacy through Missouri. Dr. Anderson is Clinical Instructor, Washington University School of Medicine, and Principal Investigator, Midwest Research short-term clinical trials and a longer-term Group, St. Louis, Missouri. maintenance-of-effect trial. Intranasal esket- Disclosures amine is indicated, in conjunction with an Dr. Mattingly receives grant/research support from Akili, Alkermes, Allergan, Boehringer, Janssen, Medgenics, NLS-1 Pharma AG, Otsuka, oral antidepressant, for adult patients with Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, and Takeda; is a TRD.2 Esketamine is a CIII controlled sub- consultant to Akili, Alkermes, Allergan, Axsome, Ironshore, Intracellular, Janssen, Lundbeck, Otsuka, Neos, Purdue, Rhodes, Sage, Shire, stance, and concerns about abuse, misuse, Sunovion, Takeda, and Teva; and is a speaker for Alkermes, Allergan, and diversion have been taken into account Janssen, Lundbeck, Otsuka, Sunovion, and Takeda. Dr. Anderson receives grant/research support from Akili, Alkermes, Allergan, within the Risk Evaluation and Mitigation Boehringer, Janssen, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Current Psychiatry Strategy (REMS) drug safety program. The Benckiser, Roche, Sage, Sunovion, Supernus, and Takeda. Vol. 18, No. 5 31 Out of the Pipeline

agent is only available through a restricted adjunctive treatment for TRD. Esketamine distribution—the REMS will mandate blocks NMDA receptors on GABA inter- that REMS certified pharmacies dispense neurons. This allows for increased pulsa- directly to a REMS certified treatment pro- tile release of glutamate into the synapse. gram. Intranasal esketamine will not be Intrasynaptic glutamate then stimulates sampled or dispensed directly to patients. postsynaptic AMPA receptors. Glutamate stimulation of postsynaptic AMPA recep- How it works tors results in an intracellular cascade that Modern research has looked beyond the activates the enzymes tropomyosin recep- monoamine system to explore the neuro- tor kinase B (TrkB) and mammalian target modulatory effects of glutamate and of rapamycin (mTOR). TrkB stimulation gamma-aminobutyric acid (GABA).3 The results in increased production and release Clinical Point yin and yang of glutamate and GABA of BDNF. mTor stimulation increases neu- Esketamine’s revolves around neural excitation vs neu- ronal membrane protein formation with ral inhibition at a local synaptic level. subsequent increased neural plasticity. inhibition of the The primary effects of the glutamate and Taken together, preclinical models show NMDA receptor GABA systems (Table 2, page 33) can be that esketamine’s inhibition of the NMDA on the GABA broken down into several key areas of receptor on the GABA interneuron results interneuron results understanding. in a cascade of increased BDNF release and Glutamate modulates ionotropic synaptogenesis with increased neuroplas- in BDNF release and N-methyl-d-aspartate (NMDA) and α-amino- ticity (Table 3, page 34). synaptogenesis 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and a family of non- Clinical implications ionic metabotropic receptors, or mGluRs. Treatment-resistant depression affects Glutamate stimulation of NMDA or AMPA nearly one-third of patients currently receptors increases Ca2+ ion influx and receiving standard antidepressant treat- enhances neural firing. Conversely, GABA ment. Major depressive disorder is cur- stimulation increases Cl– ion influx, which rently the second leading cause of disability inhibits neural firing. Antagonizing glu- for working adults within the United States tamate receptors inhibits neural firing. and one of the largest causes of disability N-methyl-d-aspartate receptors local- worldwide. The esketamine nasal spray ized on the GABA interneuron modu- could be beneficial for patients who have late GABAergic activity. Antagonism of experienced TRD with standard mono- the NMDA receptor on GABA interneu- amine antidepressants. rons decreases GABA activity. Decreased activity of the GABA interneuron pro- Supporting evidence motes intrasynaptic glutamate release Clinical trials examining intranasal esket- and enhances glutamate stimulation of amine include both short- and long-term postsynaptic AMPA receptors. Glutamate studies of patients with TRD. stimulation of AMPA receptors then stim- Esketamine was evaluated in a random- ulates a cascade of intrasynaptic signaling ized, placebo-controlled, double-blind, Discuss this article at that promotes the release of brain-derived multicenter, short-term (4-week) phase III www.facebook.com/ neurotrophic factor (BDNF) and increased study in adult patients age 18 to 65 with MDedgePsychiatry production of neuronal membrane pro- TRD (they had not responded to at least 2 teins with subsequent neural plasticity. different antidepressants of adequate dose Esketamine, the S-enantiomer of and duration).4 After discontinuing prior ketamine, has a higher affinity for the antidepressant treatments, all patients were NMDA receptor than the R-enantiomer started on a newly initiated antidepressant Current Psychiatry 32 May 2019 and has been developed as an intranasal and were also randomized to concomitant Out of the Pipeline

intranasal esketamine or intranasal placebo Table 2 as follows: Key facts: Glutamate and GABA • 114 patients were randomized to the Glutamate modulates ionotropic NMDA and intranasal esketamine plus newly initiated AMPA receptors and a family of non-ionic oral antidepressant arm metabotropic receptors • 109 patients were randomized to the Glutamate stimulation of NMDA or AMPA placebo nasal spray plus newly initiated increases Ca2+ influx and stimulates neural oral antidepressant arm firing - • The mean baseline Montgomery- GABA stimulation increases Cl influx, which inhibits neural firing Åsberg Depression Rating Scale (MADRS) Antagonizing glutamate activation decreases score for each group was 37 (ie, moderately neuronal firing to severely depressed). Decreased stimulation of GABA interneuron Newly started antidepressants included shuts off the brake on glutamate release and Clinical Point escitalopram, sertraline, duloxetine, or allows increased stimulation of post-synaptic In a long-term, extended-release venlafaxine. Esketamine AMPA receptor intranasal spray was initiated at 56 mg and AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic maintenance-of- acid; GABA: gamma-aminobutyric acid; NMDA: N-methyl- could be titrated up to 84 mg at the sec- d-aspartate effect trial, patients ond dose, based on investigator discretion. receiving esketamine The mean age was 47; 62% of the patients experienced a were female, 93% were White, and 5% significantly longer were black. The newly initiated oral anti- After 16 weeks of intranasal esketamine depressant was a selective serotonin reup- plus an oral antidepressant, stable remit- time to relapse take inhibitor in 32% of patients and an ters and stable responders were then serotonin-norepinephrine reuptake inhibi- randomized separately to continue intra- tor in 68% of patients. The time course nasal esketamine or switch to placebo of response for this 4-week, short-term nasal spray, with both groups continuing treatment study is illustrated in Figure 12 on their concomitant oral antidepressant. (page 35). While the primary efficacy mea- The primary study endpoint was time to sure was improvement of MADRS score relapse. Relapse was defined as a MADRS at Week 4, the majority of the placebo- total score >22 for more than 2 consecu- active drug separation occurred 24 hours tive weeks, hospitalization for worsening after the initial 56 mg dose of esketamine. of depression, or any other clinically rel- Between 24 hours and Day 28, intranasal evant event. The median age was 48, 66% esketamine showed continued separation were female, 90% were White and 4% were from antidepressant plus placebo nasal black. Patients in stable response or stable spray. Investigators could increase both remission experienced a significantly lon- placebo nasal spray or esketamine, with ger time to relapse compared with patients 67% of patients receiving 84 mg twice who continued their oral antidepressant weekly at Day 28. but were switched to placebo intranasal A long-term, double-blind multicenter spray. In this remission response study, maintenance-of-effect trial examined adults patients could receive intranasal treatment age 18 to 65 with TRD.5-6 Patients in this weekly or bi-weekly based on symptom study were responders in 1 of 2 short-term severity (Figure 2,2 page 36). studies or in an open-label direct enroll- ment study. Stable remission was defined Impact on driving. Two studies exam- as a MADRS total score <12 for at least 3 ined the impact of esketamine on driving of the last 4 weeks of the study, and sta- performance. One examined adults with ble response was defined as a MADRS major depressive disorder and the other Current Psychiatry reduction of >50% but not in remission. examined healthy participants. The effects Vol. 18, No. 5 33 Out of the Pipeline

Table 3 Pharmacologic profile Actions of esketamine Adverse events. The most common adverse events in patients treated with Inhibits the NMDA receptor on the GABA interneuron esketamine nasal spray were dissociation Causes decreased stimulation of GABA (41%), dizziness (29%), nausea (28%), seda- interneuron tion (23%), and vertigo (23%).2 The major- Allows increased pulsatile release of glutamate ity of these effects were short-term and Glutamate then stimulates post-synaptic AMPA resolved during the 2-hour observation receptors period. AMPA stimulation turns on TrkB and mTOR In addition to spontaneously reported enzymes events, sedation and dissociation were fur- • TrkB stimulation increases BDNF release ther monitored with specific scales. Sedation Clinical Point • mTOR stimulation increases neural was measured with the Modified Observer’s plasticity Alertness and Sedation Scale. Using this The most common AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF: brain-derived neurotrophic factor; GABA: scale, 50% of patients receiving 56 mg and adverse events in gamma-aminobutyric acid; mTOR: mammalian target 61% of patients receiving 84 mg of esket- of rapamycin; NMDA: N-methyl-d-aspartate; TrkB: patients treated tropomyosin receptor kinase B amine met criteria for sedation. with esketamine Similarly, dissociation/perceptional were dissociation, changes were measured with spontane- ously reported events and also with the dizziness, nausea, of a single 84-mg dose of esketamine nasal Clinician Administered Dissociative State sedation, and vertigo spray on a patient’s ability to drive was Scale. On this scale, 61% of patients receiv- assessed in 23 healthy adults. In this study, ing the 56-mg dose, and 69% of patients mirtazapine was used as an active con- receiving the 84-mg dose met criteria for trol. Driving performance was assessed at dissociation/perceptional changes after 8 hours after treatment with esketamine dose administration. nasal spray or mirtazapine. Driving per- Increases in blod pressure. Esketamine formance 8 hours after esketamine nasal intranasal spray was associated with a 7 to spray was similar to placebo and active 9 mm Hg increase in systolic blood pressure control. Two participants discontinued the and a 4 to 6 mm Hg increase in diastolic driving task after receiving esketamine blood pressure, both of which peaked 40 due to post-dose adverse reactions. One minutes post-dose. reported pressure behind the eyes and par- Nausea and vomiting. Intranasal esket- esthesia of the hands and feet. The other amine was associated with a 27% rate of reported headache and light sensitivity nausea at 56 mg, and 32% at 84 mg, with with anxiety. a 6% rate of vomiting at 56 mg and 12% at A second study evaluated the effects 84 mg. of repeated esketamine administration on driving performance in 25 adults with Pharmacokinetics major depressive disorder. In this study, Esketamine exposure increases from 28 to an ethanol-containing beverage was used 84 mg in a fairly dose-proportional range. as an active control. After administration No accumulation of esketamine was of a single 84-mg dose of intranasal esket- observed in the plasma following twice- amine, driving performance was the same weekly administration. Bioavailability is as a placebo at 18 hours. In the multiple approximately 48% following nasal admin- dose phase, standard driving performance istration. The Tmax for esketamine plasma was similar for esketamine nasal spray concentration is 20 to 40 minutes after the and placebo at 6 hours postdose on Days last nasal spray. Protein binding of esket- Current Psychiatry 34 May 2019 11, 18, and 25. amine is approximately 43% to 45%. The Out of the Pipeline

Figure 1 Short-term response for patients who received intranasal esketamine

0

–5 om baseline –10

–15 e change fr Clinical Point –20 Intranasal esketamine + oral antidepressant Intranasal Placebo nasal spray + oral antidepressant MADRS scor –25 esketamine should Day 0 24 hrs Day 8 Day 15 Day 22 Day 28 be administered

MADRS: Montgomery-Åsberg Depression Rating Scale cautiously in patients Source: Reference 2 receiving other CNS depressants, such as benzodiazepines brain-to-plasma ratio of noresketamine is 4 pressure. Patients receiving esketamine with to 6 times lower than that of esketamine. The concomitant use of psychostimulants should half-life of esketamine ranged from 7 to 12 be closely monitored for elevations in blood hours. The mean half-life of noresketamine pressure. was approximately 8 hours. Esketamine is Monoamine oxidase inhibitors. primarily metabolized to a noresketamine Concomitant use of esketamine with mono- metabolite via cytochrome P450 (CYP) amine oxidase inhibitors may increase enzymes, 2B6 and 3A4. Noresketamine is blood pressure. Closely monitor blood metabolized by CYP-dependent pathways pressure with concomitant use of esket- and certain metabolites undergo glucuroni- amine and monoamine oxidase inhibitors. dation. Drug interaction studies demon- Use in special populations. Because strate that intranasal esketamine had very of concerns of increased sedation, intra- little effect on pharmacokinetic interactions nasal esketamine should be administered with other medications. cautiously in patients receiving other CNS depressants, such as benzodiazepines. In Potential drug interactions patients with psychosis or a prior history of Central nervous system depressants. psychosis, esketamine should be used with Concomitant use of esketamine and other increased caution and the risk/benefit ratio CNS depressants (ie, benzodiazepines, should be carefully considered. opioids, alcohol) may increase sedation. Because of potential teratogenicity, esket- Patients receiving esketamine with con- amine is not recommended in women who comitant use of other CNS depressants are pregnant, may become pregnant, or should be closely monitored for sedation. who are currently nursing. Psychostimulants. Concomitant use Intranasal esketamine was examined in of esketamine and psychostimulants (ie, a phase III trial of 194 patients age ≥65. At amphetamines, methylphenidates, modafinil, the end of 4 weeks, there was no statisti- Current Psychiatry and armodafinil) may increase blood cally significant difference in groups on the Vol. 18, No. 5 35 Out of the Pipeline

Figure 2 Relapse prevention for patients who responded to intranasal esketamine

100

80

elaps e Placebo nasal spray + oral antidepressant

60

40 Intranasal esketamine + oral antidepressant

Clinical Point 20 Esketamine will cent of patients with a r Per 0 be administered Number of patients at risk Placebo nasal spray + oral antidepressant 59 35 19 13 4 2 2 1 1 0 0 through a REMS Intranasal esketamine 62 49 35 26 15 11 7 6 5 2 2 + oral antidepressant program only at 0 8162432404856647280 certified treatment Weeks since entering maintenance phase centers Source: Reference 2

MADRS, the primary efficacy endpoint. at certified REMS treatment centers. There were no overall differences in the Certified REMS treatment centers will safety profile in patients >65 years com- receive training on how to safely and pared with younger patients; however, the effectively counsel and monitor patients. mean esketamine Cmax and area under Prior to treatment, patients will receive the curve were higher in older patients blood pressure monitoring and antici- compared with younger adults. The mean pated adverse effects will be discussed. esketamine half-life was longer in patients Patients will be instructed to not eat solid with moderate hepatic impairment. food for 2 hours pre-dose and to not drink anything for 30 minutes prior. Abuse liability A treatment session consists of nasal Esketamine is a CIII controlled substance and administration and a minimum 2-hour concerns about abuse, misuse, and diversion post-administration observation period. have been taken into account within the Blood pressure must be assessed prior to REMS drug safety program.2 Patients with administration and if elevated, (ie, sys- a prior history of substance abuse or mis- tolic blood pressure >140 mm Hg, diastolic use should be considered with regard to the >90 mm Hg), clinicians should consider risk/benefit ratio. the risk of short-term increases in blood pressure that may occur. Do not adminis- The REMS drug safety program ter if increases in blood pressure or intra- Due to the nature of its usually transient cranial pressure pose a serious risk. adverse effects, including sedation, disso- After each intranasal administration ciation, hypertension, and nausea, intra- the patient will be observed for 5 minutes nasal esketamine will be administered before the second nasal inhaler is utilized Current Psychiatry 36 May 2019 through a REMS drug safety program and for another 5 minutes when the patient Out of the Pipeline

Figure 3 Administering intranasal esketamine: Wait 5 minutes between each device

• After the patient self- Instruct the patient to: Clinical Point administers the first device, • Rest in a comfortable position IMPORTANT: Ensure that take the device from patient. (preferably, semi-reclined) for the patient waits 5 minutes Each intranasal • Check that the indicator 5 minutes after each device. after each device to allow esketamine device shows no green dots. If you • If liquid drips out, dab nose medication to absorb. see a green dot, have patient with a tissue. is primed for spray again into the second nostril. Do not blow nose. 2 infusions for a • Check indicator again to total dose of 28 mg confirm the device is empty.

Source: Reference 2

is receiving 84 mg (ie, each inhaler equals The patient will be instructed to recline 28 mg). After administering, blood pressure the head to a 45° angle, clear his or her should be reassessed at approximately 40 nostrils prior to the first treatment, and minutes, which corresponds to the Cmax then self-administer a dose to each nostril of intranasal esketamine, and periodically while holding the reciprocal nostril closed thereafter as warranted. and inhaling. This process is then repeated The patient will then be monitored in a every 5 minutes for each subsequent quiet environment for a minimum of 2 hours device, with a maximum total dose of 3 to make sure that dissociative phenomenon, devices, or 84 mg (Figure 32). The patient sedation, and hypertensive reactions have will then be monitored for blood pressure, normalized prior to discharge from a certi- heart rate, and signs of psychologic or fied REMS treatment center. physiologic changes for the next 2 hours. Patients may not drive a car or operate any Dosing and administration type of motor equipment until the follow- Each intranasal device is primed for 2 infu- ing day after receiving a normal night’s sions (1 in each nostril) for a total dose of sleep. Patients will be released from the 28 mg of esketamine. Combinations of REMS treatment center after 2 hours if devices can be used to adjust the dose as both psychological and physical adverse appropriate for individual patients. The effects have normalized. recommended starting dose is 56 mg (ie, Missed treatment sessions. If a patient 2 devices, with a 5-minute gap between misses a treatment session and there is devices). The dose can be increased to worsening of depressive symptoms, con- 84 mg (ie, 3 intranasal devices spaced at sider returning the patient to the previous 5-minute intervals) by the second dose dosing schedule (ie, every 2 weeks to once Current Psychiatry based on clinical judgment. weekly, or weekly to twice weekly). Vol. 18, No. 5 37 continued Out of the Pipeline

Why Rx? Treatment-resistant depression is Related Resource found in nearly 1 out of 3 patients with cur- • Sullivan MG. FDA approves intranasal esketamine for refractory major depressive disorder. Clinical Psychiatry rently available monoaminergic antidepres- News. https://www.mdedge.com/psychiatry/article/195712/ sant treatment options. Patients with TRD depression/fda-approves-intranasal-esketamine-refractory- are at increased risk of physical and psycho- major-depressive. Published March 5, 2019. logical impairment, subsequent worsening Drug Brand Names of their condition, and social and occupa- Armodafinil • Nuvigil Mirtazapine • Remeron Duloxetine • Cymbalta Modafinil • Provigil tional disability. Escitalopram • Lexapro Sertraline • Zoloft Esketamine • Spravato Venlafaxine • Effexor References 1. Rush AG, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR D Report. Am J Psychiatry. 2006;163(11):1905-1917. Clinical Point 2. Spravato [package insert]. Titusville, NJ: Janssen Contraindications for intranasal esket- Pharmaceuticals, Inc.; 2019. Intranasal 3. Duman RS, Aghajanian GK, Sanacora G, et al. Synaptic amine include: plasticity and depression: new insights from stress esketamine is • aneurysmal vascular disease, includ- and rapid-acting anti-depression. Nat Med. 2016;22(3): 238-249. contraindicated ing thoracic and abdominal aortic, intra- 4. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of for patients with cranial, and peripheral arterial vessels, or intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized aneurysmal vascular arterial venous malformations clinical trial. JAMA Psychiatry. 2018;75(2):139-148. • history of intracerebral hemorrhage 5. Daly EJ, Trivedi M, Janik A, et al. A randomized withdrawal, disease double-blind, multicenter study of esketamine nasal spray • hypersensitivity to esketamine, ket- plus an oral antidepressant for relapse prevention in amine, or any of the excipients. treatment-resistant depression. Poster presented at the 2018 American Society of Clinical Psychopharmacology Annual Meeting; May 2018; Miami, Florida. Clinical considerations 6. Wajs E, Aluisio L, Morrison R, et al. Long-term safety of esketamine nasal spray plus oral antidepressants in patients Intranasal esketamine represents a unique with treatment-resistant depression: phase III open-label delivery system for the first glutamatergic safety and efficacy study. Poster presented at the 2018 American Society of Clinical Psychopharmacology Annual treatment approved for patients with TRD. Meeting; May 2018; Miami, Florida.

Bottom Line Intranasal esketamine is the first glutamatergic treatment option FDA-approved for patients with treatment-resistant depression who have not responded to standard antidepressant treatment options. In short-term trials, intranasal esketamine significantly improved depressive symptoms as quickly as 24 hours after treatment, with significant improvement maintained through 4 weeks of ongoing administration. In addition, intranasal esketamine was shown to significantly decrease time to relapse Current Psychiatry 38 May 2019 for patients who had achieved stable remission or stable response.