NMDA receptor antagonist use in a patient with treatment-resistant depression and comorbid PTSD

Presentation and history
This is the case of a young fe­male professional who was sexually assaulted by her older brother when she was in primary school. The pa­tient had not developed diagnosable psychiatric disorders until April 2023, when exposure of the childhood traumatic event triggered moderate depression (Beck Depression Inven­tory [BDI] score, 20) and mild anxiety (Beck Anxiety Inventory [BAI] score, 12) as well as severe post-traumatic stress disorder (PTSD) with full-blown symptoms, including flashbacks, in­somnia and nightmares every night, anhedonia, dissociation (2–3 times weekly) and conversion symptoms (paralysis) on her right hand and left leg. She withdrew not only from the perpetrator, but also from other fam­ily members. She had crying spells, separation anxiety with friends, and decreased work performance due to slow psychomotor speed and poor concentration. (Table)

The patient initially received oral antidepressants (sertraline 50 mg QD in August 2023; switched to duloxe­tine 30 mg QD in September 2023) followed by antipsychotic augmenta­tion (brexpiprazole 1 mg QD in Oc­tober 2023; switched to olanzapine 5 mg QD in November 2023). De­spite oral medication adjustments, her Montgomery–Åsberg Depres­sion Rating Scale (MADRS) score increased to 56, with a BDI score of 53 and a PTSD Checklist 5 (PCL-5) score of 55, indicating treatment-resistant depression (TRD) and se­vere PTSD. (Figure)

As a result of multiple suicide at­tempts and conversion symptoms, the patient was sent to the Accident & Emergency (A&E) department five times and hospitalized twice. Given her severe psychiatric symptoms and suicidality, esketamine nasal spray was initiated.

Treatment with esketamine nasal spray and response
On 11 November 2023, the pa­tient started her first dose of intra­nasal esketamine at our clinic. After dosing, she was monitored closely by our nurses for 2 hours in a pri­vate room with the company of her friends. Right after esketamine ad­ministration, she had dissociative reactions with loud screaming of “I am scared” and “Don’t come close to me”, but the reactions subsided with­in 45 minutes. She also received con­current trauma-focused cognitive be­havioural therapy (TF-CBT) the next day following each esketamine dose.

As the patient had dissociative reactions after the first two doses of esketamine, premedication with alpra­zolam 0.5 mg was given 15 minutes beforehand from the 3^rd dose to the 6^th dose. Since then, the dissociative reactions substantially reduced, and sleep quality improved. Notably, no dissociation occurred in any TF-CBT sessions or after the final dose of es­ketamine, even without premedication.

The patient tolerated esketamine well. Slight blood pressure (BP) ele­vations of 10–30 mm Hg, which re­solved within 1 hour, were observed from the 4^th to 8^th dose, but not with the first few doses, despite the disso­ciative reactions. No other side effects were reported during and between esketamine administrations, although weight gain (+5 kg) occurred with olanzapine.

The patient responded well to esketamine and TF-CBT, with rapid resolution of suicidal ideation within 2 weeks and gradual reduction in BDI, MADRS and BAI scores. (Figure) As such, olanzapine was switched to a ‘milder’ antipsychotic with less weight gain potential (mirtazapine 15 mg QD) in November 2023. On 28 November 2023, prazosin 1 mg nocte was added to reduce nightmares.¹ (Table)

Towards the end of esketamine treatment, the patient’s energy level increased, and psychomotor speed improved. Her anxiety symptoms also improved, and flashbacks significant­ly decreased. Her work performance improved and she felt comfortable without her friends' presence. (Table) Before her last dose of esketamine on 5 December 2023, there were sub­stantial reductions of both BDI (from 42 to 19) and MADRS (from 34 to 18) scores. (Figure)

After eight doses of esketamine and concurrent TF-CBT, the patient’s PCL-5 score also decreased substan­tially to 32, which, however, is still con­sidered high. (Figure) Therefore, she started repetitive transcranial magnet­ic stimulation (TMS) three times weekly for residual PTSD symptoms.

As of 17 January 2024, the patient had completed 15 sessions of TMS. Her BDI, MADRS and BAI scores were 10, 7 and 8, respectively, and PCL-5 score further decreased to 15. (Fig­ure) She had not visited the A&E or been hospitalized since starting es­ketamine treatment. (Table)

Discussion
Comorbid TRD-PTSD is associat­ed with more severe clinical presen­tation and reduced treatment efficacy than either disorder alone.² Our pa­tient with mild anxiety, severe TRD and severe PTSD did not respond to ≥2 lines of oral antidepressant treat­ment, as her psychiatric symptoms, including suicidality, worsened, re­sulting in five A&E visits and two hos­pitalizations in 7 months. Since this case was judged as a psychiatric emergency, esketamine was indicat­ed as an acute intervention, as sup­ported by results of two pivotal phase III studies, ASPIRE I and ASPIRE II.³

Pooled data from ASPIRE I (n=226) and ASPIRE II (n=230) showed that esketamine plus stan­dard of care significantly reduced de­pressive symptoms, as measured by MADRS score at 24 hours after the first dose vs placebo (least-square [LS] mean difference, 3.8; 95 per­cent confidence interval [CI], -5.75 to -1.89), in patients with major depres­sive disorder (MDD) and acute suicid­al ideation or behaviour. Rapid effect was observed as early as 4 hours af­ter the first dose (LS mean difference, -3.4; 95 percent CI, -5.05 to -1.71), and the effect was sustained at 25 days (LS mean difference, -3.4; 95 percent CI, -5.36 to -1.36).⁴

Apart from its rapid effect, esket­amine was the drug of choice for our patient because it potentially improves symptoms of both TRD and PTSD. In an open-label, single-arm, retrospec­tive pilot study of 11 patients with TRD-PTSD, mean MADRS scores significantly decreased from 38.6 to 18.2 (p<0.001) after 6 months of intra-nasal esketamine. Rapid improvement in suicidality was also observed, with the proportion of moderately to se­verely suicidal patients decreasing from 63.6 percent at baseline to 27.3 percent after 1 month of treatment.⁵ Furthermore, an open-label retrospec­tive analysis of 35 military veterans with comorbid depression and PTSD showed significant reductions in de­pressive (absolute change in Patient Health Questionnaire-9 score, -5.1; p<0.05) and PTSD symptoms (abso­lute change in PCL-5 score, -15.5; p<0.05) after 4 weeks of esketamine treatment.⁶ Similar responses were seen in our patient who achieved no­table reductions of BDI, MADRS and PCL-5 scores. (Figure)

Commencing esketamine treat­ment was life-changing for our pa­tient, who experienced rapid resolu­tion of suicidal ideation and no A&E visits or hospitalization since starting treatment. Other TRD-PTSD symp­toms, including dissociation, separation anxiety, flashbacks, mood symptoms, insomnia, and nightmares, significantly improved after 4 weeks of esketamine. Notably, her early clinical response was not adequately reflected in the BDI and MADRS score decline before the 7^th dose (response defined as ≥50 percent decrease from baseline).⁷ Clinicians should be aware that esketamine’s anti-depressant effect, especially in patients with ≥1 psychiatric disorder, can be delayed, and treatment should not be stopped too early.

In both MDD and PTSD, patients are more sensitive to negative emotional stimuli which trigger an increased activa­tion of brain regions involved in fear and stress responses, such as amygdala and prefrontal cortex. Glutamate is the main excitatory neurotransmitter in the brain and plays a crucial role in stress responsivity and the formation of trau­matic memories. It is postulated that esketamine, the S enantiomer of ketamine, modulates glutamate neurotransmis­sion, which may help restore normal func­tioning through N-methyl-D-aspartate (NMDA) receptor blockage in these brain regions and alleviate symptoms of PTSD and MDD.^3,5

Our case illustrates that esketamine can potentiate TF-CBT and the two treatment modalities can be applied in parallel, which may be due to ketamine’s mechanism of action in facilitating neu­roplasticity involved in new memory formation, fear extinction, and restruc­turing of traumatic memories. Combin­ing ketamine with psychotherapy may facilitate emotional learning through enhanced neuroplasticity, reductions in defensiveness, and enhanced treatment adherence and engagement.^5,8 Our esketamine-treated patient, for exam­ple, felt more comfortable and found it easier to share thoughts and feelings during TF-CBT sessions. (Table)

Dissociative effects are common with intranasal esketamine. However, as illustrated in our patient, pre-existing dissociation is not a contraindication to esketamine treatment. Interestingly, esketamine’s dissociative effects may promote better treatment outcomes by allowing patients to verbalize their traumatic experience and create new positive associations.⁵ In cases where esketamine-associated dissociation is excessive or disturbing to patients, it can be managed by premedication with benzodiazepines, such as alprazol­am, shortly before drug administration.⁹ Transient BP elevation is also common with esketamine, but it is often self-limiting, as observed in our patient. Some patients may experience dysgeu­sia, which can be alleviated by breathing through the mouth.^9,10

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