28 December 2024: Articles
Paradoxical Depressive Response to Intranasal Esketamine in Treatment-Resistant Depression: A Case Series
Unusual clinical course, Challenging differential diagnosis, Unusual or unexpected effect of treatment, Diagnostic / therapeutic accidents, Adverse events of drug therapy, Clinical situation which can not be reproduced for ethical reasons
Jose A. Ontiveros-Sánchez de la Barquera1ABEF*, Luis Alberto De La Garza García1ABEF, Silvia Viridiana Esquivel García1BEF, Guillermo Sánchez Torres1AC, Grecia Alejandra Perez Jalomo1ADFDOI: 10.12659/AJCR.945475
Am J Case Rep 2024; 25:e945475
Abstract
BACKGROUND: Esketamine is the only pharmacological agent with glutamatergic neuromodulator properties approved by the US Food and Drug Administration and European Medicines Agency to enhance the effects of serotonin selective or serotonin and norepinephrine reuptake inhibitors. Treatment-resistant depression (TRD) is a challenging and prevalent condition in the psychiatric field, in which patients often experience persistent and severe depressive symptoms, as well as a higher risk of suicidal thoughts and attempts. Esketamine has demonstrated its safety and effectiveness as a pharmacological therapy for TRD. Our report aims to present 2 cases of depressive symptom deterioration and suicide ideation in patients treated with esketamine.
CASE REPORT: We present 2 cases of TRD that initially responded well to intranasal esketamine but later deteriorated rapidly, with a worsening of depressive symptoms and suicidal ideation. Upon discontinuing esketamine, both patients clinically improved and showed a reduction in suicide ideation. The evaluation of affective symptoms’ response to esketamine and evolution was assessed using the Montgomery-Asberg Scale and Clinical Global Impression Severity and Improvement scales.
CONCLUSIONS: The underlying cause for the paradoxical antidepressant reaction is not entirely clear, but we observed this phenomenon in 2 patients with TRD who were treated with esketamine. Identifications of paradoxical reactions could be difficult in TRD, with highly resistant responses to treatment and suicidal ideation. However, it is relevant to know the prevalence of this phenomenon and for clinicians to be aware of the complications of esketamine treatment.
Keywords: Adverse Drug Reaction Reporting Systems, Depression, Treatment Outcome
Introduction
According to recent studies, in Mexico, 20.7% of patients with a diagnosis of major depressive disorder develop treatment-resistant depression (TRD) [1], which is when 2 or more anti-depressants fail to alleviate the symptoms, despite adequate dosing and duration. TRD is a serious condition that is associated with an increased risk of subsequent relapse, hospitalization, reduced health-related quality of life, and suicide [2]. Evidence suggests that the glutamatergic system is involved in depression pathogenesis. N-methyl-D-aspartate (NMDA) glutamate receptors have been identified as a potential target for treating major depressive disorder, including TRD [3].
Esketamine is approved by the US Food and Drug Administration (FDA) and European Medicines Agency to enhance the effects of serotonin selective or serotonin and norepinephrine reup-take inhibitors antidepressants [4]. The treatment with intranasal esketamine is divided into 2 phases: induction and maintenance [5]. Esketamine has glutaminergic properties, with rapid antidepressant effects. The esketamine mechanism of action with antagonist properties on NMDA, followed by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and downstream brain-derived neurotrophic factor and fibroblast growth factor transmissions, leads to rapid antidepressant and anti-suicidal effects [6].
The most commonly reported adverse effects during treatment with esketamine include vertigo, hypoesthesia, dissociation, sedation, dizziness, nausea, and paresthesia. Additionally, patients can experience headache, drowsiness, dysgeusia, anxiety, and a euphoric mood [7,8]. In pediatric and young adult populations, esketamine carries boxed warnings for potential abuse and misuse, sedation and dissociation, and increased risk of suicidal thoughts and behaviors [9]. Paradoxical reactions have been described for several antidepressant treatments in depressive patients, with worsening depressive symptoms.
On the long-term clinical effects of esketamine and suicide, Swainson et al reported multiple severe adverse events during long-term treatment of 1 year with esketamine, including anxiety, delusional content, delirium, and suicidal ideation [10]. These adverse events were found in 0.06% of the sample, including a total of 3 deaths due to suicide. However, the FDA states that attributing suicide to esketamine treatment is difficult, due to insufficient consistency. The present study aims to report these paradoxical phenomena, as unexpected worsening of depressive symptoms and suicidality were observed in 2 patients undergoing esketamine treatment for TRD.
Case Reports
Case 1
CASE 1:
The patient was 25-year-old man, residing in Monterrey, Mexico, and an art student. He experienced depressive symptoms since he was 18 years old and had been undergoing pharmacological treatment since then. The patient had no significant medical history, but an abnormal electroencephalography was performed when he was 19 years of age, revealing paroxysmal activity. However, he ultimately did not receive a diagnosis of epilepsy. The patient’s family psychiatric history was notable; his mother had major depressive disorder with melancholia and tragically committed suicide when the patient was 4 years old. Additionally, a paternal uncle had a diagnosis of resistant schizophrenia. The patient’s lifestyle was typical for his age and social background, with good friendships and a normal social life. However, his relationships with girlfriends tended to be chaotic and dependent. Previously, he was passive, did not play sports, had notable alcohol issues, and occasionally used marijuana. The patient’s depression was considered resistant, as he had previously received several antidepressant treatments without success. As indicated in Table 1, the patient had undergone multiple antidepressant treatments, with sufficient dose and duration. Before starting esketamine treatment, he was on valproic acid 1000 mg/day (blood levels 79.8 ug/mL), lithium carbonate 900 mg/day (blood levels 0.75 mmol/L), venlafaxine 150 mg/day, brexpiprazol 2 mg/day, and quetiapine SR 50 mg/day. In February 2023, after breaking up with his girlfriend, he stated a marked and progressive relapse of depression, with severe sadness, anhedonia, guilty feelings, and suicidal ideations. Also, he had anxiety, troubles of memory, and severe insomnia, sleeping no more than 4 h per night. The evaluation of depression with the Montgomery-Asberg Scale (MADRS) gave 38 points, while the Clinical Global Impression Severity (CGI-S) score was 6, indicating severe illness. Also, the patient started psychotherapeutic sessions 2 months before this relapse. Changes in his antidepressant treatment, such as the increase of venlafaxine to 225 mg/day, brexpiprazole to 3 mg/day, and quetiapine SR to 150 mg/day, did not improve his depressive symptoms. It must be noted that previous mood changes due to stress were successfully managed with this type of change in his medication dosage.
CLINICAL FINDINGS:
Physical examination was normal: weight 75.7 kg, height 180 cm, blood pressure 115/66 mmHg, and heart rate 66 beats/min. Also, the most recent complete blood laboratory test results, including thyroid hormone levels, did not reveal abnormal values. The mental examination was remarkable, with low mood without reactivity, which also had been observed by relatives and friends. He reported moderate anxiety symptoms and insomnia, taking at least 2 h to start sleeping. He also had low concentration, and memory troubles were observed during the interviews. He recently stopped his Bachelor of Arts program due to severe apathy and anhedonia, being isolated at home. He also admitted having severe feelings of guilt and thought that he deserved punishment for past faults. He admitted to thinking that committing suicide could be a solution to his problems but thinking about his family stopped him from these thoughts or harming himself. Psychosis symptoms were not detected.
TIMELINE: The patient had been experiencing depression since he was 18 years old and had undergone several treatments with antidepressants. He had at least 3 relapses, some of which were linked to poor compliance with his treatment. However, in the past, minor adjustments to his regimen had led to quick improvements in his symptoms (Table 1).
DIAGNOSTIC ASSESSMENT:
A complete medical and psychiatric history was obtained when the patient was 19 years old, and they were renewed yearly. The Mini-international neuropsychiatric interview (MINI) was used to corroborate the diagnosis, and a major depressive disorder with melancholic features and moderate suicidal risk were corroborated for this episode. Although the patient underwent a severe traumatic event when his mother committed suicide when he was 4 years old, he did not develop a traumatic disorder. Clear bipolar and psychotic symptoms were also not detected in the past. The patient’s affective symptoms were evaluated during each follow-up visit, with scales. For the present relapse episode, his MADRS score was 38 points, and the CGI-S score was 6, indicating severe illness. Esketamine intranasal treatment was advised due to a lack of response to antidepressant treatment and suicidal ideation.
ESKETAMINE INTERVENTION: Treatment with esketamine intranasal spray was conducted with 2 sessions of 56 mg per week. His MADRS score at baseline was 31 points and CGI-S score was 6, with moderate suicidal ideation before the first esketamine application. After 3 sessions, he presented a good evolution, with marked improvement in affective symptoms, and denied suicidal ideation (MADRS 3, CGI-S 1, Clinical Global Impression Severity Improvement [CGI-I] 1). During the fourth treatment, the patient, who was not initially depressed (based on the last evaluation scores), unexpectedly experienced intense suicidal thoughts and then continued to have severe depressive symptoms. After receiving another dose of esketamine, the suicidal thoughts and depressive symptoms worsened, as shown in Figure 1. It was decided to suspend treatment with esketamine, due to the short chronological association, and the patient was hospitalized 4 days later for severe suicidal risk. At the end of the 2-week hospitalization, a return to his premorbid depressive state was observed. He reported having mild depressive symptoms, anxiety, low motivation and anhedonia, and guilty feelings, denying any suicidal ideation. A MADRS score of 14, CGI-S score of 3, and CGI-I score of 2 were observed. Pharmacological treatment was changed during hospitalization to lamotrigine 100 mg twice daily, vortioxetine 30 mg every morning, lithium carbonate 900 mg at bedtime (qhs), risperidone 1 mg qhs, and clonazepam 0.5 mg qhs. Also, quetiapine 25 mg qhs and lorazepam 4 mg qhs were given for insomnia. The tolerance to treatment was good.
FOLLOW-UP AND OUTCOME:
The patient was in close follow-up for 1 year after his hospitalization. A pharmacogenetic study revealed that the patient had a decreased activity of MTHFR genotype, associated with decreased enzyme activity. Therefore, L-methylfolate 15 mg/day was added in September 2023. Also, vitamin D3 levels were detected to be too low, at 10 ng/mL, and 10 000 units were added in December 2023. Lithium carbonate reduction attempts caused the return of depressive symptoms and irritability. The patient remained stable, with limited depressive symptoms, no more sad mood, mild anxiety, or anhedonia related to the school program, and no more suicidal ideation (MADRS 9, CGI-S 2, CGI-I 1). Recently, he reported mild difficulties with concentration. He was also dedicated to his psychotherapy treatment program.
PATIENT PERSPECTIVE:
The patient’s first experience with esketamine treatment was remarkable. He even joked that it could be a good idea to have esketamine intravenous all day long. When he became suicidal while having esketamine treatment, he was confused about the bad experience and even drew a suicidal drawing. Later, the patient agreed to be hospitalized, due to severe and uncontrollable suicidal ideation. Presently, he had mixed feelings about his esketamine treatment experience, since at the beginning, he observed a marked improvement.
The patient gave informed consent by verbally accepting that his data would be shared for this article (Figure 1).
CASE 2:
The patient was a 24-year-old woman, living in Monterrey Mexico, with a degree in communication. The patient had depressive symptoms since she was 21 years old, without showing remission. She previously received several antidepressant treatments, with poor results. Relevant medical history was remarkable, as the patient underwent gastric bypass for obesity when she was 19 years old. Later, relevant complications were denied, but gastritis was being treated with pantoprazole 20 mg/day. Her family psychiatry history was not relevant. She has no siblings, and her parents had been divorced since she was a child. The patient’s lifestyle was normal for a young woman of her age and social level. She had a lot of good male and female friends, with normal social relationships and 2 previous boyfriends. The patient smoked 6 cigarettes per day for the last year. She denied the use of illicit drugs and had a social use of alcohol. Menstruation started at 10 years; menses were regular, with no premenstrual tension. She started her sexual life when she was 20 years old, with no actual use of contraceptives, and denied pregnancies. In February 2022, due to the worsening of her depressive symptoms, she made a suicidal attempt, taking an overdose of her antidepressant treatment, without medical complications, and was hospitalized for 2 weeks. Her previous treatment was modified to pregabalin 150 mg every morning and 300 mg qhs, fluoxetine 60 mg/day, clonazepam 2 mg twice daily, and olanzapine 10 mg qhs. The patient had not experienced significant improvement in her treatment since the onset of her depressive disorder. She had been feeling extremely sad, experiencing marked anhedonia, feelings of guilt, insomnia, and suicidal thoughts. Additionally, she reported severe anxiety and frequent panic attacks. Over the past year, following her hospitalization, she had also been unable to work. Scale evaluation showed depression, with a MADRS score of 45 points and CGI-S score of 6, indicating severe illness. The patient had undergone multiple antidepressant treatments, with sufficient doses and duration, as indicated in Table 1. Also, she had been in psychotherapy for the last 4 years.
CLINICAL FINDINGS:
Physical examination was within normal values: height 155 cm, weight 66 kg, heart rate 80 beats/min, and blood pressure 110/70 mmHg. Also, recent complete blood laboratory test results, including thyroid hormone levels, revealed normal values. Mental examination was remarkable for her severe anxiety with panic attacks and low mood with reactivity, fatigability, and apathy symptoms, which also had been observed by her mother and friends. She also reported having insomnia, taking her at least 2 h to sleep, marked lack of appetite, and trouble with concentration. Also, she reported having moderate guilty feelings and moderate suicidal ideation. She explained that she was unable to work, due to severe apathy, anxiety attacks, and anhedonia, and most of the time she was isolated at home, where friends visited her. Psychosis symptoms were not detected.
TIMELINE: The patient had been depressed since she was 19 years old and had undergone several antidepressant treatments. No treatment improved her depressive symptoms markedly. She reported having adverse effects, such as diurnal somnolence and more anxiety. Her previous suicide attempt was due to her exhaustion from not seeing improvement and experiencing anxiety attacks (Table 1).
DIAGNOSTIC ASSESSMENT:
A complete medical and psychiatric history was obtained. The MINI interview was used to corroborate the diagnosis, in which a major depressive disorder without melancholic features and moderate suicidal risk were corroborated. The patient’s depressive symptoms were evaluated with the MADRS, with 45 points, and a CGI-S of 6 points, indicating severe illness. Her physician recommended esketamine intranasal treatment, due to a lack of response to antidepressant treatment.
ESKETAMINE INTERVENTION:
Treatment with esketamine intranasal spray was conducted with 1 session per week with 28 mg per day (dosage and frequency could not be increased due to marked nausea and dizziness since the first application). Her MADRS score at baseline was 45 points and CGI-S was 6, with moderate suicidal ideation before the first esketamine treatment. After 5 weeks of esketamine, 1 application per week, she showed a marked improvement in her depressive symptoms, denying suicidal ideation (MADRS 20, CGI-S 3, CGI-I 2). The patient suspended the esketamine treatment for 1 month for administrative reasons (her mother was outside the city, and the patient had no money to pay for the treatment). The weekly esketamine treatment was restarted due to a worsening of her depressive symptoms, with a MADRS score of 32 and a CGI-S score of 4. After 3 weeks, there was noticeable improvement; her MADRS score decreased to 20, with a CGI-S score of 3 and a CGI-I score of 2, and she reported no suicidal ideation. Based on this progress, she and her mother were advised to increase the frequency of esketamine applications to twice a week for further improvement.
However, during the subsequent 6 biweekly applications, her depressive state progressively deteriorated. This decline was evident in her MADRS score, which rose to 29, and her CGI-S score increased to 5, indicating marked depression. Additionally, the patient experienced suicidal ideation again, which led to the decision to discontinue the esketamine treatment. One week after discontinuing esketamine treatment, the patient and her mother reported a significant improvement in her mood. There were no signs of suicidal ideation, and the patient experienced only mild anxiety, insomnia, and anhedonia. Her MADRS score was 16, indicating improvement, while the CGI-S score was 3, and the CGI-I score was 1. Tolerance to esketamine was considered acceptable.
FOLLOW-U AND OUTCOME:
The patient was followed up for 6 months by her physician and psychotherapist. Her condition was reported as stable, with mild depressive symptoms, such as lack of motivation, insomnia, and low appetite. Pharmacological treatment was changed to decrease adverse effects.
PATIENT PERSPECTIVE:
The patient’s experience with weekly esketamine treatment was quite positive, showing a consistent reduction in depressive symptoms. However, similar to other reports, the patient experienced a relapse after stopping the treatment prematurely. She also reported feeling more depressed when the frequency of her esketamine doses was increased. Both she and her mother were surprised by these results and wondered if they were somehow to blame. We explained to them that this reaction could be a paradoxical response to the esketamine treatment.
The patient provided informed consent by verbally accepting that her data be shared for this article (Figure 2).
Discussion
In case 1, we observed a rapid improvement in symptoms, but a worsening of depression and suicidality closely associated with esketamine administration, followed by a quicker improvement when it was discontinued. We need to consider the patient’s resistance to antidepressants, low vitamin D levels, and impairment of L-methylfolate synthesis, which has been associated with a poor antidepressant response. In our differential diagnosis, bipolar disorder was ruled out, as the patient never presented a manic or hypomanic event. Finally, we could not determine if the detected electroencephalographic abnormalities could be related. The patient was prescribed an anticonvulsant medication as a precaution. We are unsure if the relapse of depression while on esketamine and worsening of suicidal ideation was related to all the factors mentioned above.
In case 2, dosage of esketamine was related with worsening of symptoms and suicidal ideation, which was counterintuitive, as we were expecting a better improvement of depressive symptoms. The phenomena of paradoxical reactions to antidepressant treatments are well known in the literature but have not been described with esketamine treatment. Bipolar disorder and panic disorder were ruled out based on psychiatric history. Severe anxiety is linked to a poor prognosis and increased suicidal thoughts in patients with major depressive disorder, as noted here. The anxiety symptoms improved with the patient’s lifting of depression. Additionally, following her recent bypass surgery, issues with medication absorption may have been affecting her response to antidepressants. The worsening of depression due to intolerance when the frequency of esketamine treatments was increased was resolved, as the patient developed an acceptable level of tolerance. Evers et al noted an effective response with twice-weekly esketamine treatments; however, there was a symptomatic worsening after switching to weekly treatments. This observation suggests that the frequency of esketamine administration is linked to its response and effectiveness in treating TRD [11]. In the present case, a relapse was observed when the patient’s treatment was stopped for 1 month. Upon restarting the treatment, the patient responded again. It is unclear whether the paradoxical reaction observed was related to the resumption of esketamine treatment.
Our findings about the relationship between esketamine treatment and the worsening of suicidal ideation need to be compared with the findings in previous publications. Canuso et al conducted a double-blind treatment study of esketamine vs placebo in 66 patients with TRD, in which 2 (2/35, 5.7%) patients on esketamine experienced increased suicidal thoughts [12]. However, investigators considered the events doubtfully related or unrelated to esketamine. Also, 1 patient (1/35, 3.5%) experienced worsening of depressive symptoms, which was considered possibly related to treatment. Canuso et al found that elevated levels of suicidality and depression may be more common than previously believed among patients with TRD who are receiving esketamine treatment, as seen in our 2 cases. However, they also noted a significant improvement in depressive symptoms and a reduction in overall suicide risk associated with esketamine therapy, similar to what we observed in our cases.
Gastaldon et al analyzed the safety concerns of esketamine and suicidal risk [13]. While suicidal risk appears to be a reported severe adverse event in their analysis, they cannot differentiate if these patients’ suicide risk was part of their resistant depressive condition, due to a lack of efficacy in treatment with esketamine, or an adverse reaction to treatment. Still, they continue to report an increased risk for suicidal ideation with esketamine, compared with that of other antidepressant therapies [14].
McIntyre et al analyzed the occurrence of suicidal ideation, depressive symptoms related to suicide, suicidal behavior, suicide attempts, and completed suicides by examining the FDA Adverse Event Reporting System database and comparing it with lithium as a control. They claimed that the improvement stated in depressive symptoms and suicidality with ketamine and esketamine remains uncertain, as both agents have been associated with emergence of suicidality in susceptible individuals, such as the young population [15]. McIntyre et al suggested that the elevated rates of suicidality reported in patients with TRD could explain the increased suicidality associated with esketamine treatment. Our cases involving patients with TRD showed an elevated risk of suicide. However, we observed a direct chronological association between esketamine use and suicidal ideation. Interestingly, both cases aligned with observations made by McIntyre et al and other researchers regarding the later beneficial effects of esketamine treatment. Both patients ultimately showed improvements in their depression and suicidality. The lack of biomarkers and biosignatures that help to predict the therapeutic effect of glutamatergic agents is mandatory, to predict benefits and risks with these agents.
One of our cases (case 2) could be related to reports about paradoxical (depression-inducing) effects, loss of efficacy, and resistance (lack of response to previously effective pharmacological treatment when the same medication is started again after a drug-free period) to antidepressant drugs. According to Fava, the oppositional tolerance model can explain why treatment can become less effective over time. Essentially, when a person stops taking antidepressants, the body’s natural oppositional processes are no longer inhibited, which can lead to the onset of withdrawal symptoms, post-withdrawal disorders, hypomania, and resistance to treatment if it is reinstituted [16], explaining the sudden mood deterioration and suicide ideation when restarting esketamine treatment.
Research on the potential drug interactions between anti-depressants and esketamine is limited; however, based on the available literature, reports have shown that benzodiaze-pines can shorten the duration of ketamine’s antidepressant effects [17]. There are no reports of an interaction between lithium and ketamine or esketamine. However, there are indications of an interaction between antipsychotic drugs, such as haloperidol, risperidone, and clozapine, but not evidently for olanzapine, in combination with ketamine or esketamine.
Conclusions
Studies on esketamine have demonstrated its clinical effectiveness in individuals at high risk, particularly those with TRD. As its use is rapidly expanding worldwide, it is crucial to report severe adverse events, such as suicidal ideation and worsening depression, along with the clinical context surrounding these occurrences. While we cannot definitively establish a causal relationship between esketamine use and the emergence of these events, we hope our report contributes to a better prognosis and evolution of patients under its treatment. The reported adverse reactions in this case report emphasize the need for larger studies to better understand the frequency and mechanisms of these reactions.
References:
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11.. Evers A, Klein M, Aloysi A, Antidepressant effect of prolonged twice-weekly intranasal esketamine treatments after nonresponse to electroconvulsive therapy in a patient with treatment-resistant depression.: Ann Clin Psychiatry, 2022; 34(1); 61-64
12.. Canuso CM, Singh JB, Fedgchin M, Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study.: Am J Psychiatry, 2018; 175(7); 620-30
13.. Gastaldon C, Raschi E, Kane JM, Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA adverse event reporting system.: Psychother Psychosom, 2021; 90(1); 41-48
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15.. McIntyre RS, Mansur RB, Rosenblat JD, The association between ketamine and esketamine and suicidality: Reports to the Food And Drug Administration Adverse Event Reporting System (FAERS).: Expert Opin Drug Saf., 2024 [Online ahead of print]
16.. Fava GA, May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance: Ther Adv Psychopharmacol, 2020; 10 2045125320970325
17.. Ghasemi M, Phillips C, Fahimi A, Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders.: Neurosci Biobehav Rev, 2017; 80; 555-72
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