The electronic survey was distributed to 69 providers of parenteral ketamine for depression. Responses were obtained from 36 participants (52% response rate). Eight surveys were excluded from analysis as they did not complete the questions about the numbers of adverse effects of ketamine. One response was excluded from analysis due to a high degree of internal inconsistency. Therefore, 27 survey responses were included in the final analysis.
The medical specialty and nature of the practice site of the ketamine providers, as well as the number of patients they have treated with parenteral ketamine, are provided in Table 1
Collectively, the 27 survey respondents reported treating 6630 patients with parenteral ketamine for the treatment of depression. The median number of patients treated was 80. Figure 1
illustrates the breakdown of these 6630 patients in terms of the number of parenteral ketamine treatments they received. Approximately a third of these patients (34%) had been under treatment with parenteral ketamine for longer than 12 months, and a third (33%) had received more than 10 individual ketamine treatments.
After reviewing all reported adverse events and eliminating any that did not meet the stated definitions for inclusion (e.g., parenteral route, TRD indication, etc.), there were 47 patients out of the 6630 patients treated (0.7%) who required discontinuation due to an adverse effect during the treatment of depression with parenteral ketamine (Table 2
The most commonly reported adverse effect that required discontinuation was psychological distress during treatment, which occurred in 33 patients (0.5%). Other adverse events that prompted discontinuation included nausea (n = 6), bladder dysfunction (n = 3), mania/hypomania (n = 2) and psychotic symptoms (n = 1). Spontaneously reported adverse events from providers included respiratory distress (n = 1) and seizure (n = 1).
2.2. Literature Review
Our literature search revealed 19 published papers that met our stated criteria (reporting on the effects of six or more repeated ketamine treatments administered parenterally to people with TRD). Table 3
summarizes the adverse events reported in these 19 published studies.
aan het Rot et al. [19
] administered six ketamine infusions (0.5 mg/kg over 40 min), over 12 days, to 10 medication-free TRD patients with continuous vital sign monitoring. Aside from the expected significant dissociative effects in some patients, no significant adverse events were observed.
Murrough et al. [20
] reported administering six ketamine infusions (0.5 mg/kg over 40 min), over 12 days, to 21 TRD patients. None of these patients experienced any serious side effects during the infusion series or during the follow-up period that extended up to 83 days. Zhou et al. [21
] administered six ketamine infusions (0.5 mg/kg over 40 min), over 12 days, to 84 patients with unipolar and bipolar depression. Severity of depressive symptoms and several domains of neurocognition were assessed at baseline, one day following the last infusion, and again two weeks post-infusion. They reported that one patient withdrew due to a manic switch, but there were no other notable adverse events. As for neurocognition, they found significant improvements in speed of processing and verbal learning, and no deterioration in the other cognitive domains. Archer et al. [22
] conducted a chart review identifying 11 patients who received between 10 and 51 ketamine infusions (0.5 mg/kg over 40 min) over a period 6 to 49 weeks. They found no serious adverse events. Wilkinson et al. [23
] described 14 patients who received 12‒45 ketamine infusions (0.5 mg/kg over 40 min) over 14‒126 weeks. Aside from a small number of patients (n
= 4) who had a transient increase in BP during some of their infusions, they witnessed no significant adverse events, and concluded that “Ketamine treatment was generally well tolerated in patients who received infusions on a long-term basis.” Phillips et al. [24
] conducted a study of 41 subjects with treatment-resistant depression, who received single blinded infusions of ketamine and midazolam, followed by six open-label ketamine infusions administered thrice weekly for two weeks, followed by another four weekly infusions. Participants experienced transient elevations of blood pressure and heart rate, but the authors reported no serious adverse events, and no evidence of craving or drug-seeking behavior during the infusions or follow-up. None of the participants had to discontinue infusions due to cardiorespiratory effects, and no rescue medications were necessary during the study.
Vande Voort et al. [25
] administered six IV ketamine infusion (0.5 mg/kg over 40 min), thrice weekly over two weeks, to subjects with TRD. Five of the subjects received four additional weekly infusions, and were followed for 4 weeks after the last infusion. They observed only mild and transient adverse events; however, one subject developed behavioral outbursts and suicide threats during the 4-week post treatment follow-up period, and another patient died by suicide several weeks after the follow-up period. The treatment providers did not believe these events were related to the previous ketamine treatments.
Ionescu et al. [26
] conducted a study of 14 MDD patients with persistent suicidal thoughts. They received six weekly ketamine infusions, the first three at 0.5 mg/kg over 40 min, followed by three at 75 mg/kg over 40 min. They measured dissociation using the Clinician-Administered Dissociative States Scale (CADSS), but did not specifically report these results, nor did they report adverse effects.
Another study by Ionescu et al. [27
] reported 26 patients with TRD and chronic current suicidal ideation, who were randomized in a double-blind manner to receive six ketamine infusions (0.5 mg/kg over 45 min) or saline over 3 weeks. Predictably, patients who received ketamine reported significantly higher dissociative symptoms (p
< 0.001) on the CADSS during the infusion visits, with the largest difference shown at 30 min after the start of the infusion (p
< 0.01). No other adverse effects were reported.
Singh et al. [28
] conducted a study in which adults with TRD received IV ketamine infusions (0.5 mg/kg over 40 min) either thrice weekly (6‒12 infusions, N
= 11) or twice weekly (8 infusions, N
= 10). The authors report that both regimens were generally well tolerated
Mild emergent adverse events during the infusions included headache, anxiety, dissociation, nausea and dizziness, which were observed in 16‒28% of twice-weekly group, and 6‒41% of the thrice-weekly group, and all were resolved within 3 h after the infusion. Two patients discontinued due to ketamine-related emergent adverse effects in the twice-weekly group; one due to increased anxiety and another due to increased anxiety and paranoia. In the thrice-weekly group, one patient discontinued due to ketamine-related symptoms, reported as anxiety, dizziness, hypoesthesia and feeling cold.
Shiroma et al. [29
] conducted an open-label study of six ketamine infusions (0.5 mg/kg over 40 min) administered over 12 days in 12 TRD patients. The infusions were well tolerated, aside from a single episode of transient increase in blood pressure (180/92) and another single episode of vomiting, effectively countered by IV labetalol and ondansetron, respectively.
Diamond et al. [30
] enrolled 28 unipolar and bipolar TRD patients to receive a series of either three weekly (n
= 15) or six twice-weekly (n
= 13) infusions of ketamine (0.5 mg/kg over 40 min).Two patients discontinued before receiving all their infusions because of adverse reactions attributable to ketamine; one for a panic attack experienced during the infusion and the other for a vasovagal episode experienced during the fourth infusion. Other adverse events reported that did not result in discontinuation included panic attack (n
= 1), rapid cycling of mood with a mild hypomanic episode (n
= 1), emesis (n
= 2) during treatment, symptomatic cystitis (n
= 1) and a hypnogogic hallucination (n
Bryant et al. [31
] reported on six geriatric patients (65‒82 years old) who received 8‒22 ketamine IV infusions (0.5 mg/kg over 40 min) every 2‒6 weeks, based on individual maintenance interval needs. They noted only mild, transient adverse effect.
George et al. [32
] reported on 10 geriatric subjects (≥60 years) with MDD or bipolar disorder, who received 12 open-label subcutaneous ketamine injections (0.3‒0.5 mg/kg) administered twice per week for 1 month, and then weekly for one month. The injections were administered 6 months after patients received a series of three to five subcutaneous ketamine injections during a dose ranging phase. The investigators reported mild perceptual disturbances (colors or sounds seemed different), derealization, altered body perception and altered time perception, with peak effects occurring 10‒15 min after injection, resolving without intervention by 40 min after injection in all sessions. No significant treatment-emergent adverse psychiatric symptoms were reported at any time point. There were small transient increases in systolic and diastolic blood pressure, peaking at 4 h after ketamine, and four instances of heart rate increases that exceeded 120% of baseline, which never exceeded 131.5. Five patients reported mild neurologic symptoms (dizziness, n
= 5; numbness, n
= 2, headache, n
= 1) with full resolution within 2 h. One patient reported the urge to urinate slightly more often. The liver function tests as well as neuropsychological test scores were all within normal limits, except in one patient whose aspartate aminotransferase (42‒60) and alanine aminotransferase (25‒44) were elevated after 12 treatments of 0.5 mg/kg.
Albott et al. [33
] reported an open label study of 15 patients with TRD, who received a series of six ketamine infusions (0.5 mg/kg over 40 min). The authors reported no serious adverse events and no emergent adverse events, other than a transient increase in dissociative and manic symptoms (as measured by the CDSS and YMRS scales) during and immediately after the infusions.
Segmiller et al. [34
] reported a case series consisting of six TRD patients who received six ketamine infusions (0.25 mg/kg over 40 min). One patient decided to discontinue before receiving all infusions due to the transient dissociative effects, but there were no other significant adverse effects.
Szymkowicz et al. [35
] reported three patient case reports of repeated IV ketamine administrations (0.5 mg/kg over 40 min) according to individualized needs. One patient received 16 ketamine infusions over the course of a year. The patient did not have any adverse effects and returned to full functionality in all aspects of life. The second patient, with a significant history of suicide attempts and hospitalizations, received a total of 34 ketamine treatments over 12 months, and the only adverse effects reported were an exacerbation of pre-existing cognitive difficulties (driving and forgetting to take the exit, word-finding difficulties, concentration difficulties) and insomnia. These adverse effects were concurrent with a reduction in the antidepressant efficacy of the infusions (tolerance), beginning with the 20th treatment. A third patient, diagnosed with Bipolar II and “cluster-c traits”, received a total of 32 infusions over 12 months, and experienced two transient hypomanic states during that time.
Blier et al. [36
] reported on a case of a severely depressed women who experienced a tremendous improvement in her depression and cognitive function, without any adverse effects other than a transient metallic taste and transient derealization, despite receiving a total of 59 IV ketamine infusions (the majority 0.5 mg/kg over 40 min) over five months.
Lopez-Diaz et al. [37
] reported a single case of a patient with Bipolar TRD who received six ketamine infusions (0.5 mg/kg over 40 min) over 2 weeks. The authors reported that the only adverse effect the patient experienced was moderate transient sedation during and immediately after the infusions.
The publications in our review described 333 TRD subjects who received six or more parenteral ketamine treatments, 8 of whom (2.4%) discontinued treatment due to ketamine-related adverse effects.