Ketamine for major depressive disorder during an inpatient psychiatric admission: Effectiveness, adverse events, and lessons learned

INTRODUCTION:

Subanesthetic ketamine has antidepressant and anti-suicidal properties, is rapid acting, and effective for treatment resistant depression (TRD) [1–4]. In inpatient psychiatric settings, Major Depressive Disorder (MDD), is associated with elevated costs, readmission rates and high suicide risk [5–7], suggesting an important role for ketamine to treat hospitalized patients. Although ketamine treatment is now widespread in outpatient settings, less is known about its use in naturalistic inpatient settings [8]. A recent meta-analysis of clinical trials conducted in inpatient settings suggested that ECT may be superior to ketamine for reducing depression severity in MDD [9]. However, ECT requires general anesthesia and specialized training to administer, factors which may contribute to limited patient access [10, 11]. Ketamine therapy may be more rapid, a particular advantage in inpatient settings [12].

While ketamine represents a substantial therapeutic advance for MDD, the treatment may also lead to side effects including treatment-emergent mania, psychotomimetic effects, dysphoric disassociation, and suicidal ideation [13–16]. Adverse events associated with ketamine use in unmonitored settings recently led to an FDA warning for patients and healthcare providers [17]. From a safety perspective, inpatient services are logical settings to implement a ketamine trial given pre-existing infrastructure for a controlled environment and close patient monitoring. Clinical outcome and tolerability data specifically from a naturalistic inpatient cohort can also help inform inpatient psychiatrists considering implementing ketamine as a therapeutic option for MDD.

We introduced ketamine for non-psychotic MDD to our inpatient psychiatric services in 2019 based on guidelines published by the American Psychiatric Association’s Council of Research Task Force on Novel Biomarkers and Treatments [18]. The purpose of the present report is to describe the effectiveness, clinical outcomes and adverse events associated with ketamine therapy for this inpatient, naturalistic sample. We hypothesized that ketamine would be safe, effective, and well tolerated in acute psychiatric inpatients.

METHODS:

The ketamine infusion service

The use of ketamine for psychiatric indications was adopted by our institution's inpatient psychiatric program in April 2019. Patients with a diagnosis of MDD were considered for intravenous ketamine therapy on a twice-weekly schedule at a dose of 0.5 mg/kg body weight infused over 40 minutes as augmentation therapy for MDD. The 0.5 mg/kg dose was adjusted down to ideal body weight for patients with high body mass index [18]. Ketamine was given as an adjunctive treatment for patients whose primary pharmacological intervention was a monoamine antidepressant which was selected (or continued) based on individual patients’ prior psychotropic history. Concomitant use of other psychotropics was permitted, although benzodiazepines were reduced or discontinued as tolerated during the ketamine treatment course. No medications were co-administered at the time of ketamine infusion. Ketamine was offered to patients whose depressive episodes were complicated by suicidal ideation or who had TRD, as defined by a failure of two antidepressant medication trials at adequate dose for adequate duration. Patients who had Major Depression with Psychotic Features, a history of dementia, or who also met criteria for a substance use disorder in the six months preceding admission were not offered ketamine. Ketamine was offered to clinically appropriate patients regardless of insurance type, or absence of insurance. Intravenous racemic ketamine was initially used because the inpatient treatment protocol was drafted prior to the FDA approval and marketing of esketamine; we did not switch to esketamine after its approval because of higher cost of esketamine and greater dosing flexibility associated with racemic ketamine.

The ketamine treatment program was implemented across two inpatient sites within our health system. One unit consisted of 32-beds embedded in a large academic medical center campus, where ketamine was administered in a post-anesthesia care unit. The second site was a 240-bed, free-standing psychiatric hospital that constitutes the majority of our department’s inpatient program. In this larger facility, ketamine was administered in an ECT suite.

Given the dissociative effects of ketamine therapy and the possibility of infusion-related dysphoria, we adopted several strategies to help patients have positive therapeutic experiences. We started by carefully describing the dissociative experience during the informed consent process. During infusions, we dimmed overhead lights, offered eye-masks, gave patients warm blankets, and encouraged patients to listen to calming music of their choice. Infusions were administered in quiet areas separate from the general inpatient milieu. We answered patients' questions and offered supportive reassurance if patients felt frightened or dysphoric but did not perform psychotherapy during the infusions.

Informational emails and presentations to the faculty introduced the service, and the ketamine infusion team provided consultations to inpatient teams regarding specific patients. Informed consent for the intervention was obtained in writing prior to treatment. Risks, benefits, and alternative treatments (including electroconvulsive therapy) were offered to patients. Patient symptom severity was documented by the primary psychiatric team in the form of the Montgomery Asberg Depression Rating Scale (MADRS) prior to the first treatment, and again at intervals of within 96 hours of the initial infusion, twice-weekly for the first two weeks, then weekly thereafter.

Data collection and analysis:

We completed a retrospective chart review of demographic, clinical, outcome and side effect data on the first 50 psychiatric inpatients treated with ketamine, to identify outcome data for major depressive episodes. Variables of interest were recorded in a RedCap database designed for this project in accordance with local IRB guidelines. We included all patients treated during the initial three years of the program, who were identified by a clinical database maintained by the ketamine infusion service. Notably, the ketamine treatment program was halted for four months during the acute phase of the COVID pandemic (March- June 2020).

We retrieved demographic data including patient age and gender (racial/ethnic data was not consistently available). We also collected psychiatric history including comorbidities, history of prior hospitalizations, suicide attempts, non-suicidal self-injurious behavior, self-reported history of trauma or abuse, prior history of prior ECT or ketamine therapy, and psychiatric readmission within 6 months of discharge.

We then reviewed the MADRS scores pre-treatment, and at the intervals of within 96 hours of the initial infusion, twice-weekly for the first two weeks, then weekly thereafter. We classified patients as treatment responders if they had 50% or greater reduction in their MADRS total score and remitters if they achieved MADRS total score less than 10 at any point in the study. Adverse events were collected from the ketamine infusion treatment notes and primary team notes. To compare differences in clinical and demographic variables between responder and non-responder groups, we performed independent samples Mann-Whitney U Tests on continuous variables and Chi Square or Fisher’s exact tests on categorical variables.

This project was approved by the Institutional Review Board of Weill Cornell Medical College.

RESULTS:

We reviewed charts of the first 50 patients treated within the three-year period. Of these patients, 41 were included in the analysis; 6 patients were excluded because they had a diagnosis of Bipolar Disorder, and 3 were excluded because of missing MADRS data, precluding characterization of effectiveness outcome. Mean age was 46.9 years and 21 (51.2%) of the patients were women. The most common psychiatric comorbidities included anxiety disorders (19 patients; 46.3%), a history or remitted substance use disorder (10 patients; 24.4%) and personality disorders (10 patients; 24.4%). Most patients (30; 73.2%) had prior psychiatric hospitalizations and over half (22 patients; 53.7 %) had a history of prior suicide attempts. 12 patients (29.3%) had a history or prior treatment with electroconvulsive therapy. 17 patients (41.5%) had a history of trauma or abuse. Not surprisingly, responders’ length of stay in the hospital during the current admission was significantly shorter than for non-responders. Demographic and clinical characteristics of the patients are presented in Table 1.

Table 1:

Clinical and Demographic and characteristics of 41 inpatients treated with Ketamine.

Variable	Overall Sample N=41	Responders* N=19	Non-Responders N=22
Age in years (Mean, SD)	46.9 (16.9)	45.3 (13.0)	48.4 (19.9)
Gender N (% of total N)  Male  Female  Non-Binary	19 (46.3%) 21 (51.2%) 1 (2.4%)	8 (19.5%) 10 (24.4%) 1 (2%)	11 (26.8%) 11 (26.8%) 0
Psychiatric Comorbidities N (% of total N)   Anxiety   Substance Use   Personality Disorder	19 (46.3%) 10 (24.4%) 10 (24.4%)	6 (14.6%) 7 (17.1%) 3 (7.3%)	13 (31.7%) 3 (7.3%) 7 (17.1%)
Prior Psychiatric Hospitalization N (% of total N)	30 (73.2%)	13 (31.7%)	17 (41.5%)
Prior Non-Suicidal Self-Injurious Behavior N (% of total N)	13 (31.7%)	4 (9.8%)	9 (22.0%)
Prior Suicide Attempt N (% of total N)	22 (53.7%)	13 (31.7%)	9 (22.0%)
Prior Treatment with ECT N (% of total N)	12 (29.3%)	4 (9.8%)	8 (19.5%)
History of Trauma N (% of total N)	17 (41.5%)	7 (17.1%)	10 (24.4%)
Indication for Admission N (% of total N)   Suicide Attempt/Severe Suicidality   Worsening Depression w/o suicide attempt	17 (41.5%) 24 (58.5%)	9 (22.0%) 13 (31.7%)	8 (19.5%) 11 (26.8%)
Length of Stay in Days (Mean, SD)	35 (26.9%)	23.2 (9.2%)	45.1 (32.8%)+
Ketamine Dose in mg (Mean, SD)	36.5 (7.6%)	36.4 (8.4%)	36.6 (7.0%)
Baseline MADRS Score (Mean, SD)	33.2 (7.9%)	31.6 (8.6%)	34.6 (7.3%)
Psychiatric Medication at Time of Discharge (N, % of total N)   SSRI   TCA or MAOI   SNRI   Atypical antidepressant   Antipsychotic   Benzodiazepine   Mood stabilizers	13 (31.2%) 7 (17.1%) 22 (53.7%) 16 (39.0%) 30 (73.2%) 20 (48.8%) 6 (15.6%)	7 (17.1%) 3 (7.3%) 8 (19.5%) 6 (14.6%) 15 (36.6%) 9 (22.0%) 2 (5.0%)	6 (14.6%) 4 (9.8%) 14 (34.5%) 10 (24.4%) 15 (36.6%) 11 (26.8%) 4 (9.8%)
Readmission in 6 month follow-up (N, %)	9 (22%)	2 (5.0%)	7 (17.1%)

Responder defined as 50% reduction in MADRS<10 at any point in the study; responder population (N=19) encompasses all remitters (N=15).

⁺Significant difference p<0.05

Treatment outcomes and Adverse Events:

Of the 41 patients, 19 (46.5%) met criteria for response (defined by a 50% reduction of MADRS score from baseline) and a subset of 15 of 19 responders (26.5%) met criteria for remission from major depression (defined by a MADRS score ≤ 10) within five infusions. Twelve of 15 patients (80%) who achieved remission or response did so, on average, within 10 days of initial infusion (3–4 infusion sessions). Number and percentage of total patients who reached response and remission at each timepoint are listed in Table 2. Among the 22 patients (53.6%) that did not respond to ketamine treatment, eight switched to ECT and 14 continued standard psychopharmacological treatment as usual.

Table 2:

Number of patients, and percentage of total to respond and remit by MADRS administration timepoint

Assessment Timepoint Post Initial Infusion	Met Criteria for Response (N=19)	Met Criteria for Remission (N=15)
	N (%)	N (%)
Timepoint 1: Average = 4 days (+/− 1.4 days)	8 (42)	4 (27)
Timepoint 2: Average= 7 days (+/− 1.8 days)	4 (21)	3 (20)
Timepoint 3: Average= 10 days (+/− 3.5 days)	4 (21)	5 (33)
Timepoint 4: Average= 14 days (+/− 3.1 days)	3 (16)	2 (13)
Timepoint 5: Average= 19 days (+/− 0.7 days)	-	2 (13)

Response = 50% or greater reduction in MADRS score.

Remission = MADRS score of less than 10 at any point in treatment.

^*None of the responders had a fifth ketamine infusion therefore the 14-day evaluation was not administered.

Among adverse events, the treatment team discontinued the ketamine course of four non-responders due to potential side effects: two patients who experienced dysphoric disassociation (one with suicidal ideation) during infusions. One patient began engaging in self-injurious behavior that raised concern for ketamine-related disinhibition, and one developed treatment-emergent paranoid delusions. Finally, one patient whose symptoms remitted during the ketamine course died by suicide several weeks after the final infusion and hospital discharge.

DISCUSSION:

The principal finding of this study is that ketamine was safe and effective for a substantial minority of patients with treatment-resistant non-psychotic MDD in a naturalistic study of acute psychiatric inpatients. Nearly half of the patients treated for MDD had significant symptom reduction, and more than a third remitted within 5 ketamine infusions administered on a twice-weekly basis augmenting treatment as usual. These findings support the adoption of ketamine as a viable treatment option for hospitalized patients with severe forms of MDD, especially in facilities where ECT may be unavailable.

Our population had severe MDD as reflected by mean MADRS scores in the severe range [19], and most of these patients had prior histories of psychiatric hospitalization and suicide attempts. There were no significant differences between responders and non-responders in terms of symptom severity as measured by MADRS scores; responders trended towards being more likely to have had a prior suicide attempt, and less likely to have had prior ECT. Our findings have the advantage of being drawn entirely from a treatment seeking population, which may be more generalizable than work based on populations of symptomatic volunteers [20] and represent real-world data ketamine experts have called for [21]. Most of the patients who responded (84%) met the 50% symptom reduction threshold within the first three infusions.

While ECT remains the gold standard treatment for TRD, response may take several weeks or longer [22, 23]. Our findings extend prior work showing that eventual ketamine-responders show significant symptom reduction within the first hours to days after initial infusion, a particular advantage in the inpatient environment [24]. Rapid ketamine treatment response time suggests a possible protocol for inpatients with TRD: Offer two to four ketamine infusions prior to ECT. Ketamine responders can be considered for rapid discharge, while ketamine non-responders can be confidently referred for ECT.

Two of our patients (nearly 5%) experienced infusion related dysphoria, one complicated by acute suicidal ideation, leading them both to discontinue ketamine therapy in favor of ECT. One patient experienced psychotic symptoms and one experienced new-onset self-injurious behavior. In total, four (10%) had negative psychological or behavioral outcomes. These adverse events support the recommendations of APA task force [17] and the Food and Drug Administration’s Risk Evaluation and Mitigation Strategy (REMS) recommendations for intravenous ketamine and esketamine nasal spray to be delivered in monitored settings with supervision by healthcare personnel. Psychiatrists and other personnel who are responsible for treatment recommendations for patients, programmatic oversight of ketamine services and or obtaining informed consent should be aware of these risks. These findings also argue against the wide adoption of at-home or other unsupervised ketamine administration advocated by some groups [25, 26] and support a recent FDA statement warning that side effects, including dissociation, may put patients at risk for serious adverse events when given without monitoring [17]. Inpatient psychiatric units are well equipped to provide the monitoring to identify such adverse events, and thus represent an opportunity to safely initiate ketamine therapy.

The death of one of our remitted patients by suicide several weeks after discharge warrants particular attention. Although ketamine’s antidepressant and anti-suicidal properties are rapid, they may also be transient [27]. Inpatient psychiatrists administering ketamine should be mindful of the risk that a suicidal patient may experience transient improvement leading to discharge and may then be at risk of rapid relapse. Although inpatient psychiatrists have long been aware of this risk with standard antidepressant therapy, it may be exacerbated by ketamine’s rapid onset and transient benefits. The patient’s death highlights the necessity of careful risk-benefit analysis in such decisions and the importance of maintenance ketamine and close psychiatric monitoring even when patients remit. It also highlights the pressing need for additional research to identify treatments to maintain ketamine’s antidepressant effects over longer time frames [28].

Although our pilot sample was underpowered to detect statistical significance, the following differences between Responders (R) and Non-Responders (NR) were notable: Ketamine responders had higher rates of prior suicide attempts (R=68.4% vs. NR=40.9%); lower rates of comorbid personality disorder diagnoses (R=15.8% vs. NR=31.8%); were less likely to have a history of non-suicidal self-injurious behavior (R=21.1% vs. NR=40.9%) and were less likely to have a history of ECT (R=21.1% vs NR=36.4%). Future studies with larger samples should focus on understanding clinical characteristics and comorbidities that may predict response to ketamine treatment.

Several limitations of our findings are important to note. As our work is drawn from a clinical program, the raters conducting the MADRS scales were psychiatrists, psychologists, and trainees in each discipline who did not undergo standardized training in scale administration nor blinding to the intervention. We do not have comparison data on other hospitalized patients with non-psychotic Major Depressive Disorder who were not offered ketamine, or were offered and declined ketamine, and thus cannot rule out the possibility of selection bias. Similarly, the diagnoses of treatment resistant Major Depressive Disorder were not confirmed with a standardized diagnostic instrument. Because the clinical service recorded total MADRS scores but not individual response scores on specific questions, we cannot perform sub-analysis of whether individual symptom item score severity may represent moderators of treatment response, or short-term reduction in the suicidal ideation item during ketamine course in this cohort, which we hope to explore in future work. We also lack consistent outcome data for patients who switched to ECT, preventing us from assessing response rates when patients switched interventions. A limitation of our hospital EMR system is the lack of consistency in recording diversity related data such as race and ethnicity.

In conclusion, twice weekly racemic ketamine infusions of 0.5 mg/kg were safe and led to significant reduction in depression severity in nearly half of acute psychiatric inpatients with non-psychotic, treatment resistant MDD. A substantial minority of patients experienced significant intra-infusion dysphoria or other treatment-contemporaneous psychiatric side effects that required ketamine therapy discontinuation. The majority of patients who ultimately responded had significant symptom reduction within the first week of ketamine therapy, suggesting that patients who do not respond in this time frame might be considered for ECT or other appropriate treatments. Patients who do respond require close follow up and ongoing care, possibly including maintenance ketamine, and should be carefully screened for relapse and suicide risk prospectively after discharge. Additional work is necessary to assess whether dose escalation is effective for patients who do not respond to 0.5 mg/kg, and on the use of ketamine for other diagnostic indications. Psychiatrists and administrators overseeing inpatient psychiatric units should seriously consider offering ketamine infusions as a treatment option for patients with TRD or patients with MDD complicated by suicidal ideation.

Inpatient Ketamine for Depression: Consort Chart and Patient Outcomes

*Responders are inclusive of remitters