Ketamine treatment for individuals with treatment-resistant depression: longitudinal qualitative interview study of patient experiences

This longitudinal interview study (n=12) examined the subjective expectations and effects of ketamine treatment (35mg/70kg) in a population with treatment-resistant depression (TRD). The study found high expectations, side-effects for most (11/12), a reduction in suicidal ideation (SI) for many (8/12) but for some (3/12) more SI when treatment effects decreased (1 week later).

Abstract

“Background: Ketamine has recently received considerable attention regarding its antidepressant and anti-suicidal effects. Trials have generally focused on short-term effects of single intravenous infusions. Research on patient experiences is lacking.

Aims: To investigate the experiences over time of individuals receiving ketamine treatment in a routine clinic, including impacts on mood and suicidality.

Method: Twelve fee-paying patients with treatment-resistant depression (6 females, 6 males, age 21-70 years; 11 reporting suicidality and 6 reporting self-harm) who were assessed as eligible for ketamine treatment participated in up to three semi-structured interviews: before treatment started, a few weeks into treatment and ≥2 months later. Data were analysed thematically.

Results: Most participants hoped that ketamine would provide respite from their depression. Nearly all experienced improvement in mood following initial treatments, ranging from negligible to dramatic, and eight reported a reduction in suicidality. Improvements were transitory for most participants, although two experienced sustained consistent benefit and two had sustained but limited improvement. Some participants described hopelessness when treatment stopped working, paralleled by increased suicidal ideation for three participants. The transient nature and cost of treatment were problematic. Eleven participants experienced side-effects, which were significant for two participants. Suggestions for improving treatment included closer monitoring and adjunctive psychological therapy.

Conclusions: Ketamine treatment was generally experienced as effective in improving mood and reducing suicidal ideation in the short term, but the lack of longer-term benefit was challenging for participants, as was treatment cost. Informed consent procedures should refer to the possibilities of relapse and associated increased hopelessness and suicidality.”

Authors: Karen Lascelles, Lisa Marzano, Fiona Brand, Hayley Trueman, Rupert McShane & Keith Hawton

Summary

Ketamine for treatment of depression

Ketamine has been used therapeutically in psychiatry to treat people experiencing depression that has proved difficult to treat, commonly referred to as treatment-resistant depression (TRD). Ketamine can also be used to try and reduce suicidal ideation, but again with transitory benefits.

Most early trials of ketamine treatment for depression involved single infusions. Later trials involved multiple doses and transfer to other modes of ketamine treatment. Research into repeated treatments with ketamine for depression has been increasing, but there are few qualitative studies of patients’ experiences over time. This is particularly important given that some authors have urged caution regarding provision of ketamine treatment getting ahead of evidence of effectiveness.

The current study

This study explored the experiences of patients with TRD who received ketamine treatment, including their expectations, short- and long-term effects, side-effects, and overall views on ketamine treatment.

Method

The study participants were self-funding patients attending a single ketamine clinic in the UK. They were assessed to be appropriate candidates for ketamine treatment and agreeable to treatment.

At this ketamine clinic, patients are given three intravenous ketamine infusions, followed by a break of 3-4 weeks. If they have responded positively to treatment, further individualised treatment could take the form of regular oral ketamine or intermittent intravenous ketamine.

Recruitment

Individuals newly referred to the ketamine clinic were invited to take part in the study and given participant information sheets by ketamine clinic clinicians. Written informed consent was obtained from all participants.

Data collection

The interviews took place between May and December 2017. Participants kept a diary and were interviewed three times, and the Quick Inventory of Depressive Symptomatology (Self-Rated)20 was routinely completed.

One-to-one semi-structured interviews were conducted with twelve participants. Eleven out of twelve interviews were conducted face to face, and seven were conducted via phone, Skype or Facetime.

The first interview focused on participants’ clinical history, hopes, expectations and anxieties about ketamine treatment. The second and third interviews addressed participants’ experiences of treatment.

Participants were interviewed for 20-60 min and given the opportunity to receive copies of their transcripts. Two participants requested their interview transcript, and two further participants provided retrospective paragraphs via email.

Data analysis

Interviews were transcribed and thematic analysis was carried out to identify participants’ experiences and their explanations for these. Final agreement on themes was based on consensus discussion between two researchers.

Ethical approval

The authors have obtained ethical approval for all procedures involving human subjects/patients. The complete Consolidated Criteria for Reporting Qualitative Research Checklist can be accessed in Supplementary Appendix 2.

Results

The study sample comprised 12 individuals with depression, of which 8 were taking antidepressant medication, 2 were also taking mood stabilisers and 2 were taking anxiolytics. Four participants were currently engaged in psychological treatments, including counselling/therapy, cognitive -behavioural therapy and psychosocial intervention.

Eight participants attended all three research interviews, three attended only the first two interviews, and one attended the first and second interviews but was uncontactable at the time of the second interview. The third interview took place 4 months after the first interview.

Ten participants had at least three intravenous ketamine treatments, with six going on to oral treatment. They reported both short- and long-term effects on mood and suicidal ideation.

Pre-treatment: finding out about ketamine treatment and expectations of it

Participants found out about ketamine treatment by internet searching for treatments for depression or through national news coverage. All participants anticipated positive changes in their mood and functioning following ketamine treatment.

Six out of ten participants were cautious about expressing hope for a new treatment because of past experiences of treatments not working.

Impact of treatment on mood and suicidal ideation

Ten participants reported a positive impact on mood at some point during their course of ketamine treatment, including one who had a single infusion only before being withdrawn from treatment because of side-effects. The main themes relating to the lifestyle outcomes of improved mood were improved functionality, becoming less self-critical and being able to socialise.

I played golf yesterday and didn’t feel anxious, and I didn’t worry about what other people thought of me.

Initial impact (first two treatments)

Nine participants noticed some improvement in mood after the first ketamine treatment. These effects lasted between a day and right through to the next treatment.

Eight participants reported a reduction in suicidal ideation. Some participants were starkly aware that they no longer had suicidal thoughts, while others were more subtle.

‘It was like a weight had been lifted off my shoulders, I could do things again, I wasn’t thinking about suicide’ (P4, interview 2)

Subsequent impact (third treatment onward)

Ten participants had three or more ketamine treatments, and three reported sustained improvements in mood, but three reported a return of suicidal thoughts as the positive effects on mood wore off.

After changing the doses 2 or 3 times, the patient starts to lose confidence in the treatment and feels that they are heading towards oblivion again.

‘It all went downhill, I can’t remember whether I was suicidal at all, but I was anxious for something to be fixed, to be helped.’

Half of the participants were still in treatment at the end of the study, and one reported a sustained and significant improvement in mood. Three of the remaining five participants reported ongoing but dwindling positive effects on mood.

Six participants had stopped ketamine by the end of the study, one of whom reported feeling worse as a result of the ketamine treatment not working.

Side-effects of ketamine treatment

During treatment, 11 out of 12 participants experienced dissociation, blurred vision, and nausea. These effects lasted between 1 and 3 hours.

Experiences of the first intravenous ketamine treatment ranged from pleasant to unpleasant, with most people feeling somewhere in between.

Eleven participants experienced side-effects following ketamine treatment, including tiredness, headaches, and gastrointestinal symptoms. One participant experienced a debilitating 4-day long headache, which led to termination of treatment.

‘I don’t mind taking it because I know it’s not a horrible sensation, so I suppose I’ve got a slight addiction,’ said P1.

Overall perspectives on treatment

Ketamine treatment met or exceeded expectations for five participants. Three participants felt their improvement had plateaued or diminished, while others said their expectations had not been attained.

Ketamine treatments were beneficial for myself, but I lack the funds to have more treatments.

‘I was angry and sad because my improved mood stopped and I was back to the way I was. I hope this gets better with longer treatment.’

Participants who did not derive lasting benefit from ketamine were generally positive about the availability of an alternative to traditional antidepressants. Some suggested improving treatment experiences by offering more individualised dosages and closer monitoring by clinic staff.

Discussion

In this qualitative study, patients undergoing ketamine treatment for TRD reported varying levels of benefit, with improvement ranging from negligible and/or short term to substantial and sustained improvement. However, benefits diminished over time, and hope for improvement waned in some participants.

Impact on mood

Improvement in mood occurred at varying time points and for differing lengths of time following intravenous ketamine treatment. The second intravenous ketamine treatment resulted in marked improvement for some participants.

Impact on suicidal ideation

Most participants who reported a reduction in suicidal ideation associated it with improvement in mood, but some reported an independent effect.

Side-effects and other consequences of ketamine treatment

Participants in this study thought that the main side-effects of ketamine treatment were dissociation and strange or unreal sensations, and that the main side-effects following treatment were fatigue and headaches. A minority of participants thought that there might be a possibility of dependency on ketamine occurring over time.

Most participants in our study found out about ketamine via the media, suggesting that widespread reporting attracts individuals who are searching for novel treatments to provide respite from depression. Hope was a large part of the ketamine treatment experience, and some participants felt hopeless when the treatment stopped working. They suggested that closer monitoring and psychological input could improve outcomes.

Strengths and limitations

This study was conducted in a routine clinic setting rather than a trial, and thus there were no formal inclusion/exclusion criteria. The results are not necessarily generalisable, but the qualitative approach provides a nuanced understanding of experiences of patients.

The small number of participants and short duration of follow up in this study may have contributed to the variability of responses, but self-report from semi-structured interviews rather than validated clinical scales was largely relied upon when seeking information about changes/improvements to mood and hopelessness.

Ketamine nasal spray, the S-enantiomer of ketamine, has been developed and showed promising results in combination with an antidepressant. However, the UK National Institute for Health Care Excellence has not approved its use.

The findings from this qualitative study of patient experiences with ketamine treatment complement those from treatment trials. It suggests that there should be caution regarding overly optimistic interpretation of the place of ketamine treatment in the management of TRD.