Ketamine Treatment for Depression in Patients With a History of Psychosis or Current Psychotic Symptoms: A Systematic Review

This systematic review (2021) examines whether ketamine treatment in patients with a history of psychosis or current psychotic symptoms and found 9 pilot studies (n=41) which indicate that ketamine’s side effects are mild and self-limiting even among these patients. While limited in sample size, the available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients.

Abstract

“Objective: Ketamine shows rapid and robust antidepressant effects in clinical studies. Psychotic features are an exclusion criterion in most ketamine treatment studies based on the assumption that psychosis will increase with ketamine administration. As patients with treatment-resistant depression (TRD) often have psychotic features, and treatment-resistant depressive symptoms are also common in patients with schizophrenia, the aim of this systematic review is to determine whether this assumption holds true.

Data Sources: The literature was searched for data on ketamine treatment for depression or negative symptomatology in patients with a history of psychosis or current psychotic symptoms (PubMed/MEDLINE) from inception to March 2020 without date or language restrictions. The following terms were used: ketamine and psychosis, psychotic or schizo*. A filter for human studies was applied.

Study Selection: A total of 482 articles were identified; 473 articles were excluded because they did not report on the effect of ketamine treatment in patients with a history of psychosis or current psychotic symptoms.

Data Extraction: The remaining 9 articles were reviewed.

Results: Nine reports of pilot studies and case reports with a total of 41 patients have been published. These studies suggest that short-term ketamine treatment for depression and even negative symptoms in patients with a history of psychosis or current psychotic features can be both safe and effective, as side effects were mild and self-limiting.

Conclusions: The currently available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients. Data, however, are limited, and further trials are needed in this patient group.”

Authors: Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jan Spijker, Jeanine Kamphuis & Robert A Schoevers

Summary

Ketamine shows rapid and robust antidepressant effects in clinical studies. However, patients with psychotic features are often excluded from ketamine treatment studies.

Data was searched for studies on ketamine treatment for depression in patients with a history of psychosis or current psychotic symptoms.

Studies on ketamine treatment in patients with psychosis were excluded.

Data Extraction: 9 articles were reviewed.

Nine studies with 41 patients have been published, suggesting that short-term ketamine treatment for depression can be safe and effective.

Ketamine does not exacerbate psychotic symptoms in predisposed patients, but further trials are needed.

Ketamine treatment for depression in patients with a history of psychosis or current psychotic symptoms: a systematic review.

Ketamine was initially synthesized in 1962 as a short-acting dissociative anesthetic. It has since been used as an analgesic for pain management in acute and chronic settings, and as an antidepressant in unipolar and bipolar depression.

Ketamine can cause psychotic side effects, including hallucinations, feeling strange or unreal, abnormal sensations, and dissociation. These effects are dose-related and associated with higher peak blood levels of ketamine.

Ketamine has been studied for its antidepressant potential, but patients with schizophrenia or related psychotic disorders who experience treatment-resistant depressive symptoms have been excluded from the studies. Ketamine may have anti-anhedonic effects without negatively affecting long-term psychotic symptomatology in patients with schizophrenia.

Future research on ketamine treatment for depression should carefully broaden the inclusion criteria to also investigate its actual effects in patients with a vulnerability to psychosis.

METHODS

We searched the PubMed/MEDLINE database for articles on the effects of ketamine on patients with psychosis or current psychotic symptoms.

RESULTS

A total of 482 articles were identified, of which 9 reported on ketamine treatment in patients with a history of psychosis or current psychotic symptoms.

Pennybaker et al27 performed a post hoc analysis of 3 randomized, placebo-controlled crossover trials in patients with a current depressive episode receiving 0.5 mg/kg ketamine infusion over 40 minutes. Patients with a history of psychosis showed improvement in depressive symptoms after ketamine infusion, but the effects were less robust in patients with a positive history of psychosis than in patients without a history of psychosis.

Ketamine was used as an antidepressant in 2 cases by Medeiros da Frota Ribeiro et al.28,29. A 52-year-old woman with a long history of unipolar depression and psychotic features was treated with ketamine and had good results.

A 55-year-old woman with schizoaffective disorder showed a dramatic mood improvement after 0.5 mg/kg ketamine infusion, and her psychotic symptoms disappeared after the ketamine infusion.

Esketamine was administered intravenously or subcutaneously to 4 patients with severe depression with psychotic features. Three patients showed marked improvement or complete remission of both depressive and psychotic symptoms 24 hours after administration, and 2 and 4 weeks’ follow-up evaluation.

A 15-year-old adolescent male with severe TRD, psychotic symptoms, suicidal ideation, generalized anxiety disorder, and posttraumatic stress disorder was administered 6 ketamine infusions of 0.5 mg/kg over the course of 3 weeks. He was successfully discharged into community care and continued to do well during follow-up of several months.

A 30-year-old woman with severe and chronic schizophrenia was treated with IV esketamine (0.22 mg/kg). The patient showed full remission of positive symptoms with standard psychopharmacotherapy, but her depressive symptoms remained.

A pilot study of 15 patients with treatment-resistant schizophrenia found that adjunct ketamine treatment significantly reduced depressive symptoms and improved psychopathological symptoms. However, the treatment was discontinued after 58 days, and no significant differences were observed between baseline and assessment scores.

Nunes et al35 studied the effects of esketamine on persistent negative symptoms in 6 patients with schizophrenia. They found that 5 of 6 patients showed significant improvement of negative symptomatology after 4 weeks of esketamine infusions.

DISCUSSION

A review of studies on the use of ketamine and esketamine in patients with a history of psychosis or current psychotic symptoms found that no psychotic exacerbation occurred in the included patients. In several cases, comorbid psychotic symptoms improved or disappeared entirely after ketamine or esketamine administration for depression.

Ketamine has good initial antidepressant effects in most trials and in some patients are even maintained over the course of a year. However, patients with a history of psychosis have a lower effect size and future studies should enroll larger numbers of patients.

This review shows that ketamine may improve depressive symptoms in patients with MDD and psychotic features, schizoaffective disorder, and schizophrenia, although the effects are not always lasting. Ketamine use is well tolerated and does not negatively influence the course of psychotic illness.