Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review

This systematic review (2021) examines the pharmacodynamic interactions between ketamine and generally prescribed psychiatric drugs based on published evidence and found that lamotrigine and benzodiazepines attenuate and shorten ketamine’s antidepressant effects. There are also indications for interactions between ketamine and antipsychotic drugs, such as haloperidol, risperidone, and clozapine (but not olanzapine), although further research is necessary to understand their side effects.

Abstract

“Background: The use of ketamine for depression has increased rapidly in the past decades. Ketamine is often prescribed as add-on to other drugs used in psychiatric patients, but clear information on drug-drug interactions is lacking. With this review we aim to provide an overview of the pharmacodynamic interactions between ketamine and mood stabilizers, benzodiazepines, monoamine oxidase-inhibitors (MAOIs), antipsychotics and psychostimulants.

Methods: MEDLINE and Web of Science were searched.

Results: Twenty-four studies were included. For lithium, no significant interactions with ketamine were reported. Two out of five studies on lamotrigine indicated that the effects of ketamine were attenuated. Benzodiazepines were repeatedly shown to reduce the duration of ketamine’s antidepressant effect. For the MAO-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent S-ketamine use. One paper indicated an interaction between ketamine and haloperidol, two other studies did not. Four papers investigated risperidone, including three neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. Clozapine significantly blunted ketamine-induced positive symptoms in patients with schizophrenia, but not in healthy subjects. One paper reported no effect of olanzapine on ketamine’s acute psychotomimetic effects.

Conclusion: Current literature shows that benzodiazepines and probably lamotrigine reduce ketamine’s treatment outcome, which should be taken into account when considering ketamine treatment. There is evidence for an interaction between ketamine and clozapine, haloperidol and risperidone. Due to small sample sizes, different subject groups and various outcome parameters, the evidence is of low quality. More studies are needed to provide insight into pharmacodynamic interactions with ketamine.”

Authors: Jolien K. E. Veraart, Sanne Y. Smith-Apeldoorn, Iris M. Bakker, Berber A. E. Visser, Jeanine Kamphuis, Robert A. Schoevers & Daan J. Touw

Summary

Ketamine is used for depression and is often prescribed as add-on to other drugs used in psychiatric patients.

Twenty-four studies were included. Benzodiazepines, lamotrigine, haloperidol, risperidone and MAO inhibitors reduce ketamine’s treatment outcome, but the evidence is of low quality due to small sample sizes, different subject groups and various outcome parameters.

Ketamine is increasingly being used off label for the treatment of depression in the USA and Europe, often as add on to other psychiatric medication. The FDA and EMA have approved intranasal S-ketamine for treatment resistant depression. Ketamine may cause anxiety, perceptual changes and dissociation, and it is often combined with other psychiatric drugs. Knowledge on pharmacodynamic interactions is crucial when using ketamine in clinical practice.

Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist that also shows affinity for multiple other receptors. Its main mechanism of action is believed to stem from antagonism of the NMDA receptor on GABA releasing interneurons in the prefrontal cortex.

Ketamine is often used in combination with other psychiatric drugs, such as lithium, tricyclic antidepressants, bupropion, mirtazapine, etc., but some drugs may interact with ketamine, such as lamotrigine, which reduces glutamate transmission as a result of sodium channel blockage. The aim of this review is to summarize the current knowledge from human studies on the combined use of ketamine and psychiatric drugs commonly prescribed to patients with TRD.

We searched for human studies on the effects of ketamine on psychiatric medication. We included studies with a randomized controlled design, post hoc analyses from controlled trials and open label studies, and case reports. Systematic reviews were screened for studies that met our criteria and were not found with the literature search. We used Joanna Briggs Institute’s critical appraisal tools for quality assessment of the included studies.

In total 4887 studies were identified through database searching, and 1228 studies remained for full text assessment. 98 studies were excluded for the following reasons: anesthetic dosages, other outcome measures, other drugs than ketamine examined, animal models, and combinations of these reasons.

We included 2 RCTs on lithium and 7 studies on lamotrigine. We also found 1 case report, 3 post hoc analyses and a placebo controlled study on the interaction between ketamine and benzodiazepines.

Lithium does not seem to potentiate ketamine’s antidepressant effect in patients with depression, as shown by the studies Costi et al. (2019) and Xu et al. (2015).

Lamotrigine reduces glutamatergic activity and may impede the effects of ketamine. Seven studies investigated the effects of lamotrigine prior to ketamine administration in healthy subjects and found that it had an increasing effect on mood elevation after ketamine. Mathew et al. (2010) found no attenuated psychotomimetic effects in patients with MDD randomized to lamotrigine prior to ketamine, and Deakin et al. (2008) found a significant reduction in ketamine-induced total CADSS and BPRS scores when pretreated with lamotrigine.

A patient with bipolar disorder who had no response to several antidepressants and antipsychotics was treated with lorazepam and responded to repeated doses of ketamine.

In addition to this case report, we found four papers reporting on an interaction between ketamine and benzodiazepines. These papers showed that benzodiazepine users showed a significant longer time to antidepressant response, longer time to depression remission and a shorter time to depression relapse. In a study, lorazepam reduced emotional distress and distorted sensory perceptions associated with ketamine infusion, but failed to block psychotogenic, perceptual, cognitive, neuroendocrine and physiological ketamine responses.

Tranylcypromine was administered to two patients with depression who received S-ketamine in dosages ranging from 10-80 mg daily. No relevant cardiovascular or hemodynamic changes were observed.

Ketamine has been shown to enhance dopamine in vitro. Haloperidol, a D2 receptor antagonist, reduces the effects of ketamine on executive cognitive functions and anxiogenic effects.

The study of Oranje et al. (2009) found that haloperidol improved the ability of 18 healthy male subjects to reduce processing negativity.

Lahti et al. (1995) found that haloperidol did not blunt ketamine-induced psychosis in patients with schizophrenia, but did reduce some acute effects of ketamine (impairments in executive cognitive functions and anxiogenic effects).

Risperidone’s strong antiserotonergic and antidopaminergic effects might counteract ketamine’s monoaminergic enhancement. Three phMRI studies and one study investigating oculomotor performance have shown that risperidone attenuates ketamine’s effect across most ROIs. Ketamine increased centrality in phMRI and perfusion in phMRI in 20 healthy males. Risperidone pre-treatment increased the ketamine-induced perfusion changes (p 0.02) but no clinical studies have yet investigated whether this would also result in an attenuation of the antidepressant effects.

Clozapine has a wide spectrum of pharmacological actions, including blockade of the dopamine D1- and serotonergic 5-hydroxytryptamine (5-HT)2 receptors. Studies on interactions between clozapine and ketamine are inconsistent, but a low dose of clozapine (30 mg oral) reduced some of the S-ketamine responses in healthy subjects.

Olanzapine’s antagonistic effects on serotonin and dopamine receptors might cause an interaction with ketamine. However, a study found no difference in blocking ketamine-induced psychotic symptoms between olanzapine and placebo.

This review summarizes currently available information on interactions between ketamine and other psychiatric drugs. It does not find evidence for interactions between lithium and ketamine, nor for the hypothesis that lithium would strengthen the antidepressant effect through inhibition of GSK3.

Benzodiazepines might attenuate the antidepressant effects of ketamine by increasing the inhibitory tone of GABAergic interneurons and by blocking ketamine-induced dopamine release. Ketamine can interact with MAOIs and tranylcypromine, but not with antipsychotics. Ketamine’s effects are caused by its agonistic effect on dopaminergic D2 receptors, but the mechanism by which ketamine causes psychotic symptoms is not affected by D2 blockade.

Risperidone had no effect on ketamine-induced eye movements, but attenuated ketamine’s brain perfusion changes in healthy subjects. The opposing effects of ketamine and risperidone at the D2 receptor and 5-HT2A receptor may also play a role.

Three studies investigating clozapine and ketamine found inconsistent results. A low dose of clozapine (50mg) did not affect ketamine’s effects on the BPRS and CADSS in healthy subjects, but a higher dose of clozapine did affect ketamine’s positive symptoms in patients with schizophrenia.

Olanzapine may attenuate the antidepressant effects of ketamine or S-ketamine. One patient with TRD receiving olanzapine 10 mg did not achieve response or remission after six infusions 0.25 mg/kg S-ketamine.

This review contains multiple conference abstracts that have not been published in peer reviewed full text, has small sample sizes, and used ketamine as a model for psychosis. It also contains case reports that have to be interpreted with great caution.

In conclusion, this systematic review provides new insights for the clinical practitioner. It is very likely that benzodiazepines shorten the duration of ketamine’s antidepressant effects, and there are indications for an interaction between haloperidol, risperidone and clozapine but not evidently for olanzapine.

Clinical practitioners should be aware of possible drug-to-drug interactions when prescribing ketamine. Lower doses of benzodiazepines or temporary benzodiazepine withdrawal before ketamine administration may prevent an efficacy attenuating interaction.

The authors declare no competing interests. JKE Veraart, RA Schoevers, D.J. Touw and SY Smith-Apeldoorn have received funding from Janssen Pharmaceuticals, ZONMW and Chiesi Pharmaceuticals, respectively, outside the submitted work.

JKEV, SYSA, IMB, BAEV, JK, RAS and DJT contributed to the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, critical revision for important intellectual content, final approval of the version to be submitted and agreement to be accountable for all aspects of the work.