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.
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.
Papers cited by this study that are also in Blossom
Abdallah, C. G., Averill, C. L., Salas, R. et al. · Biological Psychiatry (2017)
William Deakin, J. F., Lees, J., McKie, S. et al. · JAMA Psychiatry (2008)
Han, Y., Chen, J., Zou, D. et al. · Neuropsychiatric Disease And Treatment (2016)
Ionescu, D. F., Felicione, J. M., Gosai, A. et al. · Harvard Review of Psychiatry (2018)
Since 2000, repeatedly reported rapid antidepressant effects of ketamine have led to increasing off-label use for depression and to regulatory approval of intranasal S-ketamine for treatment-resistant depression (TRD) in conjunction with an oral antidepressant. Many patients considered for ketamine are already taking other psychiatric medications, yet clinical guidance about pharmacodynamic interactions is limited. Ketamine’s principal action is as a non-competitive NMDA (N-methyl-d-aspartate) glutamate receptor antagonist, but it has affinity at multiple other targets (including monoamine transporters and several receptor classes), and its putative antidepressant mechanism involves disinhibition of prefrontal glutamate release, AMPA receptor stimulation and downstream synaptic plasticity changes in regions such as the anterior cingulate, prefrontal cortex and hippocampus. Veraart and colleagues set out to systematically review human studies reporting pharmacodynamic interactions between ketamine and commonly co-prescribed psychiatric drugs relevant to depression treatment. The review focused on mood stabilizers, benzodiazepines, monoamine oxidase inhibitors (MAOIs), antipsychotics and psychostimulants, with the aim of summarising available clinical, neuroimaging and electrophysiological evidence that might indicate potentiation or attenuation of ketamine’s effects and highlight safety signals or gaps in knowledge important for clinical practice and research planning.
The investigators searched MEDLINE and Web of Science on 9 July 2020 for human studies examining pharmacodynamic interactions between ketamine and psychiatric drugs (antidepressants, mood stabilizers, antipsychotics, benzodiazepine agonists or psychostimulants). English and Dutch filters were applied. The search combined drug generic and brand names with the term 'ketamine'; the detailed search strings were reported in supplementary material. Grey literature, including conference abstracts, was eligible. Inclusion criteria prioritised randomized controlled trials (RCTs). Where RCT data were sparse (one or no RCTs), the team included lower levels of evidence such as post hoc analyses, open-label studies and case reports if they provided relevant interaction information. Studies of ketamine given at anaesthetic doses or trials simply adding ketamine to a routine antidepressant (except MAOIs) were excluded, since safety and additive antidepressant effects of ketamine on regular antidepressants had been addressed elsewhere. Two reviewers independently screened titles, abstracts and full texts, resolving disagreements by discussion and involving a third or fourth reviewer when necessary. Data extracted included study design, sample size, population characteristics, intervention details, clinical and mechanistic outcomes and authors’ hypotheses about mechanisms. Quality assessment used Joanna Briggs Institute tools appropriate to RCTs, quasi-experimental designs and case reports. The review adhered to PRISMA reporting guidance. The extracted text notes that details of the selection process and quality assessments are available in supplementary figures and appendices.
The search identified 4,887 records; after deduplication and screening, 24 studies met the eligibility criteria and were included. Included evidence comprised a mix of study types: two RCTs on lithium, seven studies on lamotrigine, several analyses and a placebo-controlled study relating to benzodiazepines, two case reports for tranylcypromine (an MAOI), three double-blind placebo-controlled studies for haloperidol, four articles on risperidone (three using neuroimaging outcomes), three studies on clozapine and one study on olanzapine. No studies were identified that examined ketamine combined with psychostimulants. Mood stabilizers: Two RCTs examining lithium found no significant potentiation of ketamine’s antidepressant effects when lithium was co-administered. Lamotrigine (typically 300 mg administered about 2.5 hours before IV ketamine in the included studies) produced mixed results across seven reports: several studies in healthy subjects and one in patients with major depressive disorder showed attenuation of ketamine-induced effects on dissociation (CADSS), psychotomimetic symptoms (BPRS) and blood-oxygen-level-dependent (BOLD) responses in frontal and thalamic regions, whereas other studies found no interaction on resting perfusion or degree-centrality measures. The authors note heterogeneity of dose, infusion protocols and subject populations as possible explanations for inconsistent findings. Benzodiazepines: Evidence consistently indicated that benzodiazepines can diminish ketamine’s antidepressant benefits. Case reports and post hoc analyses showed that higher benzodiazepine doses were associated with delayed time to response and remission and with shorter duration of antidepressant effect after ketamine. One pooled analysis reported that benzodiazepine medication at 10 mg or more diazepam equivalent after a 0.54 mg/kg ketamine infusion predicted nonresponse within one week (odds ratio = 1.5, p = 0.0445). A healthy volunteer study showed that lorazepam 2 mg reduced some subjective distress and sensory distortions during ketamine infusion but did not fully block psychotomimetic, cognitive, neuroendocrine or physiological ketamine responses. MAOIs: Two case reports describing concurrent use of tranylcypromine (10–80 mg/day) with S-ketamine (IV doses 12.5–75 mg or intranasal doses 28–56 mg) did not report clinically relevant cardiovascular or haemodynamic changes, nor serotonergic syndrome; however, clinical experience remains very limited. Antipsychotics: Findings varied by drug and study population. Haloperidol pretreatment (oral or parenteral doses reported in the included studies) reduced certain acute ketamine effects in healthy subjects — for example, reductions in ketamine-induced impairments in executive function and anxiogenic effects — but a study in nine patients with schizophrenia on high-dose haloperidol found no blunting of ketamine-induced psychotic symptoms and, in that sample, greater increases in psychosis ratings during haloperidol treatment. For risperidone, three pharmacological MRI studies in healthy males reported that 2 mg risperidone attenuated ketamine-induced BOLD/perfusion changes and modulated degree-centrality increases; a separate study found no effect of risperidone on ketamine-induced eye-movement changes. No clinical trial data established whether risperidone attenuates ketamine’s antidepressant efficacy. Clozapine results were inconsistent: low single doses (30–50 mg) produced limited or variable attenuation of S-ketamine responses on neuroimaging or psychotomimetic measures in healthy subjects, whereas a study in patients with schizophrenia receiving higher maintenance clozapine doses (mean ~430 mg/day) showed significant blunting of ketamine-induced positive symptoms. One small study of olanzapine (5–10 mg) found no difference versus placebo in blocking ketamine-induced psychotic symptoms. Safety and other findings: Across studies, sample sizes were small (range 1–72), and several included conference abstracts. Many experiments used ketamine as a model of psychosis in healthy volunteers, limiting direct translation to antidepressant treatment contexts. Heterogeneity in ketamine formulations (racemic versus S-ketamine), doses and administration schedules, and variation in outcome measures, complicated comparisons. The authors judged the overall evidence quality as low and called for further targeted trials.
Veraart and colleagues interpret the assembled evidence as providing preliminary but clinically relevant signals about pharmacodynamic interactions with ketamine. The most consistent finding is that benzodiazepines are likely to shorten ketamine’s antidepressant duration and, at higher doses, predict nonresponse; the authors explain this mechanistically by benzodiazepine agonism at GABA receptors increasing inhibitory interneuron tone, thereby opposing ketamine’s glutamate-driven synaptic potentiation. Animal studies cited in the review support the concept that benzodiazepines (for example diazepam) can block ketamine-induced limbic metabolic and dopamine-release effects. For lamotrigine, several human studies suggest antagonism of acute ketamine effects, including reductions in dissociation, psychotomimetic scores and ketamine-induced BOLD responses, consistent with lamotrigine’s capacity to reduce glutamate transmission via sodium-channel blockade. Nevertheless, other investigations failed to detect an interaction, and the authors highlight differences in ketamine dose, infusion speed, subject population (healthy volunteers versus TRD patients) and metabolic factors as plausible explanations for discrepant results. Regarding antipsychotics, neuroimaging studies indicate that risperidone attenuates ketamine-induced perfusion and connectivity changes, but clinical data on antidepressant outcome are absent. Haloperidol reduced some cognitive and anxiogenic effects of ketamine in healthy volunteers, yet did not blunt ketamine-induced psychosis in a small sample of patients with schizophrenia. Clozapine produced inconsistent results across studies; in patients on therapeutic clozapine doses positive symptoms induced by ketamine were blunted, whereas low single doses had variable or limited effects in healthy subjects. For MAOIs (tranylcypromine) the two case reports included did not show hypertensive crises or serotonergic toxicity when combined with S-ketamine, but the authors caution that clinical experience is insufficient to exclude rare adverse events. The authors acknowledge several key limitations: inclusion of unpublished conference abstracts, small and heterogeneous samples, diverse ketamine regimens and outcome measures, and a predominance of studies using ketamine as a psychosis model in healthy subjects rather than probing antidepressant outcomes in clinical populations. They conclude these factors weaken confidence in causal inferences and generalisability. Consequently, Veraart and colleagues recommend minimising benzodiazepine (and Z-drug) use in patients receiving ketamine for depression, considering potential lamotrigine interactions when patients fail to respond, and cautious co-prescription of low-dose MAOIs with close monitoring. For future research they urge prospective trials that systematically record concomitant medications, explore dose-dependence (for example temporary benzodiazepine withdrawal or lower benzodiazepine doses), and assess both efficacy and safety of relevant combinations in patients with depression.
The systematic review found no evidence of an interaction between lithium and ketamine. Some but not all studies indicate lamotrigine can attenuate ketamine-induced effects. Available evidence suggests benzodiazepines very likely shorten the duration of ketamine’s antidepressant effects, which should inform clinical decision-making. Limited case-report evidence did not reveal acute haemodynamic or serotonergic crises when S-ketamine was combined with the MAOI tranylcypromine, but data are sparse. Overall, the evidence base is small, heterogeneous and of low quality, and the authors call for further rigorous studies to clarify pharmacodynamic interactions and their clinical implications.
Since 2000 the rapid and robust antidepressant effects of ketamine have been reported repeatedly. Ketamine is increasingly being used off label for the treatment of depression in the USAand at a slightly slower pace in Europe, often as add on to other psychiatric medication. Furthermore, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recently approved intranasal S-ketamine for treatment resistant depression (TRD) in conjunction with an oral antidepressant and for depression with imminent risk of suicide. However, to date, there are no clinical practice guidelines recommending the use of S-ketamine in depression. The use of ketamine in clinical practice entails different challenges, one of them being the acute and bothersome psychotomimetic side effects such as anxiety, perceptual changes and dissociation. In case of severe agitation or anxiety, clinicians may resort to benzodiazepines or antipsychotics as rescue medication. Furthermore, strategies to maintain the antidepressant effects of ketamine are considered a major unmet need. Ketamine is often combined with other psychiatric drugs and continuation of this psychiatric pharmacotherapy has been proposed to prevent relapse, a strategy that is already proven effective after successful electroconvulsive therapy (ECT). Since most patients for whom ketamine treatment is considered, are already being prescribed psychiatric drugs, knowledge on pharmacodynamic interactions is crucial. Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist. In addition, it shows affinity for multiple other receptors. Action at the µ, k, and σ receptors may contribute to its analgesic effects. Furthermore, there is inhibition at muscarinic and nicotinic receptors and activity as a cholinesterase inhibitor. Modulation of monoaminergic systems occurs via inhibition of reuptake transporters (dopamine, serotonine and noradrenaline) and via direct activity at the monoamine receptors (dopamine and serotonine). Inhibition of the NMDA receptor also leads to downstream enhancement of monoaminergic activity. The main mechanism of the antidepressive action is believed to stem from antagonism of the NMDA receptor on γaminobutyric acid (GABA) releasing interneurons. After a reduction in GABA inhibition, the pyramidal cells in the prefrontal cortex (PFC) release glutamate. This results in enhanced stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, Downloaded fromby guest on 10 July 2021 A c c e p t e d M a n u s c r i p t 4 activating a signalling cascade that raises neurotrophic factors and induces synaptic plasticity. Modulation of brain areas induced by ketamine are most notably found in the subgenual anterior cingulate cortex, posterior cingulate cortex, PFC and hippocampus. Many trials have studied the efficacy and safety of ketamine treatment as add on to regular antidepressant agents such as selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), bupropion, mirtazapine, etc.. However, other psychiatric drugs are also often used in combination with ketamine. The pharmacodynamic actions of ketamine may provide leads on how to optimize treatment. For instance, hypotheses on synergistic effects of ketamine and lithium through inhibition of glycogen synthase kinase 3 (GSK3) have been proposed. On the other hand, it can be hypothesized that lamotrigine might influence the effects of ketamine by reducing glutamate transmission as a result of sodium channel blockage. Anecdotal evidence and personal experience suggest that in some patients, lamotrigine might counteract the antidepressant effects of ketamine. A case report bysuggests that higher doses of benzodiazepines attenuate the antidepressant effect of ketamine. While previous data show that ketamine addition to regular antidepressants is safe and accelerates the antidepressant response, there are studies presenting enhanced monoamine levels in the rat brain effectuated by ketamine. Consequently, monoamine oxidase inhibitors (MAOIs) in combination with ketamine might increase heart rate and blood pressure or cause a serotonergic syndrome. Given the affinity of ketamine for monoamine receptors, interactions may also be expected for ketamine and antipsychotics or psychostimulants. The pharmacological interactions between ketamine and other psychiatric medications commonly used in patients with TRD have not been systematically reviewed. The aim of this review is to systematically summarize current knowledge from human studies on combined use of ketamine with psychiatric drugs commonly prescribed to patients with depression.
The electronic databases MEDLINE and Web of Science were searched on July 9, 2020 for studies that examined a pharmacodynamic interaction between ketamine and a psychiatric drug consisting of antidepressants, mood stabilizers, antipsychotics, benzodiazepine(agonist)s or psychostimulants. Filters for English, Dutch and human studies were applied. The search strategy was built as follows: ('generic name' OR 'brand name') AND ('ketamine') including multiple generic and brand names for each drug. The search strategies can be found in the supplementary material (appendix 1). We included human studies with a randomized controlled design. In case limited information from controlled trials was available (only 1 or no randomized controlled trials (RCTs)), we included studies with lower levels of evidence (post hoc analyses from controlled trials and open label studies). Furthermore, case reports were only included if they provided supporting evidence regarding an interaction between ketamine and psychiatric medication. Grey literature (e.g. conference abstracts) was included in the review. Studies that investigated the antidepressant effect of ketamine added to a regular antidepressant (except MAOIs) were excluded because the safety and additive antidepressant effect of ketamine has already been demonstrated irrefutably. Furthermore, studies investigating anesthetic doses of ketamine for induction or sedation were excluded. The references were imported in the reference manager Endnote. After removal of duplicates, two reviewers (IB and BV) independently screened the titles and abstracts and full texts. Discrepancies were solved by discussion, if necessary, a third or fourth reviewer (JV or DT) assisted to come to an agreement. Systematic reviews were screened for studies that possibly met our criteria and were not found with the literature search. We selected information on the study design, sample size, population characteristics, details on the intervention, clinical outcomes and hypothesis on the mechanisms of action. The process is shown in figure. Joanna Briggs Institute's (JBI's) critical appraisal tools for RCTs, quasi-experimental studies and case reports were used for quality assessment of the included studies. This systematic review was written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.
In total 4887 studies were identified through database searching. Screening of the reference lists of systematic reviews did not result in any additional articles. Five additional papers were proposed during the review process of this manuscript. Deduplication resulted in 3845 articles. By screening titles and abstracts, 3723 studies were excluded and 1228 articles remained for full text assessment. Subsequently, 98 studies were excluded for the following reasons: anesthetic dosages (n = 20), other outcome measures (n = 22), other drugs than ketamine examined (n = 5), animal models (n = 12), a study design that does not allow conclusions on an interaction (n = 25), or for a combination of these reasons (n = 14). Finally, 24 studies met our eligibility criteria and were included in this systematic review (figure). The results of the quality assessment can be found in the supplementary material (appendix 2). We included 2 RCTs on lithium and 7 studies on lamotrigine. Furthermore, we retrieved 1 case report, 3 post hoc analyses and a placebo controlled study on the interaction between ketamine and benzodiazepines. We found 2 case reports on concomitant use of ketamine and tranylcypromine. Three double blind, placebo controlled studies investigated an interaction with haloperidol. An interaction between risperidone and ketamine was studied in 4 articles (3 were already included for lamotrigine and these report on different outcome results from the same study). One RCT reported on an interaction between olanzapine and ketamine, and 3 on clozapine and ketamine. No studies were found investigating the concomitant use of ketamine with psychostimulants.
Based on the mechanism of action of lithium and ketamine, one would expect synergistic effects in patients with depression. The study byafter ketamine in both the lithium and valproate group and there were no significant differences between the two mood stabilizers. Taken together, lithium did not seem to potentiate ketamine's antidepressant effect in patients with depression. [Table]
Since lamotrigine reduces glutamatergic activity, an impeding interaction with ketamine can be hypothesized. Seven studies reported on the effects of 300 mg lamotrigine prior to IV ketamine administration in dosages ranging from 0.12 -0.5 mg/kg. Except from the study ofwhich included patients with MDD, these studies investigated the effects in healthy subjects. Lamotrigine did not block the ketamine-induced psychotomimetic effects measured by the Brief Psychiatric Rating Scale (BPRS) and Clinician-Administered Dissociative States Scale (CADSS) in the study by.reported that pretreatment with lamotrigine in healthy subjects showed a significant reduction in ketamine-induced Hopkins Verbal Learning Test (HVLT) impairment and a significant decrease in ketamine-induced symptoms measured by the CADSS and BPRS scores. They found an increasing effect on mood elevation after ketamine measured by the Young Mania Rating Scale (YMRS) with lamotrigine.observed no attenuated psychotomimetic effects in patients with MDD randomized to lamotrigine prior to ketamine.recorded a significant reduction in ketamine-induced total CADSS and BPRS scores when pretreated with lamotrigine. Furthermore, areas showing blood oxygenation level-dependent (BOLD) responses to ketamine assessed by pharmacomagnetic resonance imaging (phMRI) revealed greater responses after placebo infusion than after lamotrigine infusion. In addition, a trial byreported that lamotrigine administration resulted in a relatively consistent attenuation of the BOLD response in frontal and thalamic regions effectuated by IV ketamine.and(reporting other outcomes from the same study asfound no interaction between lamotrigine and ketamine on the degree-centrality pattern and resting state brain perfusion. To summarize, the studies on lamotrigine seem to confirm an antagonistic interaction with ketamine, but the relevance for clinical outcomes is still unclear. [suggested that benzodiazepines could attenuate the action of ketamine in their case of a patient with bipolar disorder who experienced a severe episode of depression with no response to several antidepressants and antipsychotics. He was treated with lorazepam and responded to repeated doses of ketamine (0.5 mg/kg IV). The antidepressant response was prolonged from 2-3 days to 10-14 days after lorazepam (3.5 mg per day) was withdrawn. In addition to this case report, we found four papers reporting on an interaction between ketamine and benzodiazepines. In a post hoc analysis of an open label study with patients with TRD,found no significant difference between four benzodiazepine users (mean daily dose 2.75 mg lorazepam equivalents) and 9 non-users in depression response rate (MADRS score ≤ 50%), remission (MADRS < 10) or depression relapse (MADRS ≥ 50% of baseline) after ketamine infusions (0.5 mg/kg/40min). However, benzodiazepine users showed a significant longer time to antidepressant response (p = 0.029), longer time to depression remission (p = 0.042) and a shorter time to depression relapse (p = 0.020). In a post hoc analysis of, benzodiazepines gave no significant difference in response rate in 10 patients with TRD. Nevertheless, they found that the mean benzodiazepine dose (0.75 mg lorazepam equivalents) was significantly lower (P = 0.026) in the responder group (response ≥ 50% reduction in MADRS scores) than in the non-responder group (3 mg).presented an analysis of two randomized controlled cross-over trials with 47 patients with MDD. This study found a significant difference in benzodiazepine dosage between responders (response ≥ 50% reduction in MADRS scores) and non-responders. Logistic regression analysis showed that benzodiazepine medication (10 mg and more in diazepam equivalent) after ketamine infusion of 0.54 mg/kg predicted nonresponse anytime during one-week follow-up (odds ratio = 1.5, p = 0.0445). In a study of, lorazepam 2 mg reduced emotional distress and it tended to reduce distorted sensory perceptions associated with ketamine infusion (0.26 mg/kg bolus, followed by 0.65 mg/kg/hour) in 30 healthy subjects. It also reduced the inability to produce a proverb interpretation, perhaps an indication of reduced thought blocking. However, it failed significantly to block psychotogenic, perceptual, cognitive, neuroendocrine and physiological ketamine responses. In conclusion, these studies indicate that higher doses of benzodiazepines can delay the time to response and remission and shorten the antidepressant effects of ketamine. Furthermore, higher doses of benzodiazepines predicted nonresponse.]
No reports were found that confirmed the hypothesized risk of hypertensive crisis or serotonergic syndrome caused by the combination of MAOIs and ketamine. We retrieved two case reports about patients with depression receiving tranylcypromine in dosages ranging from 10-80 mg daily in combination with S-ketamine. Two patients were administered intravenous (IV) S-ketamine (dosages 12.5-75 mg) while the other patient received intranasal (IN) S-ketamine (dosages 28-56 mg). No relevant cardiovascular or hemodynamic changes were observed. [Table]
Even though the clinical impact in humans remains unknown, ketamine has shown dopamine enhancing effects in vitro. The dopamine D 2 receptor antagonist haloperidol might therefore interact with ketamine's effects.reported that in 35 healthy subjects, impairments in executive cognitive functions (assessed with the Wisconsin card sorting test (WCST) and the Gorham's Proverb's test) produced by ketamine infusion, bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour, were reduced by haloperidol pretreatment (5 mg). In addition, haloperidol reduced the anxiogenic effects and increased the sedative and prolactine responses to ketamine. The study offound an improving effect of 2 mg of oral haloperidol on ketamine-induced (0.3 mg/kg IV) reduction of processing negativity (p < 0.05) in 18 healthy male subjects. Processing negativity is a negative deflection in the event-related potential (ERP), representing the ability to focus on one source of information, when multiple sources of information are present.found that a fixed high dose of haloperidol (0.3 mg/kg/day) did not blunt ketamine-induced psychosis in 9 patients with schizophrenia receiving ketamine (injections of 0.1, 0.3 and 0.5 mg/kg) while on and off haloperidol. In fact, the patients experienced greater increases in psychosis ratings after ketamine administration during haloperidol treatment when compared to a drug free period. Interestingly, ketamine did not produce a significant worsening in the latter group. In summary, some acute effects of ketamine (impairments in executive cognitive functions and anxiogenic effects) were reduced by haloperidol pretreatment whereas no blunting of ketamine-induced psychosis was achieved with haloperidol in schizophrenic patients. [Table]
The strong antiserotonergic and antidopaminergic effects of risperidone might counteract ketamine's monoaminergic enhancement. For the combined use of risperidone and ketamine, we found three phMRI studies and one study investigating oculomotor performance.reported no effect of 2 mg of risperidone on ketamine-induced (IV targeted to a concentration of 100 ng/ml) eye movement changes. In the study ofin healthy subjects, analysis of different regions of interest (ROI) revealed significant positive and negative BOLD responses to ketamine infusion (targeted to a plasma level of 75 ng/ml). Risperidone 2 mg attenuated the ketamine effect across most ROIs, including the medial prefrontal and cingulate regions and the thalamus. For the negatively responding regions in the subgenual cingulate and ventromedial prefrontal cortex, risperidone strongly attenuated the negative BOLD response. In the same sample,found that ketamine increased the degree centrality (DC), defined as the number of links incident upon a node in phMRI. Risperidone pre-treatment significantly modulated the ketamine-induced centrality changes in 20 healthy males.performed an analysis of resting brain perfusion in the same subjects. Ketamine showed positive weights (postketamine > pre-ketamine) in prefrontal and cingulate regions, thalamus and lateral parietal cortex in comparison with pre-ketamine in phMRI, with strongest negative contributions in the occipital lobes. Pretreatment with risperidone significantly increased the ketamineinduced perfusion changes (p < 0.02). To summarize, an interaction between ketamine and risperidone was found based on brain perfusion changes in imaging studies but no clinical studies have yet investigated whether this would also result in an attenuation of the antidepressant effects. [Table]
Clozapine has a wide spectrum of pharmacological actions, including blockade of the dopamine D 1 -and serotonergic 5-hydroxytryptamine (5-HT) 2 receptors. Hypotheses on possible interactions are not straightforward.showed that clozapine 50 mg pretreatment before 0.5 mg IV ketamine did not reduce the BPRS 5 key positive or 3 key negative scores in 7 healthy subjects, but there was a trend for a reduction in perceptual alteration as measured by the CADSS (p = 0.09). Clozapine in a mean dose of 430 mg a day for several weeks significantly blunted the positive symptoms induced by ketamine in 10 patients with schizophrenia, but not the negative symptoms as reported by. An imaging studywith 20 healthy subjects shows that a low dose of clozapine (30 mg oral) reduced some of the S-ketamine (0.006 mg/kg/min) responses. The results of these three studies are inconsistent on interactions between ketamine and clozapine. [Table]
The antagonistic effects of olanzapine on serotonin and dopamine receptors might cause an interaction with ketamine. One paper studied an interaction between olanzapine and ketamine.investigated ketamine administration (0.3 mg/kg) in 5 healthy subjects treated with a low dose of 5 mg olanzapine and an unknown number of schizophrenic patients treated with 10 mg. They found no difference in blocking ketamineinduced psychotic symptoms between olanzapine and placebo. [Table]
This review summarizes currently available information on interactions between ketamine and other psychiatric drugs, derived from human studies investigating clinical, neuroimaging and electrophysiological outcomes. Knowledge on potentiating and antagonistic interactions are of utmost importance for the optimization of ketamine treatment for depression.
We found no evidence for interactions between lithium and ketamine, nor for the hypothesis that lithium would strengthen the antidepressant effect through inhibition of GSK3. Three studiesreported attenuating effects of lamotrigine pretreatment on ketamine-induced effects on the BPRS, dissociative symptoms and BOLD responses. As lamotrigine reduces glutamate transmission by sodium channel blockage, these ketamine responses are thought to result from an increase in glutamatergic activity. Four other studiesdid not confirm the interaction. This might be explained by differences in dose or infusion speed of ketamine, or differences in drug metabolism and functional brain characteristics between TRD patients and healthy controls could contribute to the contrasting results. Interestingly,described an increasing effect on mood elevation in healthy subjects. These participants may have benefitted from the decrease of dissociative, psychiatric and learning impairment symptoms which could have resulted in increased awareness of mood elevating effects. This however could reflect a different mechanism than antidepressant effects in patients with depression.
All papers reporting on benzodiazepines in combination with ketamine indicate an interaction. This could be the result of GABA-receptor agonism by benzodiazepines. By increasing the inhibitory tone of GABAergic interneurons, benzodiazepines might decrease excitatory glutamatergic signal transduction and attenuate the antidepressant effects of ketamine. Moreover, an animal studyhas shown a ketamine-induced enhanced metabolism in the limbic system, and this action is selectively blocked by administration of diazepam. Ketamine-induced dopamine release was similarly blocked by diazepam as reported by another animal study.
Both included case reports on S-ketamine in combination with tranylcypromine correspond to previous literature stating no relevant cardiovascular or hemodynamic changes. Also, no serotonergic syndrome has been reported in the combination of MAOIs and ketamine, but clinical experience is limited. An increase in monoamines is probable not the most relevant pharmacodynamic effect of ketamine.
An interaction with the dopamine D 2 receptor antagonist haloperidol can be expected because ketamine shows modest activity at the dopamine transporter at subanesthetic doses. Two studies in healthy subjects reported a reduction in ketamine induced effects (impairments in executive cognitive functions, anxiogenic effects and processing negativity) with haloperidol pretreatment. This implies that these effects of ketamine are caused by its (direct or indirect) agonistic effect on dopaminergic D 2 receptor activity. The only study investigating schizophrenic patients on and off a high dose of haloperidol did not find blunting effects on We found no studies investigating the effects of an interaction between risperidone and ketamine on the clinical antidepressant effect or side effects. Risperidone had no effect on ketamine-induced changes in eye movements, which are biomarkers in drug development and the evaluation of treatment effects. However, three imaging studies showed attenuating effects of risperidone on ketamine's brain perfusion changes in healthy subjects. The opposing effects of ketamine and risperidone at the D 2 receptor, similar to the interaction with haloperidol, may play a role here. Furthermore, 5-HT 2A receptor antagonism by risperidone might also mitigate the effects of ketamine. Although no clear conclusions can be drawn from these case reports, a few examples of concomitant ketamine and risperidone use in patients with depression suggest that use of risperidone does not attenuate ketamine's antidepressant effects in doses of 1 -4 mg/day. The results of three studies investigating clozapine and ketamine were inconsistent. No significant interaction was reported in the study investigating a low dose of clozapine (50mg) on ketamine's effects on the BPRS and CADSS in healthy subjects. On the other hand, an even lower dose of 30 mg clozapine did reduce some of the S-ketamine responses on neuroimaging outcomes. Furthermore, a higher dose of clozapine (mean 430 mg) did alter ketamine's positive symptoms in patients with schizophrenia. The differences in subject characteristics, dosages and ketamine formulation (racemic vs. S-ketamine) are reason to compare and interpret the results with caution. Dose-response studies with clozapine show that doses of at least 300-600 mg/day are required to achieve a therapeutic response in patients. Clozapine is a relatively weak antagonist at striatal dopamine D 2 -receptors, and produces a more potent blockade of central dopamine D 1 -, cholinergic, serotonergic 5HT 2 -, histamine H 1 -, and adrenergic α 1 -and α 2receptors. One paper found no blocking of ketamine induced psychotic symptoms with olanzapine, which corresponds to the results with haloperidol but is in contrast with higher doses of clozapine. Some evidence from uncontrolled trials suggests that concomitant use of with TRD receiving olanzapine 10 mg (in addition to lithium, mirtazapine and zopiclone 11.25 mg) did not achieve response or remission (Hamilton Depression Rating Scale scores decreased from 19 to 11) after six infusions 0.25 mg/kg S-ketamine. The open label study ofreports olanzapine use (2.5 -20 mg/day) in 22.7% of responders and 25.8% of nonresponders to six ketamine infusions of 0.5 mg/kg in patients with depression. It should be noted that other causes of reduced antidepressant effect cannot be excluded in these reports.
The present study should be interpreted in the light of some limitations. First, our review contains multiple conference abstracts (N = 4) that have not been published in peer reviewed full text. Second, the studies have small sample sizes, ranging from 1 -72 subjects. As the different outcomes in patients and healthy subjects of the clozapine studies show, the underlying mechanism of the interaction may be different in patients than in healthy subjects. In addition, there may be a concentration dependent effect regarding interactions. Many studies included in this review used ketamine as a model for psychosis. In these studies, the focus is not necessarily on exploring an interaction with respect to the antidepressant effect of ketamine. Furthermore, results were based on various intervention methods (racemic vs. Sketamine and different dosages, intermittent/bolus administration vs. continuous infusion), and outcome measures which complicates comparison of the trials. Finally, the case reports gave new insights but have to be interpreted with great caution due to limited generalizability.
In conclusion, this systematic review provides new insights for the clinical practitioner. The pharmacodynamic interactions between ketamine and generally prescribed psychiatric drugs were analyzed based on published evidence. The literature provided no reports of an interaction between lithium and ketamine. Some but not all studies on lamotrigine provided evidence for attenuation of ketamine-induced effects. Based on available literature it is very likely that benzodiazepines shorten the duration of ketamine's antidepressant effects. This should be taken into account when considering ketamine treatment. In addition, several cases suggested that no relevant changes in vital signs occurred when ketamine was combined with the MAOI tranylcypromine. There are indications for an interaction between the
Clinical practitioners should be aware of possible drug-to-drug interactions when prescribing ketamine. To optimize treatment effects, we would recommend minimizing benzodiazepine (and Z-drug) use in patients receiving ketamine for depression. Furthermore, a possible interaction with lamotrogine should be considered when patients show a lack of response to ketamine during concomitant lamotrigine use. We believe prescribing ketamine as add-on to lower doses of MAOI is possible but only with careful monitoring of vital signs. For future studies, we recommend trials focusing on the antidepressant efficacy and side effects of the combination of ketamine and psychiatric drugs in patients with depression. It would for instance be worthwhile to investigate whether lower doses of benzodiazepines, or temporary benzodiazepine withdrawal before ketamine administration, could prevent an efficacy attenuating interaction. Additional research on the safety of combining ketamine and MAOIs is warranted. Furthermore, we suggest that researchers and clinicians systematically record and report the use of co-medication in ketamine trials to detect possible interactions. Healthy subjects Lamotrigine 300 mg oral, or placebo, about 2,5 hour prior to ketaminea Ketamine 0.12 (mean) mg/kg IV in 1 min followed by approximately 0.31 mg/kg/hb,c The lamotrigine condition was not distinguished from placebo for post-infusion scans. Lamotrigine had no significant effect on resting brain perfusion. No clear interaction of lamotrigine in combination with ketamine on brain perfusion described. Ketamine IV, 10 infusions of 0.5mg/kg The response to the first two infusions extended over 2-3days. Subsequent infusions produced responses of no more than 24hours. After lorazepam was withdrawn the duration of the response to ketamine extended from several days to 10-14days. In animals administration of ketamine causes increased metabolism in the limbic system and this action is selectively blocked by administration of diazepam. Ketamine-induced dopamine release is similarly blocked by benzodiazepines.
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Joules, R., Doyle, &. O. M., Schwarz, A. J. et al. · Psychopharmacology (2015)
Kishimoto, T., Chawla, J. M., Hagi, K. et al. · Psychological Medicine (2016)
López-Díaz, A., Fernández-González, J. L., Luján-Jiménez, J. E. et al. · Therapeutic Advances in Psychopharmacology (2017)
Papers in Blossom that reference this study
Pepe, M., Bartolucci, G., Marcelli, I. et al. · Brain Sciences (2023)
Martinotti, G., Vita, A., Fagiolini, A. et al. · Journal of Affective Disorders (2022)
Alnefeesi, Y., Chen-Li, D., Jawad, M. Y. et al. · Journal of Psychiatric Research (2022)