Ketamine for Unipolar and Bipolar Depression

Ketamine for Unipolar and Bipolar Depression

Early clinical trials demonstrate that using intravenous and intranasal ketamine for unipolar and bipolar depression offers the possibility for safe and rapid relief of symptoms with high response rates (up to 88%) and pronounced antisuicidal effects.

Administration of Ketamine for Unipolar and Bipolar Depression

The article below is part of Frshmind’s “Psychedelic Science Snapshot Series” where Frshminds reviews the latest in psychedelic research.

Original authors: Christoph Kraus, Ulrich Rabl, Thomas Vanicek, Laura Carlberg, Ana Popovic, Marie Spies, Lucie Bartova, Gregor Gryglewski, Konstantinos Papageorgiou, Rupert Lanzenberger, Matthäus Willeit, Dietmar Winkler, Janusz K. Rybakowski & Siegfried Kasper

Summarized by: Emily Fewster

Introduction to the Use of Ketamine for Treatment of Unipolar and Bipolar Depression

Treatment-resistant depression (TRD) is defined as non-response to more than two antidepressant trials, occurs in about 10–30% of all major depressive disorder patients (Schosser et al. 2012; Balestri et al. 2016), and is associated with higher risk of suicide, high relapse rates and large socioeconomic burden for patients as well as for health care providers (Schosser et al. 2012; Mrazek et al. 2014; Kautzky et al. 2015). 21 years ago, the antidepressant effects of ketamine were tested for the first time in depressed patients (Berman et al. 2000) due to issues of efficacy with conventional antidepressants. Since ketamine has been used as an anesthetic for over 40 years at dosages two to five times higher than those applied in antidepressant treatment regimes, toxicity, possible side effects, and pharmacokinetic characteristics are well known.

However, at the time of this paper’s publication, usage in clinical psychiatry had not yet been approved by regulatory agencies due to unanswered questions in regard to various factors such as application modality, interactions with other medications, safety in long-term administration, and side effects in a vulnerable population such as TRD-patients. As a result, a growing number of ‘ketamine-clinics’ would provide off-label antidepressant ketamine treatment and promise illusory success, discarding scientific and available clinical standards (Schak et al. 2016). Thus, the authors of this study aimed to assess the effects of ketamine in a clinical context for the treatment of unipolar or bipolar depression and to provide guidance for clinical treatment, including information on potential adverse effects.

Authors selected 19 clinical trials, 12 concerning unipolar MDD (Berman et al. 2000; Zarate et al. 2006; Price et al. 2009; aan het Rot et al. 2010; Mathew et al. 2010; Larkin & Beautrais 2011; Thakurta et al. 2012; Murrough et al. 2013; Sos et al. 2013; Ghasemi et al. 2014; Lapidus et al. 2014; Singh et al. 2015) and 7 on bipolar depression (Diazgranados et al. 2010; Luckenbaugh et al. 2012; Zarate et al. 2012; Rybakowski et al. 2012; Permoda-Osip et al. 2013, 2014, 2015). Each study had been published in peer-reviewed journals, ascertained clinical symptoms of unipolar or bipolar depression using DSM-IV or a similar set of criteria, and only used standardized and reliable outcome measures.

The amount these outcome measures included measures for depression; the Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), and the Quick Inventory of Depressive Symptomatology (QIDS). The primary outcome parameter in every study was a change of depression rating scores (HAM-D, MADRS, BDI or QIDS), with assessments performed in most trials at 24-h post-treatment. Seven trials indicated response and remission rates, with response defined as a 50% reduction of baseline depression scores in all studies. Secondary measures in some trials included visual analogue scales for intoxication, the Young Mania Rating Scale, the Clinician-administered Dissociative States Scale (CADSS), the systematic assessment for treatment effects self-report inventory, the scale for suicide ideation (SSI), and the clinical global impression (CGI) scales.

Ketamine in unipolar depression

Ketamine Study Results

Across the 12 clinical trials, a total of 226 major depressive (MDD) patients were treated with ketamine using various methods of administration, dose amount, and dose frequency. All studies identified a rapid and robust antidepressant effect, with ketamine always statistically superior to placebo and average response rates of 59% (ranging between 37% and 88%) after 24h. This equalled an average reduction of 10.91 points on the HAM-D, 15.7 points on BDI and 20.8 points on MADRS. Three consecutive administrations of ketamine also proved to be superior to three ECT sessions as measured 48h, 72h and 1-week post-ketamine and ECT treatment, with the largest effects observed 24-h post-treatment and lasting for several days (Ghasemi et al. 2014).

The study by Murrough et al. (2013) indicated that the response to the first infusion is predictive to the subsequent outcome in the sense that responders remain responsive to ketamine and vice versa. Regarding relapse rates, the first two published trials reported 92% of all patients receiving ketamine relapsed within two weeks post-treatment. In the study by aan het Rot et al., eight out of nine patients who received repeated infusions relapsed within an average of 30 days after the first infusion or 19 days after the sixth infusion (aan het Rot et al. 2010). Mathew et al. (2010) reported a relapse rate of 62% (eight out of 13 patients) in a time period of 30 days, and Murrough et al. (2013) also reported relapse rates of about 60% after 30 days.

Ketamine in bipolar depression

Diazgranados et al. (2010) conducted the first study reporting the beneficial effect of i.v. ketamine as an adjunct to mood stabilizers (lithium or valproate) for bipolar depression, with clinical improvement lasting for 14 days in 71% of patients. This was replicated by Zarate et al.
(2012), who demonstrated improvement in 12 of 15 bipolar depressed patients (79%), again maintained for 14 days.

Another study by the Department of Adult Psychiatry at Poznan University of Medical Sciences investigated response criteria after a single infusion in 53 bipolar patients (Rybakowski et al. 2013). All patients received at least one mood-stabilizing drug and had previously been treated with antidepressant drugs without much improvement. HAM-D scores after 24 h were an average of 15.6, to 14.2 on the third day, to 12.5 on the seventh day and finally to 11.8 2 weeks following ketamine infusion.

On the seventh day after ketamine infusion, 27 subjects met the criterion for response and interestingly, response after ketamine infusion occurred significantly more frequently in male (77%) than in female (43%) bipolar subjects. This aligns with a recent meta-analysis (Coyle & Laws 2015) in which male sex was a predictor of antidepressant response at seven days, though the exact reasons are unclear. These results correspond to other trials indicating a substantial antidepressant effect of a single ketamine infusion in bipolar depressed patients receiving lithium or valproate, though the percentage of patients with improvement after 7 days in this study was somewhat lower than in the two previous trials in bipolar depression (Diazgranados et al. 2010; Zarate et al. 2012) (52% versus 71% and 79%). The effect sizes were larger in MDD patients as compared with patients suffering from bipolar disorder, which hints towards the different neuropathologies of bipolar disorder.

Safety and Tolerability of Ketamine Treatment for Unipolar and Bipolar Depression

Five studies measured psychotic (positive) symptoms during and shortly after ketamine infusion using the ​Brief Psychiatric Rating Scale (​BPRS) (Zarate et al. 2006; aan het Rot et al. 2010; Mathew et al. 2010; Lapidus et al. 2014; Singh et al. 2015). Zarate et al. (2006) reported entirely reversible positive symptoms only detectable at 40-min post-infusion which was confirmed by aan het Rot et al., who showed a change in and subsequent return to baseline BPRS scores by 2-h post-infusion (aan het Rot et al. 2010).

Other studies made similar observations (Sos et al. 2013; Singh et al. 2015), and interestingly, one study found stronger reductions in HAM-D scores upon more psychotic symptoms (Sos et al. 2013), though others failed to detect this correlation (aan het Rot et al. 2010; Mathew et al. 2010; Lapidus et al. 2014). The occurrence of adverse events was very minimal, with only one study reporting hypotension/bradycardia (decreased heart rate) and a suicide attempt (Murrough et al. 2013), with the hypotension/bradycardia linked to a stress response during the puncturing of the vein. Another study reported an adverse event where one patient fell and sustained an injury to the wrist, though this was classified as not related to the treatment intervention (Singh et al. 2015). Other than these events, no other study reported serious events.

Regarding general adverse effects, Murrough et al. (2013) found that of the 47 patients receiving ketamine, 17% had dissociative symptoms such as feeling outside of their bodies or reported altered perception of time, though these states were transient and no severe psychotic symptoms occurred in any patient. Zarate et al. (2006) also found transient perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness and increased libido. Moreover, adverse events were recorded by aan het Rot et al. (2010) with a self-report inventory (SAFTEE), and it was found that abnormal sensations and weakness/fatigue increased in prevalence during the second week of infusions, yet symptoms were no greater than ‘mildly bothersome’. Intranasal ketamine was associated with small increases in systolic blood pressure to baseline (Lapidus et al. 2014) and generally less side effects.

Compared with other treatments for TRD, such as ECT, ketamine is less invasive. Even intravenous ketamine does not need supervision by an anesthetist and can be performed in. a controlled outpatient setting in stable patients (aan het Rot et al. 2010; Murrough et al. 2013). Nevertheless, cardiovascular monitoring during infusion is recommended, and careful observation of potential adverse effects during and after treatment is necessary. Administration of ketamine with other medications like monoaminergic antidepressants seems to be safe at low, and even higher doses (Bartova et al. 2015), but ketamine metabolites might be reduced by diazepam, suggesting it might be beneficial to taper out or pause benzodiazepines during ketamine treatment (Idvall et al. 1983).

At long-term follow-ups, there was no evidence of increased substance use, though studies on the addictive potential and long-term effects of ketamine for treating depression are lacking. From an investigation in 1285 chronic ketamine abusers, 17% of users developed a dependence on ketamine. Regarding urinary symptoms, potentially from ketamine-induced inflammation of the bladder, 26.6% of recent ketamine users reported these, and it was found that higher doses resulted in more symptoms. 51% reported improvement upon cessation of use and 3.8% reported prolonged deterioration after stopping ketamine (Winstock et al. 2012). Another study reported memory problems, schizophrenia-like symptoms, and stomach lining and bladder inflammation as the main long-term side effects (Kalsi et al. 2011). It’s important to note that these patients are polydrug users and likely have differing side effect profiles from TRD patients due to the contexts in which the drug is used. However, this data suggests it might be safer to limit repetitive ketamine dosages to a maximum lifetime amount and not to perform excessive repetitive dosing to achieve a response.

Discussion Treating Unipolar and Bipolar Depression with Ketamine

In the trial by Price et al. (2009), 81% of patients exhibited a drop of an average 2.08 points in the MADRS suicidal ideation subscale after a single infusion, resulting in zero or one post-infusion rating. The rapid antisuicidal effect of ketamine is also underlined by the results of Murrough et al. (2015), showing a rapid reduction of acute suicidality in post-traumatic stress disorder, bipolar disorder, borderline personality disorder and MDD. Another meta-analysis further confirmed this effect and discussed the development and efficacy of further NMDA-receptor modulators (Newport et al. 2015). Due to the urgent need for those resistant to conventional antidepressant treatments, the glutamatergic neurotransmitter system has gained a lot of attention due to the “ketamine revolution”, and the pharmacological mechanisms of the drug have been investigated as a means to understand its role in the treatment of MDD and to explain the neurobiological basis of the disorder.

Ketamine’s primary method of action is blocking (antagonism) of the NMDA glutamate receptor. Simultaneously, it induces a substantial presynaptic release of glutamate by increasing the firing rate of glutamatergic neurons (Moghaddam, Adams, Verma, & Daly, 1997). This increase in glutamate release then favors AMPA glutamate receptors over NMDA receptors because the latter is blocked by ketamine, causing a greater throughput through the former and AMPA-mediated synapse strengthening. These findings are consistent with the “glutaminergic model” of depression. Indeed, post-mortem and genetic studies show increased levels of glutamate and decreased levels of AMPA receptor subunits in the prefrontal cortex (Beneyto & Meador-Woodruff, 2006; Hashimoto, Sawa, & Iyo, 2007; Scarr, Pavey, Sundram,

MacKinnon, & Dean, 2003), and reduced NMDA receptor binding and subunit expression in the temporal and two frontal brain regions of individuals with MDD (Choudary et al., 2005; Nudmamud-Thanoi & Reynolds, 2004). Furthermore, a study applying magnetic resonance spectroscopy (MRS) found an association between a lower glutamine/glutamate ratio in the prefrontal cortex and treatment response to ketamine, suggesting a lack of glial cells in MDD because glutamine is mainly found in astrocytes (Salvadore et al. 2012). However, the connection of these findings to ketamine’s mechanisms of action is still debated and yet to be concretely drawn (Carlson et al. 2013).

Conclusion and Future Perspective on Treating Depression with Ketamine

The reviewed clinical trials demonstrate that intravenous and intranasal ketamine offers the possibility for safe and rapid relief of depression in unipolar and bipolar depressive disorder, with high response rates (up to 88%) and pronounced antisuicidal effects. It should be noted that the authors reported larger effects in open-label infusion studies, and easily detectable signs such as dizziness and dissociative symptoms make blinding difficult in ketamine studies. Future placebo-controlled studies should focus on active control or low-dose comparators. The main unresolved issue is that its effects are transient and until now, there are no established methods to prolong ketamine’s antidepressant effects. Ketamine might, therefore, find its main application in acute antisuicidal and antidepressant treatment in psychiatric emergencies and in severely depressed subjects resistant to currently available antidepressants, as in relation to more invasive treatments for TRD such as electroconvulsive therapy (ECT), the remission of rather mild side effects after a short period of time is beneficial.

However, there are patient and cost-friendly strategies to prolong efficacy, such as repeated intranasal, sublingual or oral doses of ketamine (Schoevers et al. 2016). In this regard, potential adverse drug reactions such as tolerance or ketamine dependency must be carefully considered by experienced psychiatrists, administration has to be well monitored and potential long-term side effects have to be noted. Ketamine, with its unique mechanisms of action, has sparked the development of a new generation of antidepressant medications targeting the glutamatergic neurotransmitter system, with preliminary trials involving new NMDA-modulating agents yielding promising results (Newport et al. 2015). Additional therapeutic targets in the glutamate system might emerge in search of ketamine’s distinct antidepressant mechanisms of action and shed more light on our understanding of MDD.

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About the Author

Passionate about studying the psychedelic/mystical experience from a neuropsychological lens, Emily is a member of MAPS Canada Research Committee and graduated with an Honours BSc in Cognitive Neuropsychology from York University.  She currently leads a team of RAS with a randomized, double-blind, placebo-controlled clinical trial investigating microdosing psilocybin for persistent depressive disorder.

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