Background

The use of sub-anesthetic doses of ketamine in the management of treatment-refractory psychiatric disorders is receiving increasing attention. The rapid onset of response, unique mechanism of action, and demonstrated benefits in patients who have not responded to traditional therapies are the primary drivers of the growing interest and use of ketamine in clinical psychiatry.Reference Grady, Marsh and Tenhouse¹ Furthermore, ketamine has been shown to dramatically reduce acute suicidal ideations, which could theoretically prevent hospitalizations and decrease mortality.Reference Diaz Granados, Ibrahim and Brutsche² Most of the published literature on ketamine in psychiatry has focused on depressive symptoms. A recent review found five well-controlled studies in unipolar depression and two in bipolar depression. The total sample size in unipolar depression in these trials was n = 152. Intravenous administration was the route of delivery used in all but one study. In bipolar depression studies, the total sample size was n = 33.Reference Newport, Carpenter and McDonald³ There are even fewer well-powered, controlled trials supporting the use of ketamine in anxiety-related conditions. Funding for ketamine trials is hampered by the medication’s off-patent status. However, increasing evidence suggests that ketamine may also reduce anxious symptoms and possibly play a role in the management of treatment-resistant anxiety disorders. Here, we review the limited controlled studies that are available, as well as case reports and case series that demonstrate proof-of-concept of the potential efficacy of ketamine in the management of anxiety disorders.

Anxiety disorders are among the most prevalent psychiatric conditions and, like depression, are associated with high rates of morbidity, mortality, and disease burden. The 12-month prevalence rates for anxiety disorders are estimated to be between 10.3% and 19.1%, compared to 6.7% of US adults with depression.Reference Kessler, Petukhova and Sampson⁴ In the most recent update of the Diagnostic and Statistical Manual (DSM-5), the classification of previous anxiety disorders was revised into three categories: anxiety disorders, obsessive compulsive disorder (OCD), as well as trauma and stressor-related disorders. While OCD and post-traumatic stress disorder (PTSD) were re-classified into their own category, we will include them in our review of ketamine effects on anxiety spectrum disorders. The DSM-5 still acknowledges that anxiety is a significant component of both these conditions.⁵

Several of the published reports on ketamine in the management of anxious symptoms are in patients exhibiting comorbid depression and anxiety symptoms. While anxiety is not considered a symptom of depression, the most recent updated DSM-5 added the specifier “with anxious distress” to major depressive disorder acknowledging the effect of anxiety on treatment choices and patient response. Additionally, 50–60% of adults with lifetime major depression also have a history of an anxiety disorder, with anxiety and depressive disorders often co-occurring.Reference Kaufman and Charney⁶ In the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) Trial, nearly 50% of those treated for depression had clinically significant levels of anxiety. Patients with anxiety took longer to respond to treatment, were less likely to achieve remission, and experienced more side effects to medication.Reference Fava, Rush and Alpert⁷ Similarly, other studies have demonstrated that comorbid anxiety and depression is associated with worsening symptom severity, longer duration of illness, increased rates of suicidal behavior, higher rates of mental health utilization, greater medical costs, and increased risk of re-occurrence.Reference Wiethoff, Bauer and Baghai⁸

Current pharmacologic therapies for anxiety disorders primarily target the monoaminergic system. Unfortunately, their use is limited by a delay in onset to action (6–8 weeks), low rates of remission (25–35%), and high rates of non-response (40–50%).Reference Gorman and Kent⁹ Additionally, true rates of non-response may be underreported because these data do not reflect those individuals who may have initially responded to treatment but experienced a relapse.Reference Roy-Byrne¹⁰ Benzodiazepines are well known to provide immediate relief of symptoms of anxiety, but these are associated with long-term concerns about dependence and tolerance. GABA-ergic anti-epileptic drugs and atypical antipsychotic agents have also shown some effectiveness in reducing anxiety symptoms, but there is limited data supporting their use, and concerns over tolerability and side effect profile with these classes exist.Reference Cassano, Rossi and Pini¹¹

There is increasing evidence that glutamate dysfunction plays a significant role in depression, anxiety, and trauma-related disorders. Glutamate is the major excitatory neurotransmitter in the brain, and 80–90% of cortical synapses are glutamatergic. Glutamate is important in fear extinction, regulating neuropeptides in the stress response, and in several second messenger and downstream effects that may affect anxious symptoms and the development of anxiety disorders.Reference Davis and Myers^12–Reference Uys, Stein and Daniels¹⁴ The glutamate system also exerts a role in synaptic and neural plasticity. In anxiety disorders, there is substantial evidence of neuronal damage induced by stress. This includes neuronal atrophy, reduced synaptic density, reductions in dendritic complexity and spine density in prefrontal cortex (PFC) neurons and CA3 pyramidal cells of the hippocampus, diminished neurogenesis in the hippocampus, and decreased number of glia in the medial PFC.Reference Duman and Aghajanian¹⁵

Ketamine has been used in clinical practice for over 50 years as an anesthetic agent and has a favorable safety profile. The antidepressant and antianxiety properties of ketamine were recognized in the 1990s in both preclinical studies and clinical observations.Reference Trullas and Skolnick¹⁶ Linking a pharmacological mechanism to its observed clinical effect is a challenge for many pharmacologic therapies, particularly in the field of behavioral health. The antidepressant effects of ketamine are often attributed to its selective antagonistic effects on the NMDA receptor, one of the four subtypes of inotropic glutamate receptors located throughout the central nervous system that regulate signaling at excitatory synapses.Reference Aguado, Antonio and Pérez^17, Reference Garcia, Comim and Valvassori¹⁸ A preclinical study evaluating chronic administrations of 17 different antidepressants showed adaptive changes in radioligand binding to NMDA receptors in the cerebral cortex. Two antidepressants (imipramine and citalopram) and electroconvulsive therapy were studied in detail, and the authors observed that changes developed slowly over time and persisted after treatment was stopped.Reference Skolnick, Layer and Popik¹⁹

However, NMDA receptor antagonism alone may not fully explain the psychiatric benefits of ketamine since other NMDA antagonists have not consistently demonstrated antidepressant effects.Reference Zarate, Singh and Quiroz²⁰ There are a number of other immediate and delayed effects of ketamine that may account for its efficacy in mood and anxiety disorders. Ketamine induces a hyperglutamatergic state, which also impacts AMPA receptors, kainate receptors, and delta-opioid receptors.Reference Autry, Adachi and Nosyreva²¹ In the central nervous system, these receptors mediate excitatory synaptic transmission and play a role in synaptic plasticity, which impacts learning and memory.Reference Collingridge, Olsen and Peters²² Although an increased synaptic availability of glutamate is short-lived following ketamine administration, its antidepressant effects persist long after blood levels of ketamine have diminished. There is evidence that ketamine produces a hyperglutamatergic state, leading to changes in synaptic connectivity and downstream signaling, which may contribute to synaptogenesis through the inhibition of eukaryotic elongation factor kinase and increases in BDNF levels.Reference Monteggia, Gideons and Kavalali²³ In animal models, ketamine has been shown to reverse structural and functional changes, including a deficit in dendritic spine density associated with anhedonia and chronic stress exposure.Reference Li, Liu and Dwyer²⁴ Ketamine also impacts regulators of protein translation, mediators of translation and synaptic plasticity, and elevations of synaptic proteins.Reference Murrough²⁵

Anxious Symptoms in Depressed Patients

Some of the earliest published reports of ketamine’s effects in anxiety were provided in a case series of patients in hospice care, a setting in which depression and anxiety are highly prevalent. Up to 42% of hospice patients have depression and 70% have anxiety related to their terminal condition. Conventional antidepressant treatments often do not provide rapid relief of symptoms or are ineffective in this population. This particular case series reported on two patients who were given one dose of oral ketamine (0.5 mg/kg) and showed rapid improvements in symptoms of depression and anxiety (within an hour), with a sustained effect up to 1 week.Reference Irwin and Iglewicz²⁶

In a larger open-label, proof-of-concept study, oral ketamine (0.5 mg/kg) was given to 14 patients with life-limiting illness receiving hospice care, who also suffered from depression and anxiety symptoms. The Hospital Anxiety and Depression Scale (HADS), which is used to rate overall depression and anxiety symptoms at baseline, was administered on days 3, 7, 14, 21, and 28. All subjects who completed the trial had a reduction in both anxiety and depression symptoms when given ketamine treatment. The mean time to response for anxiety symptoms with ketamine was 8.6 days (n = 8, median 7, SD = ±6 days), while the mean time to response for depressive symptoms was 14.4 days (n = 8, median 10.5, SD = ±19.1 days). All subjects maintained this response to ketamine treatment through day 28 on both measures. There were no serious adverse events reported. In addition to the open-label design, limitations of this study included that although the subjects had prominent depressive and anxious symptoms, they were not formally diagnosed with depressive or anxiety disorders.Reference Irwin, Iglewicz and Nelesen²⁷

The effect of ketamine on anxiety symptoms in patients diagnosed with treatment-resistant depression has been examined in several small studies. Ionescu et al. (2014) treated 26 inpatients with treatment-resistant depression with a single dose of 0.5 mg/kg of intravenous ketamine and performed a post hoc analysis of efficacy in anxious vs. non-anxious depression based on the Montgomery-Asberg Depression Rating Scale (MADRS). Anxious patients had significantly fewer depressive symptoms compared with non-anxious depressed patients at days 1 through 5, 9 through 12, 15 through 17, and 25. There were no differences in dissociative, psychotic, or other side effects between the groups.Reference Ionescu, Luckenbaugh and Niciu²⁸

Ballard et al. (2014) analyzed data from four previously published clinical trials on ketamine in treatment-resistant depressed patients to determine whether the improvement in suicidal ideation was related or independent to the effect on depressive and anxious symptoms. A group of 133 subjects diagnosed with major depression (n = 98) or type I (n = 19) or II (n = 16) bipolar depression were administered 0.5 mg/kg ketamine intravenously over 40 min. Outcome measures included the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAM-A) at 230 min post-infusion. Suicidal ideation has been shown to diminish within the first hour of ketamine administration. While depression and anxiety also improved with ketamine treatment, the reduction in suicidal ideation could not be completely explained by reductions in those symptoms. The authors concluded that changes in suicidal ideation were related but also independent of the antidepressant and antianxiety effects of ketamine. They acknowledge the relationship between depression and suicidal ideation but suggest that reductions in anxiety may be just as important in decreasing suicidal risk.Reference Ballard, Ionescu and Vande Voort²⁹ In fact, anxiety has been associated with immediate and long-term risk of suicide and is purported to play a role in transitioning from suicidal ideation to behavior.Reference Goldberg and Fawcett^30, Reference Nock, Hwang and Sampson³¹

Generalized Anxiety Disorder

Ray et al. (2016) reported a single case of an adult woman with severe panic attacks, agoraphobia, and generalized anxiety disorder (GAD) whose anxiety failed to respond to high-dose SSRI medications, lamotrigine, electroconvulsive therapy (ECT), cognitive-behavioral therapy, and prolonged exposure response prevention (ERP) therapy, and she was homebound due to her anxiety symptoms. She was treated with a single dose of 0.5 mg/kg of intravenous ketamine for severe cervicalgia due to two herniated discs. Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scores dramatically improved immediately after infusion, and the treatment exhibited continued benefit over 10 weeks. She also remained free of panic attacks in the 10-week follow-up.Reference Ray and Kious³²

Glue et al. (2017) studied the efficacy and safety of subcutaneous administration of ascending does of ketamine (0.25, 0.5, 1 mg/kg) delivered at weekly intervals in patients with treatment-resistant GAD and/or social anxiety disorder (SAD). All 12 patients had a diagnosis of SAD, and only 2 patients did not have a comorbid diagnosis of GAD. Ten of 12 patients were treatment-responders at 0.5–1.0 mg/kg with reduced anxiety reported within 1 h of drug administration. Eight of 12 patients (67%) had a >50% reduction in HAM-A and/or Fear Questionnaire (FQ) after 0.5–1 mg/kg doses at 2 h post-infusion. Dose responses for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate were observed, and ketamine was considered well tolerated in the study group without serious adverse events.Reference Glue, Medlicott and Harland³³

The same authors examined the efficacy and safety of ketamine as maintenance therapy in treatment-refractory GAD and SAD. Twenty patients (10 men and 10 women) who responded to acute open-label ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were given one or two weekly ketamine doses of 1 mg/kg subcutaneously. Fifteen patients had a diagnosis of GAD, and 18 were diagnosed with SAD, with some patients having both anxiety disorders. FQ ratings decreased by ~50%, as did HAM-A ratings. Clinician-Administered Dissociative States Scale (CADSS) mean scores decreased from 20 points at week 1 to 8.8 points at week 14. Ketamine was considered well tolerated. There were mild side effects to ketamine treatment, including nausea, dizziness, and blurry vision, as well as non-clinically significant increases in systolic and diastolic blood pressures. Eighteen subjects reported improved social functioning and/or work-related functioning during maintenance treatment.Reference Glue, Neehoff and Medlicott³⁴

Anxious Symptoms in Bipolar Disorder

Zarate et al. (2012) evaluated the antidepressant and antianxiety effects of a single intravenous dose of ketamine (0.5 mg/kg) vs. a placebo antidepressant in a double-blind, placebo-controlled study of 15 patients with bipolar disorder type I or II. All patients were maintained on therapeutic doses of lithium or valproic acid during treatment. Both depression and anxiety symptoms improved as early as 40 min post-infusion across various outcome measures, including the MADRS, Hamilton Rating Scale for Depression (HDRS), self-rated BDI, and Visual Analog Scale (VAS)-Depression, as well as the HAM-A and VAS-Anxiety scales. The population studied was notable for frequent hospitalizations, failing multiple medication trials, history of suicide attempts, high rates of comorbid anxiety, and significant disability.Reference Zarate, Brutsche and Ibrahim³⁵

Another study of 18 treatment-resistant bipolar disorder patients using a randomized, double-blind, crossover design of a single intravenous ketamine (0.5 mg/kg over 40 min) infusion vs. saline given 2 weeks apart showed significant antidepressant effects with high response and remission rates after day 1. HAM-A was performed as a secondary measure and showed significant improvement after the first post-infusion observation and at 230 min through day 3. Significant differences in ketamine compared to placebo occurred at day 10, but not at days 7 or 14. Improvements in ketamine-treated patients were also noted on VAS-Anxiety.Reference Diazgranados, Ibrahim and Brutsche³⁶

Previous studies have demonstrated that comorbid anxiety predicts worse outcomes to treatment in bipolar depressed patients.Reference El-Mallakh and Hollifield³⁷ A post hoc analysis was published on the two above studies that combined data from two separate but identically performed randomized, crossover studies examining the antidepressant effects of a single infusion of intravenous ketamine (0.5 mg/kg over 40 min) in bipolar depression. The goal of the study was to evaluate if those patients with anxious vs. non-anxious bipolar depression were less likely to respond to ketamine treatment.

The analysis included 36 treatment-resistant inpatients who had not responded to traditional therapies and were treated concurrently with lithium or valproic acid. They had high anxiety symptoms with a HDRS Anxiety/Somatization Factor Score >7. Anxious patients (n = 21) had similar improvement in depression based on MADRS and HDRS to non-anxious patients (n = 15) and did not have a greater incidence of side effects, including dissociation or worsening anxiety.Reference Ionescu, Luckenbaugh and Niciu³⁸

Social Anxiety Disorder

SAD is a highly prevalent condition and the third most common psychiatric disorder in the general population.Reference Grant, Hasin and Blanco³⁹ While often misconstrued with extreme shyness, SAD is associated with significant functional impairment, and nearly half of these patients report moderate to severe impairment in areas of education, work, family, and other social relationships. There is also a high association of SAD with other co-occurring psychiatric conditions.Reference Schneier⁴⁰ Several SSRI and SNRIs are FDA-approved for SAD, but there are still high rates of non-response to medications ranging from 30% to 45%.Reference Stein, Liebowitz and Lydiard^41, Reference Katzelnick, Kobak and Greist^42, Reference van Vliet, den Boer and Westenberg⁴³

One single-dose and one maintenance study were reviewed above since these included patients with GAD as well as SAD. In one double-blind, randomized, placebo-controlled crossover study on 18 adults with SAD, ketamine (0.5 mg/kg over 40 min) and placebo infusions were given in a random order with a 28-day washout between infusions. The primary self-report outcome measure was VAS-Anxiety, and the primary clinical reported scale was the Leibowitz Social Anxiety Scale (LSAS). Ratings were performed 3 h after dosing and days 1, 2, 3, 5, 7, 10, and 14 days post-infusion. Response was defined as 35% on LSAS and 50% on VAS-Anxiety. Those receiving ketamine were more likely to have a beneficial response on VAS (88.9% vs. 52.9%) vs. placebo, but this did not reach statistical significance. Subjects receiving ketamine were statistically more likely to show a response on LSAS (33.3% vs. 0%) vs. placebo in the first 2 weeks post-infusion. The authors discussed concerns about the use of saline as a placebo comparator, since most participants correctly identified they were on active medication, which could have affected the reliability of the study.Reference Taylor, Landeros-Weisenberger and Coughlin⁴⁴

Obsessive Compulsive Disorder

OCD is a severely disabling condition with low response and remission rates to standard therapies. Numerous studies have focused on the most common pharmacological therapies for this indication – SSRIs – which typically showed a 25–35% decrease in symptoms on the Yale Brown Obsessive Compulsive Scale (Y-BOCS) for approximately 60% of patients, but did not significantly improve their quality of life.Reference Haan, Oppen and Balkom⁴⁵ Studies of SSRIs demonstrated a significant delay in onset of action, and the durations of treatment benefits are short. In a 5-year longitudinal study, only 39% of patients had either a partial (22.1%) or full (16.9%) recovery.Reference Eisen, Sibrava and Boisseau⁴⁶ Long-term follow-up of individuals treated for OCD indicated that 83% of them had improvement in symptoms, with 20% being asymptomatic and 28% having only subclinical symptoms. Fifty-nine percent of participants showed a relapse during a follow-up of almost 50 years.Reference Skoog and Skoog⁴⁷ Glutamate abnormalities have been identified using neuroimaging, genetic, and neurochemical studies as indicators to the pathogenesis of OCD. Small published studies using pharmacological agents targeting glutamate such as riluzole, N-acetylcysteine, and memantine have demonstrated some benefits in OCD symptomology.Reference Pittenger, Bloch and Williams⁴⁸

One published case report examined the efficacy of intranasal ketamine given twice weekly in a Caucasian male in his mid-20s with treatment-resistant OCD under hospital admission. He was given 50 mg of ketamine delivered intranasally in 5–10-mg doses over 20 min. While OCD symptoms reduced following the first week of ketamine administration, suicidality rapidly decreased after the first dose. Compliance with ERP therapy markedly improved in this patient after starting ketamine treatment. The authors suggest that ketamine may augment the efficacy of ERP and encourage studying the concurrent use of ketamine and extinction-based ERP in OCD.Reference Adams, Bloch and Pittenger⁴⁹

Bloch et al. (2012) conducted an open-label clinical trial of intravenous ketamine (0.5 mg/kg over 40 min) in 10 patients with treatment-resistant OCD. Response to ketamine in reducing OCD symptoms was defined as >35% on the Yale Brown Obsessive-Compulsive Scale (Y-BOCS) and >50% on depressive symptoms using HDRS-17 measured between 1 and 3 days after infusion. No response in OCD symptoms was demonstrated in any of the 10 subjects. Four of the seven patients with comorbid depression had an antidepressant response in the first 3 days post-infusion. OCD symptoms did improve in the first few hours post-infusion, but some of the changes were postulated to be attributable to the dissociative and euphorigenic effects of ketamine. The improvement in OCD symptoms was <12%, and the reduction in depression scores was significantly greater than the improvement in OCD scores.Reference Bloch, Wasylink and Landeros-Weisenberger⁵⁰ However, this group also reported in a separate case series that two patients showed a worsening in delayed suicidal ideation, dysphoria, and anxiety with ketamine infusion. While these patients had a history of major depression, their depressive symptoms were regarded as minimal at the start of infusion.Reference Niciu, Grunschel and Corlett⁵¹

Rodriguez et al. (2013) conducted the first randomized, placebo-controlled, crossover design study in OCD patients. A single dose of intravenous ketamine (0.5 mg/kg) or saline, given 1 week apart, was administered to 15 drug-free patients endorsing near-constant obsessional thoughts. Ketamine (n = 8) was associated with a significant improvement in obsessional thoughts as measured by OCD-VAS compared to receiving placebo (n = 7). Fifty percent of patients met the criteria for treatment response to ketamine (>35% Y-BOCS), 0% to placebo, 1 week post-infusion.Reference Rodriguez, Kegeles and Levinson⁵² This study demonstrated rapid anti-obsessional effects that persisted for at least 1 week post-infusion. The authors hypothesized that their study may have yielded positive results because their subjects had more constant obsessions, suggesting that there may be a subtype of OCD more sensitive to ketamine. Participants in Bloch et al. were not required to have constant obsessional thinking as an entry criterion. Subjects in the Rodriguez et al. study had to be medication-free, whereas participants in the Bloch et al. study were allowed concomitant medications, including SSRIs, antipsychotics, and benzodiazepines, which may have affected the outcomes. Other differences in the two studies included higher levels of dissociation and lower rates of comorbid depression, suggesting that dissociation may predict response rates and that higher levels of comorbid depression with OCD may represent a subtype less responsive to ketamine.

Post-traumatic Stress Disorder

Currently, several SSRIs are FDA-approved therapies for the treatment of PTSD. As with other anxiety disorders, pharmacologic treatments for PTSD are also associated with low rates of remission and high rates of treatment non-response. Glutamate has been shown to modulate stress response, traumatic memory formation, and may impact PTSD symptoms. Glutamate also plays a role in the regulation of neurosteroids, such as corticotropin-releasing factor, which has been associated with the pathophysiology of PTSD.Reference Nair and Ajit⁵³ While ketamine has been explored as a potential therapeutic option for treatment-resistant PTSD, there are concerns that possible side effects, including hyperarousal and dissociation, could exacerbate PTSD symptoms during ketamine administration.

Clinically, ketamine is often given in the emergency room setting for analgesia, or as a sedative. S-ketamine is an enantiomer of ketamine that has a fourfold higher affinity to the glutamate NMDA receptor than R-ketamine. It is thought to have a similar mechanism of action to ketamine and was recently approved via an intranasal delivery system for treatment-resistant depression.Reference Molero, Ramos-Quiroga and Martin-Santos⁵⁴ There has been mixed data published from small, poorly controlled trials examining the potential risks of triggering or worsening PTSD symptoms, such as dissociation, in accident victims. One retrospective trial followed 56 moderately injured patients 1 year post-injury and found that those given peritraumatic S-ketamine experienced higher dissociative and acute stress disorder symptoms measured by the Peritraumatic Dissociative Experiences Scale (PDEQ), Acute Stress Disorder Scale (ASD), and Impact of Events Scale (IES-R). All received a single dose of S-ketamine, opioids, or racemic ketamine. Those given S-ketamine had elevated PTSD symptoms, while there was no difference between opioid- or racemic ketamine-treated patients.Reference Schönenberg, Reichwald and Domes⁵⁵

In a naturalistic, prospective study, accident victims admitted to a hospital were screened for ASD using PDEQ, ASD, and the Traumatic Life Events Questionnaire (TLEQ). Patients received racemic ketamine (n = 13), non-opioids (n = 13), or opioids (n = 24). There were no differences between the groups with regard to demographics, injury severity, or prior trauma. There was an association between ketamine administration and increased dissociation, re-experiencing, hyperarousal, and avoidance, which, the authors postulated, could contribute to long-lasting symptomology.Reference Schönenberg, Reichwald and Domes⁵⁶

A study examined the effects of PTSD development with ketamine administration in burn victims in military service using a PTSD Checklist-Military (PCL-M). Among the 147 soldiers who received surgery, 119 received ketamine and 28 did not. The prevalence of PTSD was 27% in those receiving ketamine during surgery and 43% in those who did not. The authors concluded that those receiving perioperative ketamine had lower rates of PTSD than those who did not receive ketamine, despite having larger burn areas, higher injury severity scores, more ICU time, and more surgeries.Reference McGhee, Maani and Garza⁵⁷

There is one published case report of a veteran given a single dose of intravenous ketamine (35 mg) and propofol (34 mg) over 20 min for the management of severe, treatment-resistant depression with suicidal ideation. His depression improved immediately post-infusion, and his PTSD scores dropped significantly on PCL-M. Unfortunately, he had a return of symptoms at 14-day follow-up.Reference D’Andrea and Andrew Sewell⁵⁸

Feder et al. (2014) conducted a proof-of-concept, single-dose, randomized, double-blind, crossover study comparing intravenous ketamine (0.5 mg/kg) with active placebo midazolam (0.045 mg/kg) in 41 patients with chronic PTSD. Ketamine demonstrated a significant and rapid reduction in PTSD symptoms after 24 h of infusion compared to midazolam using IES-R. Both crossover and first-period analysis showed significant improvements in PTSD symptoms on IES-R and the Clinical Global Impression Scale (CGI) to ketamine even after adjusting for baseline and 24-h depression symptom severity. Comorbid depression symptoms also improved, and ketamine was well tolerated without persistent dissociative symptoms. Secondary measures, including MADRS and Quick Inventory of Depressive Symptomatology (QIDS-SR), at 24 h did not show a statistically significant benefit of ketamine vs. placebo. The Clinician-Administered PTSD Scale (CAPS-IV) at day 7 post-infusion did not show a significant change in symptom severity to ketamine vs. placebo. While the study demonstrated rapid improvements in chronic PTSD symptoms with ketamine treatment, a sustained response to the treatment was not demonstrated.Reference Feder, Parides and Murrough⁵⁹

Zeng et al. (2013) examined patients enrolled in one of three separately conducted intravenous ketamine trials for treatment-resistant depression and bipolar disorder type I or II. They found that 10 subjects had comorbid PTSD, another 12 and 8 had histories of sexual abuse and physical abuse, respectively. There were no differences in improvements in the positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS) in those with or without comorbid PTSD or trauma history. The authors did not detect differences in symptoms of dissociation, psychosis, or anxiety between those with or without trauma and/or PTSD 1 week after ketamine infusion. While acknowledging the small sample size, the authors concluded that a history of trauma may not negatively impact the antidepressant effect of ketamine on depression.Reference Zeng, Niciu and Luckenbaugh⁶⁰

A study was conducted to evaluate the efficacy, safety, and durability of repeated ketamine treatments in 15 individuals with comorbid PTSD and treatment-resistant depression. Subjects received six intravenous infusions of 0.5 mg/kg of ketamine over 12 days and were assessed weekly for 8 weeks. MADRS and PTSD Checklists of DSM-5 (PCL-5) were both used as outcome measures. There were significant improvements in PTSD remission (80%) and depression response rates (93.3%). While repeated infusions were associated with transient worsening of dissociative symptoms, there was no worsening of overall PTSD symptoms throughout the study. A median time to relapse of depression in responders was 20 days post-infusion.Reference Albott, Lim and Forbes⁶¹

Side Effects and Tolerability

Anxiety disorders are often associated with physical symptoms such as tachycardia, elevated blood pressure, shortness of breath, and gastrointestinal disorders. Many currently approved antidepressants have been associated with short-term worsening of anxiety, and ketamine may be no exception.Reference Gollan, Fava and Kurian^62, Reference Malhi, Byrow and Cassidy⁶³ Dissociation as well as elevations in pulse and blood pressure, which can mimic anxious symptoms, can be common side effects of ketamine infusion.Reference Suleiman, Kolawole and Bolaji⁶⁴ Castle et al. (2017) reported on the use of CADSS in assessing dissociative symptoms after ketamine infusion. They found that CADSS is a reliable instrument in monitoring dissociative side effects and that dissociative ratings increased in a dose-dependent manner in patients with anxiety disorders.Reference Castle, Gray and Neehoff⁶⁵

Other studies on ketamine in treatment-resistant depression also showed similar side effects of dissociative symptoms, mild elevations in pulse and blood pressure, dizziness, blurry vision, headache, nausea, poor coordination, and restlessness. There have been a few isolated cases of reported mania and little evidence for worsening of anxiety, OCD, PTSD, or panic symptoms.Reference Serafini, Howland and Rovedi^66, Reference Katalinic, Lai and Somogyi^67, Reference Girish, Prutha and Prahlad⁶⁸

Safety and tolerability of ketamine in 97 treatment-resistant depressed patients undergoing a total of 205 infusions from three separate clinical trials was reviewed. The overall discontinuation rates due to side effects were low at 1.95% (4 of 205 infusions). The most common side effects within the first 4 h post-infusion were drowsiness, poor coordination, blurry vision, and feeling strange and unreal. One-third had transient hemodynamic changes, including mild elevations in pulse and blood pressure. Fourteen percent received medication intervention for these changes. In all but two cases, blood pressure responded quickly to intervention. In the other two cases, blood pressure returned to normal within minutes of infusion discontinuation. There were small but significant increases in psychomimetic and dissociative symptoms, none of which persisted at long-term follow-up. There was no evidence of ketamine cravings, drug cravings, and substance abuse at follow-up.Reference Wan, Levitch and Perez⁶⁹