Part I: Identification
Depression is a debilitating illness. The World Health Organization reports that globally 264 million people of all ages suffer from depression. The National Institute of Health reports that about 7% of all adults in the United States experience at least one episode of depression in their lives. Although depression is a treatable illness, access to treatment can be limited due to several factors including financial, cultural, and logistical limitations. Depression is one of the main causes of disability in the United States and all around the world, and suicide is the second leading cause of death in 15- to 29-year-olds.
Certain characteristics of the disorder can complicate and impede treatment response. For example, history of trauma, periods of medication noncompliance, and other health problems can impair recovery. In addition to external stressors, depression itself can have features that result in the illness to become more resistant to treatment. Anxiety is one of these features, and its prevalence is noted to be significantly high. The National Institute of Health reports an estimated 31% of US adults experience any anxiety disorder at some point in their lives and an estimated 19% of US adults had any anxiety disorder in the past year. The same source reports that, among adults with any anxiety disorder within the past year, an estimated 22.8% experience serious impairment.
In this chapter, we will review depression with anxious distress, also referred to as “anxious depression,” and focus on its prevalence, clinical features, and treatment options including pharmacotherapies and neuromodulation techniques such as electroconvulsive therapy (ECT), ketamine, and transcranial magnetic stimulation (TMS).
Defining anxious depression
The Diagnostic and Statistical Manual-5 (DSM-5; ) includes 7 specifiers: with mixed features, melancholic features, psychotic features, catatonia, peripartum onset, seasonal pattern, and anxious distress. These specifiers can guide the clinician in their treatment plan. DSM-5 requires at least 2 of the following 5 symptoms to meet criteria for anxious distress: (1) feeling keyed up or tense; (2) feeling unusually restless; (3) difficulty concentrating because of worry; (4) fear that something awful might happen; and/or (5) feeling that the individual might lose control.
Aligning with the DSM-5 criteria, Zimmerman and colleagues developed a brief scale to standardize the measurement of depression with anxious distress. A total of 773 psychiatric outpatients completed the Clinically Useful Depression Outcome Scale (CUDOS) with the DSM-5 anxious distress specifier (A). The study found CUDOS-A to be a valid and reliable measure of the DSM-5 anxious distress specifier for major depressive disorder ( ).
In research trials, a common operationalization of anxious depression (which is frequently referenced to in his chapter), consists of symptoms of major depressive disorder and high levels of anxiety, defined as a baseline anxiety/somatization factor score of ≥ 7 from the 17-item or 21-item Hamilton Depression Rating Scale ( ). This score includes a summary of the following items: hypochondriasis, insight, general and gastrointestinal somatic symptoms, and psychic and somatic anxiety ( ).
About half of outpatients with major depressive disorder have clinically meaningful levels of anxiety ( ). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a clinical trial funded by the National Institute of Health, assessed the effectiveness of depression treatments in patients diagnosed with major depressive disorder, in both primary and specialty care settings (NIH). It is the largest and longest study ever conducted to evaluate depression treatment (NIH). In level 1 of Star*D, 53.2% of patients were found to have anxious depression. Patients with anxious depression had lower remission rates, higher number of visits, and less time in treatment compared to those without anxious depression ( ). The same study also found that side effect frequency, intensity, and burden were significantly greater in the group with anxious depression.
Once clinicians identify anxious depression in a patient who has already demonstrated a degree of treatment resistance, what should be the next step? The treatment strategy working with depressed patients with cooccurring anxiety tends to be complicated. Next, we review the evidence-base behind pharmacological strategies, as well as neuromodulation, psychotherapy, and emerging treatment approaches when working with TRD patients who present with cooccurring anxiety.
Part II: Management
Pharmacological strategies
Patients with anxious depression overall have a poorer outcome than depressed patients without a significant anxiety component. Although they respond to SSRIs, SNRIs, TCAs and MAOIs, this group of patients usually cannot maintain response or remission, compared to patients with pure depression ( ). In this section, we will review data on monotherapy and augmentation strategies across classes of medications for patients with anxious depression (see Table 29.1 ). For additional reading, we also refer the reader to a comprehensive metaanalysis conducted by Ionescu and colleagues on the pharmacologic treatment of anxious depression ( ). As emphasized in this review, patients with anxious depression are less likely to experience remission compared to patients with pure depression. Moreover, despite comparable effectiveness with SSRIs and SNRIs, given their side effect profile, TCAs and MAOIs are not deemed first-line treatment for this population. Both SSRIs and SNRIs are considered safe, effective, and tolerable first-line treatments for patients with anxious depression.
| Study | Participants | Design | Outcome |
|---|---|---|---|
| MDD plus HDRS A/S score ≥ 7 at baseline | Randomized, double-blind, w/fluoxetine, sertraline, or paroxetine. 10–16 week study | All treatments were well tolerated. Similar response and remission rates | |
| MDD plus HDRS A/S score ≥ 7 at baseline | Post hoc, 5 randomized, double blind studies comparing fluoxetine versus sertraline | Treatment response in anxious depression was found similar for both sertraline and fluoxetine, with ≥ 70% response rate; 47% remission rate for both treatment groups | |
| MDD plus HDRS A/S score ≥ 7 at baseline | Post hoc, randomized, double-blind, placebo-controlled. Fluoxetine and placebo versus fluoxetine and clonazepam | Difference in remission rates between the cotherapy and monotherapy groups with anxious depression were numerically (not statistically) higher than remission rates for nonanxious depression ( ) | |
| MDD and HARS ≥ 18 | Randomized, open-label, controlled study with mirtazapine versus paroxetine. 60 participants | Mirtazapine and paroxetine were found equally effective and well tolerated for the depressive symptoms in MDD patients with the high level of anxiety symptoms. Mirtazapine was, however, more effective in reducing the anxiety symptoms than paroxetine in the early weeks of treatment | |
| MDD and HDRS A/S score ≥ 7 | Post hoc, 10 double-blind, randomized studies, bupropion compared with SSRIs | Response rate greater in SSRIs. No difference in remission rates | |
| MDD plus HDRS A/S score ≥ 7 at baseline | Open label study with duloxetine. Total of 249 patients, 109 with anxious depression | Anxious depressed on duloxetine had greater improvements in total HAMD17 scores and HAMD17 A/S Factor scores compared to nonanxious depressed. Similar remission and response rates between groups, but anxious depressed’s median time to respond was shorter than the nonanxious depressed | |
| Same group as above | Post hoc, open label, duloxetine | Higher scores on HDRS A/S predicted poorer response and remission | |
| First analysis: MDD plus HDRS A/S score ≥ 7 at baseline Second analysis: MDD plus scores greater than the median for the sum of HDRS psychic and somatic anxiety item | Post hoc, 11 double-blind, placebo-controlled trials with duloxetine | First analysis: Higher response rate with anxious depression; however, anxious depression had a lower chance for remission due to greater severity of depression Second analysis: No difference in response rates but lower remission rates in anxious depression | |
| MDD and HDRS | Randomized, double-blind, amitriptyline versus fluoxetine | Similar response rates, however, fluoxetine is better tolerated | |
| MDD (DSM or NIMH Research Domain Criteria), 1 study used bipolar, plus HDRS A/S ≥ 7 | Post hoc metaanalysis, 19 double-blind, fluoxetine versus placebo and fluoxetine versus TCAs | No difference in response between TCA and fluoxetine groups | |
| MDD plus HDRS A/S score ≥ 7 at baseline | Post hoc, 2 randomized, double-blind, placebo controlled studies of quetiapine extended release with 788 patients with anxious depression and 180 with nonanxious depression | No significant difference in response to quetiapine extended release between patients with anxious depression and without anxious depression, however, those with anxious depression with significantly more adverse events than those with nonanxious depression | |
| MDD plus HDRS A/S score ≥ 7 at baseline | Post hoc pooled data from 2 randomized, double-blind, placebo-controlled trials; 384 patients with anxious depression (aripiprazole: n = 183, placebo: n = 201) were compared to 259 patients with nonanxious depression (aripiprazole: n = 138, placebo: n = 121) | Adjunctive aripiprazole was found to be an effective and well-tolerated treatment for patients with major depression presenting with either anxious or atypical features | |
| MDD and HDRS A/S | Secondary analysis on multicenter, randomized, double-blind, placebo-controlled study | Adjunctive pimavanserin was associated with significant improvement in response and remission | |
| MDD and HDRS A/S | STAR*D Study Level 1: post hoc, open label to citalopram Level 2: post hoc open label randomized to switch to bupropion sustained release, sertraline, venlafaxine extended release, or cognitive therapy or to augment citalopram with bupropion, buspirone, or cognitive therapy | In Level 1 remission was significantly less likely and took longer to occur in the participants with anxious depression. The same group also experienced greater side effects In Level 2, patients with anxious depression were found significantly worse in both the psychopharmacology and cognitive therapy switching and augmentation options | |
| MDD; one study with dysthymia with or without double depression | Post hoc metaanalysis of 40 studies (38 double-blind and 2 single-blind); total of 2416 patients comparing moclobemide, imipramine, maprotiline, amitriptyline, mianserin, and placebo | Sedative and nonsedative antidepressants had comparable efficacy for treating anxious depression and previous treatment failures lowered the response rate to trial drugs |
Monotherapy with SSRIs
About two decades ago, Fava and colleagues examined tolerability and efficacy of different selective serotonin reuptake inhibitors ( ). The group conducted a multisite, randomized, double-blind study using head-to-head comparison of three SSRIs, fluoxetine, sertraline and paroxetine, in 108 patients with anxious depression, defined by a score of 16 or greater on the HAMD-17 and 7 or greater on the HAM-D-Anxiety/Somatization Factor. After placebo responders were eliminated, patients were randomized to 4 weeks of double-blind treatment with fluoxetine (20 mg/day), sertraline (50 mg/day), or paroxetine (20 mg/day). Patients who achieved a CGI-Severity score of 1 or 2 at week three and week four of active treatment continued therapy at their original dose for an additional 6 weeks. Patients not achieving the required CGI-Severity scores entered an optional 1- to 6-week dose titration phase. During this phase, the clinician was allowed to titrate dosages (20–60 mg/day for fluoxetine, 50–200 mg for sertraline, and 20–60 mg for paroxetine). The dose that was found effective (a CGI-Severity score of 1 or 2 for two consecutive weeks) was continued for an additional 6 weeks. Patients received 10–16 weeks of active drug therapy. Baseline-to-endpoint improvement scores were similar in fluoxetine, sertraline, and paroxetine groups. Change-over-time improvement was similar among the antidepressants, except that fluoxetine and sertraline had greater improvement at week one compared to paroxetine. Overall, all treatments were well tolerated.
Feiger and colleagues conducted a post hoc pooled combined analysis of 5 double blind studies to examine response and remission rates in outpatients treated with sertraline or fluoxetine who were suffering from anxious-depression and severe depression ( ). Data were pooled from randomized, double-blind studies comparing fluoxetine versus sertraline for the treatment of major depression. Clinical outcome was assessed via the Hamilton Depression Rating Scale (HAM-D) and the Clinical Global Impression-Improvement scale (CGI-I). One thousand and eighty-eight patients were randomized, with 654 (60%) meeting criteria for anxious depression and 212 (19%) meeting criteria for high severity depression. A total of 334 patients were on sertraline and 320 patients were on fluoxetine. Treatment response in anxious depression was similar for both sertraline and fluoxetine, with ≥ 70% response rate and 47% remission rate for both treatment groups ( ).
SSRIs with anxiolytics
It is not uncommon to combine a first-line antidepressant with an anxiolytic for a short period of time, especially at the beginning of a medication trial or transitioning from one agent to another or when anxiety is difficult to control and debilitating. In a post hoc analysis of a 3-week, randomized, double-blind study, cotherapy with fluoxetine and clonazepam was compared with fluoxetine monotherapy ( ). Of a total of 80 patients with MDD, 46 were identified as having anxious depression. The difference in remission rates between the cotherapy and monotherapy groups for patients with anxious depression did not reach statistical significance, though at trend level suggested higher rates of remission for the cotherapy.
SSRIs versus mirtazapine
In a randomized, open-label, controlled study, mirtazapine was compared with paroxetine in terms of efficacy and tolerability in treating patients with MDD with high anxiety ( ). A total of 60 patients with MDD and a score above 18 on the Hamilton Anxiety Rating Scale (HARS) were included in the trial. Patients were randomly assigned to mirtazapine (15–30 mg/day) or paroxetine (10–20 mg/day) for 8 weeks. Patients were assessed with the HARS and the 17-item Hamilton Depression Rating Scale (HDRS) at weeks 1, 2, 4, and 8 after treatment. Mirtazapine and paroxetine were found equally effective and well tolerated for the depressive symptoms in MDD patients with a high level of anxiety symptoms. Mirtazapine was, however, more effective in reducing anxiety symptoms than paroxetine in the early weeks of treatment.
SSRIs versus bupropion
Efficacy of bupropion was compared to SSRIs (escitalopram, fluoxetine, sertraline, and paroxetine) in anxious depression ( ). Data from 10 double-blind, randomized studies with 2122 participants were pooled. Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score ≥ 7. Among patients with anxious depression ( N = 1275), response rates were greater with the SSRI group than the bupropion group based on the HAM-D-17 and the Hamilton Rating Scale for Anxiety; however, remission rates did not differ.
Monotherapy with SNRIs
Clinically, many practitioners hesitate to use SNRIs to treat anxiety symptoms, as this group of medications can cause a transient increase in anxiety symptoms. We next review data on the effectiveness of SNRIs in this group of patients.
Fava et al. examined the efficacy and tolerability of duloxetine in anxious versus nonanxious depression in a 12 week open-label study (2007). Anxious depression was defined by a HAMD17 Anxiety/Somatization Factor score greater than or equal to 7, of which 109 of 249 (43.8%) patients met criteria. Participants in a major depressive episode ( N = 249) were followed on duloxetine treatment for up to 12 weeks. Anxious depressed patients on duloxetine showed greater reductions in total HAMD17 scores and HAMD17 Anxiety/Somatization Factor scores compared to nonanxious depression. Remission and response rates at endpoint were similar between groups, but patients with anxious depression evidenced a significantly shorter median time to respond than the group with nonanxious depression. Moreover, an additional study utilizing the same dataset examined factors predicting reduced response to duloxetine ( ) and found that higher HDRS A/S scores were associated with lower rates of response and remission when continuous scores were examined ( ).
A pooled analysis from 11 double-blind, placebo-controlled trials of duloxetine examined whether specific antidepressant effects are reduced in anxious depression during treatment of MDD with duloxetine ( ). Eleven trials included 2841 patients of whom 1326 were classified as anxious. Anxious depression was defined by ≥ 7 on the anxiety/somatization factor of the HAMD (HDRS A/S). Change on the HAMD was greater with duloxetine compared to placebo, in both anxious and nonanxious groups. Patients with anxious depression had a higher rate of response; however, their chance of remission was lower due to greater severity of depression. A second analysis was conducted with anxious depressed patients who were defined as MDD plus scores greater than the median for the sum of HDRS psychic and somatic anxiety items. While patients with anxious depression evidenced similar response rates to treatment compared to the nonanxious depressed group, they were noted to have significantly lower remission rates compared to nonanxious depressed patients.
Taken together, selective norepinephrine reuptake inhibitors should be considered safe and effective medications for patients with anxious depression. That said, it is of note that while response can happen relatively quickly, remission rates tend to be lower in anxious depression compared with nonanxious depressed patients.
Tricyclic monotherapy
As reviewed next, the efficacy between SSRIs and tricyclic antidepressants in the treatment of depression are not significantly different; importantly, however, more patients on a tricyclic antidepressant withdraw from treatment because of side effects ( ). Because of their advantages with regard to safety, dosing, and tolerability, SSRIs are usually chosen over TCAs initially, though are appropriate to prescribe if SSRIs (or SNRIs) fail to achieve full efficacy or lose their efficacy, and the patient can tolerate the TCA.
compared the effects of fluoxetine versus amitriptyline in patients with anxious depression. In this double-blind comparison, 157 patients were randomized to either fluoxetine or amitriptyline for 8 weeks. Assessment instruments included: 21-item Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Clinical Global Impressions, Raskin Depression Scale, and Covi Anxiety Scale. Fluoxetine was given at a fixed dose of 20 mg/day and amitriptyline was given in a range of 50 to 250 mg/day (mean of 138.1 mg/day). Fluoxetine was comparable to amitriptyline in all efficacy measures except the HAMD sleep factor. As expected, side effects were more frequent and more severe in the amitriptyline group.
conducted a post hoc metaanalysis of 19 randomized, double-blind clinical trials comparing fluoxetine versus placebo, and fluoxetine versus TCAs. A total of 3183 patients were diagnosed with major depression; a total of 631 with anxious depression were in the fluoxetine versus placebo group and a total of 511 patients with anxious depression were in the fluoxetine versus TCA analysis. The efficacy of fluoxetine and TCAs was comparable across all measures for all groups. Discontinuation due to adverse events was significantly higher with fluoxetine than placebo and with TCAs than fluoxetine.
In summary, even though tricyclic antidepressants have been available since the early 1950s and they have been proven as effective as first-line treatment options such as SSRIs and SNRIs, given their relatively high side effect profile and withdrawal rates, clinicians are advised to use this group of medications only after first-line options fail. Tricyclics can be added to the existing dose of the SSRI/SNRI or started after a wash out period.
Antipsychotics are another group of psychotropics clinicians use for the treatment of anxious depression. Importantly, side effects from antipsychotics range from mild (e.g., sedation diabetes) to major (e.g., tremor, tardive dyskinesia) and can be lethal. Therefore, physicians should adhere carefully to monitoring guidelines should they chose to utilize antipsychotics as monotherapy or adjunctive treatment, both options which we briefly review below.
Antipsychotic monotherapy
A post hoc study that pooled data from 2 randomized, double-blind, placebo controlled studies of quetiapine extended release (50–300 mg/day) was conducted to evaluate its efficacy in anxious depression ( ). A total of 788 of 968 patients included in the analysis were categorized with anxious depression (defined as HAM-D anxiety/somatization factor score ≥ 7) and 180 (18.6%) were categorized as nonanxious. Outcomes included change from randomization at Week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total score for patients with anxious and nonanxious depression. There was no significant difference in response to quetiapine extended release between patients with and without anxious depression. Adverse events were seen more often in the anxious depression group.
Antipsychotic augmentation
assessed the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with major depressive disorder. In this post hoc study, data was obtained from 2 randomized, placebo-controlled trials. 384 patients with anxious depression (aripiprazole: n = 183, placebo: n = 201) were compared to 259 patients with nonanxious depression (aripiprazole: n = 138, placebo: n = 121). Adjunctive aripiprazole was found to be an effective and well-tolerated treatment for patients with major depression, regardless of anxiety. Remission rates were significantly higher with adjunctive aripiprazole versus adjunctive placebo.
Pimavanserin is an atypical antipsychotic approved for the treatment of Parkinson’s disease psychosis and is under research for schizophrenia and Alzheimer’s disease psychosis. The original multicenter, randomized, double-blind, placebo-controlled CLARITY trial conducted by tested the efficacy and safety of adjunctive pimavanserin on depressed patients who did not respond to SSRIs or SNRIs. The study found pimavanserin to be effective, as assessed with changes on the HDRS-17. A secondary study conducted by examined the efficacy of Pimavanserin for patients with anxious depression; compared to placebo, both response and remission rates were significant, based on changes in HAMD-A/S factor scores.
Inter-class comparisons
and conducted post hoc analyses on the STAR*D study to compare antidepressant treatment as well as cognitive therapy outcomes for patients with anxious and nonanxious major depression. In Level 1 of STAR*D, a total of 2876 adult outpatients with major depressive disorder received citalopram. Nonremitters and patients who did not tolerate citalopram then entered the Level 2 Phase of the study where they were randomly assigned either to switch to sustained-release bupropion ( N = 239), sertraline ( N = 238), extended-release venlafaxine ( N = 250), or cognitive therapy, or to continue taking citalopram and receive augmentation with sustained-release bupropion ( N = 279) or buspirone ( N = 286). Treatment lasted up to 14 weeks in each level. Patients were designated as having anxious depression if their anxiety/somatization factor score from the 17-item Hamilton Depression Rating Scale (HAM-D) was 7 or higher at baseline. In Level 1 of STAR*D, 53.2% of patients had anxious depression. Remission was significantly less likely and took longer to occur in the participants with anxious depression. The same group also experienced greater side effect frequency, intensity, and burden, as well as the number of serious adverse events. Similarly, in Level 2, patients with anxious depression fared significantly worse in both the psychopharmacology and cognitive therapy switching and augmentation options.
Although not commonly used since the advent of the SSRIs, monoamine oxidase inhibitors are effective medications in the treatment of depression. A post hoc metaanalysis of 40 studies (38 double-blind and 2 single-blind) were conducted to compare the efficacy of nonsedative, reversible MAO-I moclobemide, with imipramine, and sedative antidepressants (amitriptyline, mianserin, maprotiline), and placebo ( ). A total of 2416 patients were included in the analysis (moclobemide n = 1215; imipramine n = 619; sedative antidepressants n = 340). Sedative antidepressants included cases on maprotiline ( n = 122), amitriptyline ( n = 80), and mianserin ( n = 40). Findings demonstrated that the sedative and nonsedative antidepressants had comparable efficacy for treating anxious depression, and previous treatment failures lowered the response rate to trial drugs.
In sum , various medications from multiple classes of psychotropics can be utilized in the treatment of anxious depression. Given the safety, efficacy, and tolerability profile, SSRIs and SNRIs are deemed the first-line treatment for this group of patients. When patients demonstrate nonresponse or limited response to maximal dose of SSRIs, a next step is usually switching or adding an SNRI, and if still not effective, then considering augmentation strategies such as adding an anxiolytic for a limited period of time, or using an antipsychotic while monitoring the side effect profile. Depending on the patient’s side effect tolerability, TCAs and MAOIs can also be effective treatment options. Tricyclics may be associated with difficult side effects but, if tolerated, are likely to help a patient with anxious depression achieve a clinically adequate response. Data on the efficacy of moclobemide (a nonsedative MAOI) suggest that this medication is as effective as imipramine and sedative antidepressants in treating anxious depression, however, just like TCAs, it is not considered a first-line treatment given the side effect profile and tolerability. TCAs can be added to the SSRI/SNRI while an MAOI must be initiated following a complete washout of the initial antidepressant(s).
Given the resistant nature of anxious depression, research focused on interventional treatments, including ketamine, electroconvulsive therapy, and transcranial magnetic stimulation, has surged in recent years, which we turn to next.
Interventional psychiatric approaches: Ketamine
A pioneering study examining baseline anxious depression as a predictor of treatment outcome was conducted by Ionescu and colleagues as secondary analyses of a larger clinical trial ( ). In this study, patients received a single, open-label intravenous infusion (0.5 mg/kg) over 40 min and were assigned to the placebo (rather than riluzole) condition. Patients with anxious depression were defined categorically by a Hamilton Depression Rating Scale Anxiety Somatization (HAMD-AS) score ≥ 7, which comprised 58% ( n = 15) of their sample. Given poorer response to traditional monoaminergic antidepressants, authors hypothesized that anxious depressed patients would evidence poorer outcomes, and analyses compared groups following a single infusion of ketamine over a course of 28 days. Contrary to expectations, the anxious group showed comparable or greater improvements in symptoms of depression as measured with the MADRS and the HDRS; the largest effect was seen on day 2. Moreover, anxious depressed patients had slower time to relapse as measured on the MADRS. Notably, with regard to change in anxious symptoms, improvements in anxiety as measured with the Hamilton Anxiety Rating Scale were greater for the anxious depressed group for all but two time points. Dissociative and psychotic symptoms during the infusion were not different between groups. Taken together, this was one of the first pieces of evidence that anxious depressed patients may respond appropriately to ketamine—but it was far from conclusive, particularly given the small sample size. That said, it was consistent with an earlier metaanalysis showing that comorbid anxiety disorders at baseline do not contribute to significant heterogeneity in outcomes up to 7 days post infusion among TRD patients receiving IV ketamine ( ).
Follow-up studies have been largely consistent. For example, among patients with treatment-resistant bipolar depression ( ), secondary analyses were completed on patients in two separate but identical randomized, placebo-controlled crossover trials of ketamine combined with lithium or valproate monotherapy. All analyzed patients received a single, open-label intravenous infusion of ketamine (0.5 mg/kg) over 40 min. Consistent with , anxious depressed patients ( n = 21, 58%), categorized based on HDRS-AS, did not evidence worse outcomes on depression (MADRS, HDRS) or anxiety (Hamilton Anxiety Rating Scale). Findings suggested that bipolar TRD patients with anxious depression may not respond worse to a single infusion of ketamine, despite their being more severe at baseline. Consistently, in another multisite, double-blind, placebo-controlled trial ( ), 99 unipolar TRD participants received a single infusion of IV ketamine or midazolam and patients with and without anxious depression (similarly defined by HAMD-AS scores) were compared at 1 and 3 days postinfusion. At days 1 and 3, collapsing across ketamine dose, there were no significant interactions, indicating the treatment group did not impact score change. When stratifying based on infusion dosage, anxious TRD patients who received 0.1 mg/kg did worse as measured by the MADRS and HAMD-6 than TRD patients without anxious depression (at the same 0.1 mg/kg dose). This effect was not significant at the other three doses of ketamine (0.2, 0.5, 1.0 mg/kg). The anxious TRD group had lower levels of dissociation reported—one post hoc explanation was that this group may have had higher proportion of benzodiazepine use, which could blunt dissociative symptoms. This study, along with , have been cited in support of ketamine’s appropriateness in patients with anxious depression, though these studies have not been powered to detect this exploratory aim, and comparisons have focused on changes in mood (and, to some extent, anxiety), following a single infusion of ketamine.
Of note, a recent study contradicts this growing body of research. Specifically, conducted a randomized, placebo-controlled trial of 71 TRD patients, randomizing patients to one of three groups—a single 40-min intravenous saline infusion mixed with 0.0, 0.2, or 0.5 mg/kg of ketamine and similarly comparing patients with or without anxious depression based on HAMD-AS scores. Patients without anxious depression did significantly better at 0.5 and 0.2 mg/kg compared to placebo; in contrast, patient with anxious depression did not do significantly better with 0.5 or 0.2 mg/kg compared to placebo. Comparing anxious to nonanxious depression, the depressive symptom reduction between groups was specifically detected at 0.5 mg/kg and was not significantly different between anxious and nonanxious depressed patients at 0.2 mg/kg or placebo. In reconciling these findings, the authors wondered if anxious TRD patients might benefit from a higher dose, such as 1.0 mg/kg.
Importantly, to increase ecological validity of these findings, recent work has examined anxiety as a predictor of treatment response following an acute course of IV ketamine. analyzed 209 adults with unipolar or bipolar depression and categorized anxious depression based on item responses to the QIDS-SR16 and the GAD7. Following patients naturalistically over a course of four infusions, QIDS-SR16, GAD7, and suicidal ideation improved among all patients, and change in QIDS and GAD7 was more pronounced among patients with anxious-distress. Consistently, in a sample of 97 TRD patients with unipolar or bipolar depression ( ), patients were classified as anxious TRD (consistent with the HAMD-AS scores described previously), as melancholic (defined based on the SCID-5 criteria), as melancholic-anxious (if they met criteria for both), or as no subtype. Following patients over six ketamine infusions, patients with melancholic and melancholic-anxious features showed a worse trajectory, including in changes on the MADRS and Hamilton Anxiety Rating Scale; in contrast, patients in the anxious group had greater MADRS reductions compared to those in the melancholic and melancholic anxious groups, and patients in the anxious group had faster score reductions on the HAMA compared to the melancholic group and those without a subtype group.
Taken together, recent research crossing from randomized clinical trials to open label effectiveness trials have generally supported the appropriateness of IV ketamine for patients presenting with anxious distress at baseline (though see for an exception), and it is notable that this finding has been replicated in studies with minimal exclusion criteria ( ; ).
Extrapolating from related areas of research
Additional ways to consider if ketamine may be appropriate for patients with cooccurring anxiety is to examine the impact and tolerability of ketamine on patients with primary anxiety disorders, as in the preclinical literature there is evidence that ketamine may have an anxiolytic effect ( ; ). Though a comprehensive clinical review is beyond the scope of this chapter, we highlight seminal work from which to extrapolate below and secondly direct the reader to a recent review by for a more thorough discussion.
One relevant study was conducted by Glue and colleagues in an ascending single-dose, uncontrolled, open label study in 12 patients with refractory DSM-IV GAD and/or SAD ( ). To analyze response in treatment-resistant anxiety and reduce potential confounds due to depression, patients with MADRS scores of 20 or greater were excluded. The study found support for rapid anxiolytic effects, which wore off over 3 to 7 days. Moreover, examining dose response relationships, the maximum reduction in anxiety was greatest for 0.5 to 1 mg/kg, and the greatest duration of anxiolytic effects was for 1 mg/kg. Authors summarized their data as the first evidence that ketamine improves symptoms of anxiety in nondepressed patients with treatment-resistant GAD and SAD and was also safe and well-tolerated. Follow-up work conducted by was largely consistent, demonstrating dose-response relationships for anxiolytic effects as well as dissociative side effects and changes in blood pressure and heart rate, in a more rigorous experimental design among nondepressed patients with treatment-resistant GAD and/or SAD.
Though no longer listed as anxiety disorders in the DSM, to increase comparison of ketamine data with the ECT data (described next), we also briefly review the literature on the use of ketamine in patients with OCD and PTSD.
Obsessive compulsive disorder
In the first randomized, placebo-controlled crossover study of OCD patients ( ) receiving a single dose of IV ketamine (0.5 mg/kg), patients receiving ketamine ( n = 8) showed a significant improvement in obsessional thoughts compared to patients receiving placebo ( n = 7). One-week postinfusion, half of the patients who received ketamine showed more than a 35% reduction on the Y-BOCS, indicating that treatment response may persist for at least a week. Additional research has tested if ketamine may work synergistically with cognitive behavioral therapy (CBT), as it may enhance plasticity and extinction learning. In 10 unmedicated OCD outpatients with intrusive obsessions ( ), patients received a single 0.5 mg/kg dose of IV ketamine followed by 10 sixty-minute exposure sessions over 2 weeks. Eight of the 10 patients reported a rapid reduction in obsessive severity (measured the OCD Visual Analog Scale) up to 230 min postinfusion (for 7 patients). OCD severity, measured with the YBOCS, significantly decreased over time including at week 2 and week 4, suggesting the potential for ketamine and CBT to be used together to maintain and extend gains, a finding consistent with a case report of treatment-resistant OCD in which the patient received intensive CBT with concurrent racemic ketamine hydrochloride (50 mg) twice weekly, delivered in five 10 mg doses over a 20-min period ( ).
Posttraumatic stress disorder
IV ketamine has also been examined for patients with treatment-resistant posttraumatic stress disorder (PTSD), with or without cooccurring TRD. In one of the major proof-of-concept RCTs ( n = 41), showed that a single 0.5 mg/kg infusion (compared to midazolam) led to significant reductions in PTSD severity 24 h after infusion, and this effect remained significant after adjusting for baseline and 24-h depressive severity. Importantly, as there are concerns that ketamine can exacerbate PTSD symptoms including dissociation, this trial found that dissociative symptoms after treatment had resolved by the next assessment 120 min from the start of the infusion, only 1 patient dropped out due to dissociative effects, and there was no emergence of psychotic or manic symptoms. Expanding this finding, conducted post hoc analyses of three RCTs of TRD patients (unipolar or bipolar) with trauma history or comorbid PTSD receiving a single dose of 0.5 mg/kg of ketamine. Results demonstrated no significant increase in psychosis, dissociation, or anxiety in the trauma group up to 7 days postinfusion. Moreover, in an open-label trial, treated 15 Veterans with comorbid PTSD and TRD with 6 doses of 0.5 mg/kg of ketamine over 12 days. Consistent with previous studies, there were significant improvements in PTSD and depression and minimal problems with dissociative side effects. None of the patients experienced a worsening of PTSD during the trial.
Taken together, the preponderance of data suggests that IV ketamine is appropriate for patients with cooccurring symptoms of anxiety. More work is needed to understand the trajectory of change in symptoms of anxiety following treatment, but core symptoms of depression seem likely to improve. Importantly, there is evidence that patients with primary anxiety disorders can tolerate and respond to the treatment, including treatment-resistant OCD and PTSD, providing tangential support that TRD patients with anxious depression may similarly experience anxiolytic as well as antidepressant benefits. Thus, it may be reasonable to infer that IV ketamine is not contraindicated and may be beneficial for TRD patients who present with cooccurring anxiety, though more research is needed.
Practical considerations and contraindications
Benzodiazepine and naltrexone use in anxiety patients
Data suggests that benzodiazepine and naltrexone use may interfere with the therapeutic effects of ketamine ( ; ; ; ). Best practices include withholding benzodiazepines at least 24 h prior to an infusion ( ) and, if feasible, to withhold naltrexone for the duration of the treatment course.
Anxiety about the treatment
Anxiety is the most common acute psychiatric side-effect of IV Ketamine (followed by agitation or irritability) and is the second most common psychiatric reason for withdrawal from a ketamine trial, following worsening mood ( ). Little empirical research examines if baseline anxiety is a predictor of an anxious response to ketamine. Of note, initial evidence suggests that anxiety about the treatment may predict poorer response—and that low levels of openness to experience, rather than state or trait anxiety, may be a predictor of that treatment anxiety. For example, after a series of 6 infusions, 17 responders and 14 nonresponders did not differ in baseline anxiety but did differ in “anxious ego disintegration,” more specifically driven by the following subscales of the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC; ): experiences of negative derealization, reduced self-control, and reduced body control. These constructs were inversely related to openness to experience—but were not related to state or trait anxiety at baseline ( ). Though more research is warranted, this finding suggests that baseline anxiety is not synonymous with anxiety about the treatment, and expectations about the treatment itself could potentially be a point of intervention prior to or after the first infusion.
Thus, anxiety alone may not be a contraindication for ketamine. The most caution should be taken in high-risk patients exhibiting nonmodifiable risk factors such as those with a psychotic illness, active substance use, or any condition that can result in dire medical consequences as a result of elevation in blood pressure (aneurysm, uncontrolled hypertension) or intracranial pressure secondary to ketamine use ( ). Many clinicians would like their patients to be off any recreational substances for at least 3 to 6 months prior to starting ketamine. Modifiable factors such as benzodiazepine use and expectancies and anxiety following the treatment can and should be addressed on an ongoing basis to increase the likelihood of success.
Non-IV ketamine
To our knowledge, no studies have examined anxious depression as a predictor of outcome among patients receiving intranasal ketamine. In a randomized, double-blind, crossover study examining the efficacy of esketamine in TRD patients ( ), 18 MDD patients completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. Ketamine was superior to placebo in improving anxiety symptoms at 24 h as measured by HAM-A scores. In another seminal esketamine trial ( ), patients with primary anxiety disorders were excluded from the trial, and no anxiety outcomes were reported. In a recent metaanalysis of esketamine augmentation in TRD ( ), anxiety was not included as a predictor of heterogeneity or as an outcome. Thus, it remains inconclusive to what extent intranasal ketamine may improve symptoms of anxiety.
In a recent investigation, oral ketamine was investigated in a multiple dose, open-label, uncontrolled study of patients with treatment-resistant DSM-5 major depressive episode (MDE) and/or SAD and/or GAD who had previous positive responses to IV ketamine ( ). Seven patients were administered flexible doses of a 60 to 240 mg tablet over 4 days. Patients significantly improved on measures of anxiety (as measured by the HAM-A and Fear Questionnaire) and depression (as measured by the MADRS) and reported only mild adverse events including headache, dizziness, and dissociation.
Thus, more research will be critical to understanding how efficacious alternative forms of administration may be among TRD patients with significant cooccurring anxiety.
Summary and recommendations: Ketamine
IV ketamine appears to be appropriate for TRD patients with cooccurring anxiety (see Table 29.2 ). The majority of this research has defined anxious depressed patients based on scores to six items from a larger structured clinical interview for depression (HDRS). Ketamine’s appropriateness for patients with cooccurring anxiety can be inferred from secondary analyses of clinical trials that examine anxious depression as a predictor of response following a single infusion of IV ketamine, from initial effectiveness work following patients during an acute course of ketamine, as well as from extrapolating from research on ketamine’s effectiveness in patients with primary anxiety disorders.
| Study | Diagnosis | Comparison | Dose, # of treatments | Primary outcome | Anxiety outcome | Notes |
|---|---|---|---|---|---|---|
| 26 unipolar TRD patients | Anxious depression ( n = 15, 58%) versus no anxious depression | 0.5 mg/kg, single infusion | Anxious depressed patients slower time to relapse on MADRS | Anxious depressed patients have greater improvements on the Hamilton Anxiety Rating Scale | Secondary analysis of a larger clinical trial | |
| 36 TRD patients, bipolar depression | Anxious depression ( n = 21, 58%) versus no anxious depression | 0.5 mg/kg, single infusion | Anxious depression not associated with worse outcomes on MADRS or HDRS | Anxious depression not associated with worse outcomes on the Hamilton Anxiety Rating Scale | Secondary analyses, 2 separate RCTs, ketamine + lithium or valproate monotherapy | |
| 99 unipolar TRD patients | Anxious depression ( n = 45, 45%) versus no anxious depression | 0.1, 0.2, 0.5, or 1.0 mg/kg, single infusion | Anxious TRD patients did worse as measured by MADRS and HAMD6 only at 0.1 mg/kg | – | Secondary analyses, RCT comparing ketamine to midazolam | |
| 71 Taiwanese unipolar TRD patients | Anxious depression ( n = 42, 59%) versus no anxious depression | 0.0, 0.2, or 0.5 mg/kg, single infusion | At 0.5 mg/kg, nonanxious patients do significantly better than placebo on the HDRS; anxious patients do not | – | Secondary analysis or RCT | |
| 209 patients with unipolar ( n = 117) or bipolar ( n = 26) TRD | Anxious distress ( n = 94, 45%) | 2 infusions at 0.5 mg/kg, dose optimized up to 0.75 mg/kg if needed for infusions 3 and 4 | Anxious distress patients have greater reductions on QIDS-SR16 | Anxious distress patients have greater reductions on GAD7 | Naturalistic study, open label | |
| 97 TRD patients unipolar ( n = 77) or bipolar ( n = 20) TRD | Anxious, melancholic, melancholic-anxious, or no subtype | 6 infusions of 0.5 mg/kg delivered over 2 weeks | Anxious patients have greater MADRS reductions compared to melancholic and melancholic anxious patients | Anxious patients have faster score reductions on the HAMA compared to melancholic and no subtype groups | Single-arm, open-label study | |
| Intranasal ketamine | ||||||
| 18 unipolar TRD patients | Full sample | Crossover design, 2 treatment days, Intranasal ketamine hydrochloride (50 mg) or saline solution | Significant improvement on the MADRS at 24 h after ketamine compared to placebo | Significant improvement on Hamilton Anxiety Rating Scale scores compared to placebo | ||
| Oral ketamine | ||||||
| 7 patients with TRD and/or SAD and/or GAD with previous positive response to IV ketamine | Full sample | Multiple dose open-label flexible dose, range 60 mg–240 mg, over 4 days | All seven patients had 50% or greater reductions in MADRS compared with baseline | All seven patients had 50% or greater reductions in Hamilton Anxiety Rating Scale compared with baseline. Six of seven patients had 50% or greater reductions on the fear questionnaire compared with baseline | Open-label, uncontrolled study | |
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