Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression

Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression

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ABSTRACT

Objective: The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans.

Methods: Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion.

Results: Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d‘ ²] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d‘ ² = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration.

Conclusions: This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD.

Trial Registration: ClinicalTrials.gov identifier: NCT02577250

J Clin Psychiatry 2018;79(3):17m11634

To cite: Albott CS, Lim KO, Forbes MK, et al. Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Clin Psychiatry. 2018;79(3):17m11634.

To share: https://doi.org/10.4088/JCP.17m11634

aDepartment of Psychiatry, University of Minnesota Medical School, Minneapolis, Minnesota

bMental Health Service Line, Minneapolis VA Health Care System, Minneapolis, Minnesota

cGeriatric Research Education and Clinical Center, Minneapolis VA Health Care System, Minneapolis, Minnesota

dDepartment of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota

eDepartment of Anesthesiology, Minneapolis VA Health Care System, Minneapolis, Minnesota

*Corresponding author: C. Sophia Albott, MD, MA, Department of Psychiatry, University of Minnesota Medical School, F282/2A West, 2450 Riverside Ave, Minneapolis, MN 55454-1495 (albot002@umn.edu).

Trauma has a variety of psychiatric sequelae, often including multiple comorbid psychiatric diagnoses. Major depressive disorder (MDD) co-occurs in a majority of individuals with posttraumatic stress disorder (PTSD), and the co-occurrence of these disorders is associated with a more severe clinical presentation compared to either disorder alone.1-5 Individuals with comorbid PTSD and MDD have worse functional impairment6,7 and increased risk for suicide8-10 compared to individuals with only one of these disorders. Further, the presence of either disorder diminishes treatment efficacy for the other and increases risk for treatment resistance.10-12 Overall, the co-occurrence of PTSD and MDD appears to be an indicator of a more severe response to trauma exposure.13 The high rates of comorbidity between PTSD and MDD have thus led to the suggestion that their co-occurrence may be better conceptualized as a general traumatic stress construct.4,14,15

Antidepressant agents, such as serotonin reuptake inhibitors, are recommended as first-line pharmacologic agents for the treatment of PTSD and MDD.16,17 However, these agents have limited efficacy in establishing remission for either disorder in a substantial proportion of individuals. Data from the largest and longest clinical trial for the treatment of MDD, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial,18 demonstrated that only 36.8% of individuals remitted from MDD after treatment with a first-line antidepressant medication. Similarly, antidepressant pharmacotherapy for PTSD is associated with high rates of residual PTSD symptoms, even among individuals who respond to these agents.19-21 This literature attests to the inadequacy of standard antidepressant pharmacotherapy as a treatment for many individuals with a diagnosis of PTSD or MDD, let alone for individuals with the more complex and severe comorbid presentation.

As a consequence of the shortcomings of traditional antidepressants, there has been growing interest in the rapid antidepressant effects of ketamine—an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist.22-24 Six randomized clinical trials22-29 of single-dose ketamine have been conducted in individuals who failed to respond to multiple antidepressant treatments, a subgroup described as having treatment-resistant depression (TRD). These trials demonstrated consistent patterns in treatment trajectories, including a rapid antidepressant response that peaks 24 hours after ketamine administration and subsequently declines over the following 7 to 14 days.22-29 Single-dose studies30 of ketamine have demonstrated that acute stress symptoms do not worsen in subjects with PTSD and a history of trauma. A recent double-blind placebo-controlled trial31 of a single dose of ketamine in individuals with chronic PTSD demonstrated rapid reduction in PTSD symptoms. Consonant with single-dose studies of ketamine for depression, improvement in PTSD symptoms was transient, with only 24.1% of individuals who received ketamine maintaining improvement 14 days post-infusion.31

While treatment response is short-lived after single-dose ketamine infusions, open-label case series32-35 have demonstrated repeated ketamine infusions are more effective, with a longer period of antidepressant response in individuals with TRD. However, no studies have examined repeated ketamine infusions for PTSD. It was therefore imperative to determine whether a repeated dosing regimen would extend the short-lived improvement in PTSD symptoms and to examine the efficacy of this dosing regimen for treating comorbid PTSD and TRD. On the basis of the reported efficacy for PTSD or TRD separately, we hypothesized that benefit would accrue in demonstrating the efficacy of ketamine for comorbid PTSD and TRD. Addressing this premise, we examined (1) the efficacy and safety of repeated ketamine infusions (6 infusions over a 2-week period) for individuals with comorbid PTSD and TRD; (2) the time to relapse, following repeated infusions, for both PTSD and depressive symptoms; and (3) whether the efficacy of repeated infusions for PTSD is limited to symptoms that overlap with depressive symptoms (eg, negative alterations in cognition and mood) or extends to symptoms unique to PTSD (eg, intrusion symptoms).

clinical points

  • Although comorbid posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) commonly co-occur and represent a sizeable public health burden, few evidence-based treatments address this common constellation.
  • For individuals with comorbid PTSD and MDD as well as 2 or more antidepressant failures, this study provides the first open-label evidence that serial ketamine infusions may represent an efficacious treatment alternative.

METHODS

Participants

The study was conducted at the Minneapolis VA Health Care System (MVAHCS) from May 2015 to June 2016; it was approved by the Institutional Review Board and registered at ClinicalTrials.gov (identifier: NCT02577250). Written informed consent was obtained from all participants before participation. Study participants included male and female veterans, aged 18-75 years, with diagnoses of moderate-to-severea TRD and chronic PTSD. A trained study clinician determined PTSD and MDD diagnosis using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)37,38 and the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Clinical Trials Version,39 respectively. TRD was operationalized as a failure to achieve remissionb from a minimum of 2 antidepressant medications in their current depressive episode according to the Antidepressant Treatment History Form.40 Participants continued on stable doses of their current psychotropic medication(s) for the study duration. Exclusion criteria included any unstable medicalc or nonpsychiatric central nervous system condition, moderate-to-severe traumatic brain injury, active substance use disorder (per DSM-5 criteria) in the previous 6 months, lifetime history of DSM-5-defined psychosis or bipolar I or II disorder, or active suicidal ideation judged to present imminent risk. Women of childbearing potential were required to have a negative urine pregnancy test result and to remain on a medically accepted contraceptive for the study duration.

Procedures

Baseline assessments occurred up to 2 weeks before infusion commencement. All infusions occurred on the Flexible Acuity Ward at the MVAHCS and were administered by an advanced cardiovascular life support-trained study physician.d Each participant was confirmed to be nil per os (NPO) before infusion commencement. Digital pulse oximetry, blood pressure, heart rate, and respiratory rate were monitored throughout the infusion and recovery period. Participants completed 6 intravenous (IV) infusions (0.5 mg/kg ketamine hydrochloride given during 40 minutes) on a Monday-Wednesday-Friday schedule during a 12-day period. Side effects were recorded before each infusion, following infusion completion (40 minutes), and at 100 and 160 minutes post-infusion. All participants were monitored for a minimum of 2 hours post-infusion to ascertain the absence of clinically significant side effects.

Measures

The primary outcomes were change in PTSD symptom score, assessed with the PTSD Checklist for DSM-5 (PCL-5),41 and change in depression score, assessed with the Montgomery-Asberg Depression Rating Scale (MADRS).42 Secondary outcomes included change in CAPS-5 score, proportion of individuals in remissione from PTSD (defined as PCL-5 total score < 33)43 following completion of the infusion series, proportion of individuals meeting depression response criteria (≥ 50% improvement in baseline MADRS score) and depression remission criteria (MADRS score ≤ 9)44 at the conclusion of the infusion series, change in scores on PCL-5 subscales (intrusion, avoidance, negative alterations in cognition and mood, and marked alterations in arousal and reactivity), and proportion of individuals relapsing for either PTSD or depression during the follow-up period. The PCL-5 and MADRS were administered 1 hour before and 24 hours after each infusion. Primary and secondary outcome measures were obtained weekly throughout an 8-week period following the sixth infusion.

Side effects and tolerability were assessed using the Clinician-Administered Dissociative States Scale (CADSS),45 the 4-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS+),46 and the single elevated-mood item from the Young Mania Rating Scale (YMRS-1).47

Statistical Analysis

Descriptive statistics were calculated to summarize sociodemographic variables, primary and secondary outcomes, and side effect measures. Changes in outcome measures from baseline (pretest) to 24 hours after the sixth infusion (posttest) were examined using repeated-measures analyses of variance. Magnitude of change during treatment (pretest to posttest) and following treatment (posttest to follow-up after 4 weeks) were compared for PTSD and depression symptoms using the small sample size bias-adjusted Cohen d (d‘ ²) on a z-score distribution. Time to relapse was estimated using Kaplan-Meier survival analysis with a log rank test for participants who met criteria for PTSD remission and/or depression response at the conclusion of the infusion series.f Changes in side effects between time points were analyzed using paired t tests.

RESULTS

Study Participants

Twenty-four individuals provided signed informed consent and underwent screening procedures. Eligibility criteria were met by 19 participants; 2 participants withdrew consent before treatment, and 1 individual withdrew from the study after the first infusion due to personal circumstances. Another individual completed all 6 infusions; however, this individual’s outcome data were incomplete secondary to a change in the study protocol and thus were excluded from the analyses. Table 1 presents sociodemographic and baseline characteristics of participants who received all 6 infusions and had complete outcome data (N = 15).

Table 1

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Efficacy

The mean within-subject change in PTSD symptoms significantly decreased over the course of treatment from baseline to 24 hours after the sixth ketamine infusion (F2.62,36.70 = 30.169, P < .0005, d‘ ² = 2.17) (Figure 1A; Table 2). Similarly, the mean within-subject change in depression symptoms significantly decreased over the course of treatment (F2.79,39.03 = 56.713, P < .0005, d‘ ² = 4.64) (Figure 1B; Table 2). The effect size for mean decrease in symptom severity during treatment was 2.14 times larger for depression compared to PTSD, and this difference was significant (z = 2.92, P = .003).

Secondary Outcomes

PTSD symptom severity assessed by clinician interview (CAPS-5) demonstrated a significant reduction in total score after completion of the 6-infusion series (t14 = 6.44, P < .0005, d‘ ² = 1.85) (Table 2). After the first infusion, 9 (60.0%) of 15 individuals remitted from PTSD, whereas 12 (80.0%) of 15 individuals were in PTSD remission after the sixth infusion (Figure 1). Depression response criteria were met by 3 (20.0%) of 15 participants after the first infusion whereas 14 (93.3%) of 15 individuals showed depression response after the sixth infusion. Depression remission was observed in 2 (13.3%) of 15 individuals after the first infusion and in 9 (60.0%) of 15 individuals after the sixth infusion. Repeated ketamine infusions demonstrated significant reductions in all 4 PTSD symptom clusters (d‘ ² 1.49) (Table 2).

Relapse Rate

Individuals whose PTSD symptoms were in remission (n = 12) and/or whose depression symptoms responded (n = 14) to the ketamine infusion series were followed for up to 56 days to estimate time to relapse (Figure 2). All 12 individuals in remission from PTSD also had response for depression; 3 individuals demonstrated depression response without PTSD remission. At 14 days posttreatment, 80% of the total sample (n = 12) were in PTSD remission, 40% (n = 6) were in depression remission, and 66.7% (n = 10) had response for depression. Of the 12 individuals in PTSD remission, the median time to relapse was 41 days, with the 50th and 75th percentiles at 41 and 27 days, respectively (Figure 2A). The 25th percentile was not calculated because 6 individuals (50% of individuals in PTSD remission; 40% of the total sample) remained in remission from PTSD throughout the follow-up period. Of the 14 individuals with depression response, the median time to relapse was 20 days with the 25th and 75th percentiles at 34 and 13 days, respectively (Figure 2B). Two individuals (14.3% of individuals with depression response; 13.3% of the total sample) did not have a relapse of depression symptoms and remained responders through the follow-up period.

Figure 1

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Table 2

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Paired-samples t tests showed that the mean PTSD symptom severity was significantly higher at 4 weeks’ follow-up (n = 10), compared to symptoms 24 hours after the sixth infusion (t9 = 3.42, P = .008), but this change was associated with a small effect size (d‘ ² = 0.24). The mean depression symptom severity was also significantly higher at 4 weeks’ follow-up (n = 11) compared to symptoms 24 hours after the sixth infusion (t10 = 4.76, P = .001) and was associated with a large effect size (d‘ ² = 1.42). The effect size for mean increase in symptom severity at 4 weeks’ follow-up was 5.92 times larger for depression compared to PTSD, and this difference in effect sizes approached significance (z = 1.92, P = .054).

Side Effects

A small increase in dissociative symptoms was observed immediately after each ketamine infusion, but these symptoms returned to baseline levels by the end of the recovery period (Figure 3). Pre-infusion increases in psychotomimetic symptoms (in the form of paranoia) were observed in 7 individuals. However, ketamine was associated with a decrease in psychotomimetic symptoms post-infusion, which persisted through the recovery period (Figure 3). No significant increase in elevated mood symptoms was observed (Figure 3). There was no trend suggesting an increase in dissociative or psychotomimetic side effects over the 6-infusion course (Figure 3). No veterans experienced a worsening of PTSD symptoms from baseline at any point during the trial. Three participants (20%) required treatment with β-blockersg because of blood pressure elevation (systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 100 mm Hg).

Figure 2

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Figure 3

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DISCUSSION

Our data provide the first evidence that repeated infusions of subanesthetic ketamine effectively and rapidly reduce symptoms associated with comorbid chronic PTSD and TRD in a veteran population. Although this was a diagnostically complex and severely ill population, we found substantial and enduring response in PTSD and depression symptoms using the repeated infusion regimen, which was safe and well-tolerated. These findings have important therapeutic implications for previously treatment-resistant individuals.

Compared with previous studies of antidepressant agents for PTSD, the 6-infusion regimen achieved larger effect sizes.h In a recent meta-analysis48 of treatments for PTSD, the largest effect size for antidepressant pharmacotherapy was for paroxetine (g = 0.74), with the majority falling in the small to medium range (g = 0.14-0.74). In this study, repeated ketamine infusions also demonstrated significant improvement across PTSD symptom clusters, which highlights the effectiveness of the repeated dosing regimen for PTSD symptoms over and above depressive symptom response. The greatest treatment effect sizes were observed for the negative alterations in cognition and mood cluster and for the marked alterations in arousal and reactivity cluster, which may be related to depression symptom overlap. However, large effect sizes were also observed for improvements in the avoidance and intrusion clusters, which suggests an effect of ketamine on PTSD-specific symptoms. Moreover, the effectiveness of the ketamine intervention across PTSD symptom subclusters and depression symptoms suggests the disorders may share a common underlying substrate, supporting the idea of a generalized traumatic stress syndrome.4,14,15

Repeated infusions resulted in a longer period of symptom reduction for PTSD and depression compared to single infusions for either disorder. In the only other study of ketamine for PTSD,31 24.1% of individuals receiving a single ketamine infusion demonstrated significant PTSD symptom reduction 2 weeks post-infusion. In the current study, 80% of our sample with PTSD remission maintained response for 2 weeks, more than 3 times the rate reported for a single infusion.31 Moreover, the median time to PTSD relapse was 41 days, with 50% of the sample remaining in remission throughout the follow-up period. The results were similarly positive for depression symptom reduction compared to results with single infusions. A meta-analysis49 of randomized controlled trials of single infusions of ketamine for depressive symptoms reported a pooled response rate of 10.9% and a pooled remission rate of 2.6% at 14 days posttreatment. In contrast, following repeated ketamine infusions, 66.7% of individuals remained in response, and 40% of individuals continued in remission from depressive symptoms 14 days post-infusion series. It is important to note that the aforementioned studies were placebo-controlled and, as such, the response and remission rates are not directly comparable to the present open-label study. Nevertheless, our higher response rates provide preliminary evidence that multiple ketamine infusions may achieve a more durable period of response for both PTSD and depression symptoms.

This study was not powered to detect moderating or mediating effects for improvement or relapse in depression symptoms on PTSD symptoms, or vice versa. Nevertheless, comparison of effect sizes for depression and PTSD symptoms enables standardized contrasting of the degree of symptom change. There was a statistically significant difference in effect sizes between depression symptoms and PTSD symptoms after the 6-infusion series, in which the treatment effect for depressive symptoms was significantly greater than that for PTSD symptoms. Depressive symptoms also had a 5.9 times larger effect size for mean symptom relapse in the 4 weeks following treatment compared to PTSD symptoms. Thus, while it appears that the acute treatment response was stronger for depression, the PTSD treatment response may be more sustained. This observation was also reflected in the median times to relapse, which were greater for PTSD than for depression.

Differences in the magnitude of effect after the infusion series and at 4 weeks of follow-up suggest that differences, and commonalities, may exist in biological processes or neural circuits affected by the ketamine intervention. The effect of ketamine on these processes may impact disease symptoms in different ways. Preclinical studies50,51 have demonstrated that glutamatergic signaling plays a role in depression, stress responsivity, traumatic memory formation, and the pathophysiology of PTSD. Chronic stress has been shown to mediate reciprocal neuroplastic changes in the amygdala compared to the prefrontal cortex and hippocampus52—structures known to be affected in PTSD and depression.53-57 Thus, the improvement across PTSD symptom clusters, as well as differences in PTSD and depression relapse rates, supports the notion that ketamine has differential effects on neuroplastic processes depending on the neuroanatomical locations. Alternatively, the study design, which required individuals to evaluate their PTSD symptoms daily to weekly, may have represented a form of exposure therapy that facilitated extinction learning. Given ketamine’s demonstrated role in rapidly stimulating synaptic plasticity,58,59 ketamine may have enhanced extinction learning via these mechanisms, thereby extending the period of remission for PTSD symptom clusters. Other glutamatergic modulators, such as d-cycloserine, have demonstrated similar effects.60

This study also demonstrated that the regimen of repeated ketamine infusions was safe and well-tolerated. Ketamine was associated with transient increases in dissociative symptoms that peaked immediately following infusion cessation but resolved within 2 hours. We also saw no significant emergence of manic or psychotic symptoms associated with repeated infusions. This finding replicates those of Feder et al.31 Our results extend those findings by demonstrating that multiple exposures to a dissociative anesthetic does not result in the sustained worsening of dissociative symptoms in individuals with chronic PTSD.

The strengths of this study include the enrollment of individuals with moderate-to-severe symptom levels and the inclusion of military veterans with chronic PTSD. In previous studies,61,62 veterans from the Vietnam era with combat-related PTSD have been noted to be particularly treatment refractory with regards to both medication and psychotherapy. In the current study, 50% of the participants were Vietnam-era veterans, all of whom responded to the intervention. Repeated ketamine infusions may be well-suited to this highly refractory population.

Our study had several limitations. Notably, the open-label design without a placebo control limits the interpretation of efficacy. Our preliminary findings warrant further examination in a larger placebo-controlled clinical trial. A larger study could also address moderating and mediating effects of improvement and relapse in PTSD and depression symptoms.

In conclusion, this study is the first prospective study of repeated infusions of subanesthetic ketamine for comorbid PTSD and TRD. The treatment was associated with rapid response of PTSD symptoms and symptoms of previously treatment-resistant depression. Further, the maintenance of response for both PTSD and depressive symptoms was more durable than the periods of response reported in extant single-infusion studies. Repeated infusions were well-tolerated by all individuals without any worsening of dissociative symptoms outside of the acute infusion period. In short, repeated ketamine infusions may represent an efficacious, durable, and safe treatment for a clinically complex and high-risk population that has historically been difficult to treat.

Submitted: April 5, 2017; accepted October 17, 2017.

Published online: May 1, 2018.

Potential conflicts of interest: Drs Albott, Lim, Forbes, Erbes, Tye, Grabowski, Thuras, Wels, and Shiroma and Ms Batres-y-Carr report no financial or other relationship relevant to the subject of this article.

Funding/support: This research was supported by the Mental Health Service Line at the Minneapolis VA Health Care System. Drs Albott and Forbes are supported by a Training Award (T320A037183) from the National Institute on Drug Abuse. Dr Shiroma receives support from the Veterans Health Administration Office of Research and Development, Clinical Science Research and Development Merit Review Award for Clinical Trials.

Role of the sponsor: The funding sources had no role in the study design, analysis, or interpretation; the writing of the report; or the decision to submit this study for publication.

Previous presentation: Poster including preliminary results presented at the 71st Annual Meeting of the Society for Biological Psychiatry; May 9, 2016; Atlanta, Georgia 55th Annual Meeting of the American College of Neuropsychopharmacology; December 5, 2016; Hollywood, Florida.

Acknowledgments: We wish to thank the nursing staff at the MVAHCS Flexible Acuity Ward for their assistance with study procedures and care of study participants. Foremost, we wish to thank the patients and their families for their participation in this study.

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aDepression severity was assessed using the 17-item Hamilton Depression Rating Scale with all participants required to have a score greater than or equal to 14.36

bRemission was defined as elimination of depressive symptoms with restoration of premorbid level of functioning.

cAll participants were confirmed to be medically fit to receive ketamine by physical examination, review of systems, vital signs, weight, and consultation with the study anesthesiologist.

dBecause the doses of ketamine were considered moderate sedation, our institution did not require infusions to be administered by a clinician trained in conscious sedation, although the study anesthesiologist was available for consultation throughout the infusion and monitoring period.

eAlthough depression symptom response is a well-defined metric in depression research, there is no equivalent metric for PTSD. Thus, only remission from PTSD was assessed as an outcome.

fIe, individuals who were able to relapse.

gOne-time dose administered during the infusion.

hAlthough Hedges g and sample size-adjusted Cohen d (d’ ) use different calculations for determining effect sizes, they are comparable standardized metrics using the same convention for interpreting magnitude of effect.

Editor’s Note: We encourage authors to submit papers for consideration as a part of our Early Career Psychiatrists section. Please contact Erika F. H. Saunders, MD, at esaunders@psychiatrist.com.

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