Charles R. Conway

Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial

BACKGROUND N-methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD. METHODS In this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment. RESULTS Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%-45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, -4.8 points, 95% confidence interval [CI], -1.8 to -7.8 points, p = .002; at 24 hours, -5.5 points, 95% CI, -2.5 to -8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45-35.79; OR for remission, 3.0, 95% CI, .31-28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity. CONCLUSIONS This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.

The combined use of bupropion, lithium, and venlafaxine during ECT : A case of prolonged seizure activity

There is limited literature addressing the safety of administering electroconvulsive therapy (ECT) to patients concomitantly receiving bupropion monotherapy or in combination with other drugs that may alter the seizure threshold. We describe a prolonged seizure occurring during the first treatment of a course of ECT in an adult patient receiving long-term bupropion therapy, lithium, and venlafaxine.

Toward an Evidence-Based, Operational Definition of Treatment-Resistant Depression: When Enough Is Enough

While perusing posters at a recent international psychiatry conference, a prominent subject garnering intensive interest was the understanding and treatment of treatment-resistant depression (TRD). The definition of TRD, however, was notably vague: ranging from 1 to as many as 8 failed antidepressant treatment trials. This lack of a consensual TRD definition creates enormous problems: it limits the ability to do comparative treatment research, to understand the biological underpinnings of TRD, and produces ambiguous medical insurance coverage issues. This disparity in defining TRD begs the question: When does major depressive disorder (MDD) become resistant? Approximately 30% of patients with MDD have a failed response to antidepressant medications or psychotherapy1 and are referred to as having “treatmentresistant depression.”1,2 Compared with other patients with MDD, those with TRD have lower productivity, higher medical comorbidity, and more suicide attempts.3 Naturalisticantidepressanttreatmentstudiesdemonstratethat TRD response rates are poor: Dunner and colleagues,4 studying community-based patients with TRD, observed a low (approximately 10%) 1-year response rate to standard MDD treatments. However, there is reason for hope: recently, multiple novel TRD treatments have emerged, includingrepetitivetranscranialmagneticstimulation (rTMS), intravenous/intranasal ketamine, inhaled nitrous oxide, vagus nerve stimulation, deep brain stimulation, and buprenorphine, among others. Though still under study, the new nonpharmacological MDD treatments appear to have better response durability in TRD compared with medication alternatives (vagus nerve stimulation5 or rTMS6). rTMS and vagus nerve stimulation are US Food and Drug Administration (FDA)– approved for TRD; however, variability in insurance reimbursement has limited patient access. One significant factor limiting use of these treatments is the lack of a standardized operational TRD definition. We propose consideration of an evidence-based, operational definition as a starting point for identifying TRD. On April 27, 2016, the Centers for Medicare & Medicaid Services (CMS) sponsored a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) for TRD. This public meeting was intended to provide independent guidance and expert advice to CMS and obtain the MEDCAC panel’s recommendations regarding a definition of TRD in clinical research; the committee was to advise CMS on the feasibility of defining TRD for coverage with evidence development trials and treatment outcomes. The MEDCAC panel did not officially define TRD; however, it strongly supported that an evidence-based, operational TRD definition is achievable. This conclusion is critical: it will potentially influence research and reimbursement for all future FDAapproved TRD treatment modalities. The field of psychiatry now needs to move toward an acceptable operational TRD definition applicable in research, clinical care, and insurance reimbursement.

Association of Cerebral Metabolic Activity Changes with Vagus Nerve Stimulation Antidepressant Response in Treatment-Resistant Depression

BACKGROUND Vagus nerve stimulation (VNS) has antidepressant effects in treatment resistant major depression (TRMD); these effects are poorly understood. This trial examines associations of subacute (3 months) and chronic (12 months) VNS with cerebral metabolism in TRMD. OBJECTIVE (17)Fluorodeoxyglucose positron emission tomography was used to examine associations between 12-month antidepressant VNS response and cerebral metabolic rate for glucose (CMRGlu) changes at 3 and 12 months. METHODS Thirteen TRMD patients received 12 months of VNS. Depression assessments (Hamilton Depression Rating Scale [HDRS]) and PET scans were obtained at baseline (pre-VNS) and 3/12 months. CMRGlu was assessed in eight a priori selected brain regions (bilateral anterior insular [AIC], orbitofrontal [OFC], dorsolateral prefrontal [DLPFC], and anterior cingulate cortices [ACC]). Regional CMRGlu changes over time were studied in VNS responders (decreased 12 month HDRS by ≥50%) and nonresponders. RESULTS A significant trend (decreased 3 month CMRGlu) in the right DLPFC was observed over time in VNS responders (n = 9; P = 0.006). An exploratory whole brain analysis (P(uncorrected) = 0.005) demonstrated decreased 3 month right rostral cingulate and DLPFC CMRGlu, and increased 12 month left ventral tegmental CMRGlu in responders. CONCLUSIONS/LIMITATIONS VNS response may involve gradual (months in duration) brain adaptations. Early on, this process may involve decreased right-sided DLPFC/cingulate cortical activity; longer term effects (12 months) may lead to brainstem dopaminergic activation. Study limitations included: a) a small VNS nonresponders sample (N = 4), which limited conclusions about nonresponder CMRGlu changes; b) no control group; and, c) patients maintained their psychotropic medications.

Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: a potential marker for response?

BACKGROUND Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD). METHODS Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥ 50% reduction in HDRS from baseline. RESULTS Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n=11) from nonresponders (n=4) and correlated with HDRS change (r=.64, p=.01). In a regression analysis, lower anterior insular cortex CMRGlu (p=.004) and higher orbitofrontal cortex CMRGlu (p=.047) together predicted HDRS change (R(2)=.58, p=.005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r=.78, p=.001). LIMITATIONS Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled. CONCLUSIONS This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.

Successful use of right unilateral ECT for catatonia: a case series.

Catatonia is a neuropsychiatric syndrome involving motor signs in association with disorders of mood, behavior, or thought. Bitemporal electrode placement electroconvulsive therapy (ECT) is a proven effective treatment for catatonia, and this mode of ECT delivery is the preferred method of treatment in this condition. Studies in major depressive disorder have demonstrated that suprathreshold, nondominant (right) hemisphere, unilateral electrode placement ECT has fewer adverse effects, especially cognitive adverse effects, than bitemporal ECT. This case series describes the use of right unilateral (RUL) ECT in 5 patients with catatonia. Before ECT, all 5 patients in this series initially failed therapy with benzodiazepines and psychotropic medications. Each catatonic patient received a series of 8 to 12 RUL ECT in an every-other-day series. After ECT, 4 of the 5 patients had a full recovery from catatonia. One patient achieved only partial response to RUL ECT, and no additional benefit was obtained with bitemporal ECT. All patients in this case series tolerated RUL ECT without major adverse effects. This case series illustrates successful use of RUL ECT in patients with catatonia and adds to the early literature demonstrating its effective use in treating this complex condition.

Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: A preliminary PET study

Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazoles antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[(18)F]-fluoro-3,4-dihydroxy-l-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; 11 responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity.

Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15–30% of MDD patients. There has been recent interest in N-methyl-d-aspartate receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have focused on ketamine, although psychotomimetic and other side effects may limit ketamine’s utility. These considerations prompted a recent promising pilot clinical trial of nitrous oxide, an NMDAR antagonist that acts through a mechanism distinct from that of ketamine, in patients with severe TRMD. In this paper, we review the clinical picture of TRMD as a subtype of MDD, the evolution of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.

High-sensitivity Cardiac Troponin Elevation after Electroconvulsive Therapy: A Prospective, Observational Cohort Study

Background: While electroconvulsive therapy is widely regarded as a lifesaving and safe procedure, evidence regarding its effects on myocardial cell injury is sparse. The objective of this investigation was to determine the incidence and magnitude of new cardiac troponin elevation after electroconvulsive therapy using a novel high-sensitivity cardiac troponin I assay. Methods: This was a prospective cohort study in adult patients undergoing electroconvulsive therapy in a single academic center (up to three electroconvulsive therapy treatments per patient). The primary outcome was new high-sensitivity cardiac troponin I elevation after electroconvulsive therapy, defined as an increase of high-sensitivity cardiac troponin I greater than 100% after electroconvulsive therapy compared to baseline with at least one value above the limit of quantification (10 ng/l). Twelve-lead electrocardiogram and high-sensitivity cardiac troponin I values were obtained before and 15 to 30 min after electroconvulsive therapy; in a subset of patients, an additional 2-h high-sensitivity cardiac troponin I value was obtained. Results: The final study population was 100 patients and a total of 245 electroconvulsive therapy treatment sessions. Eight patients (8 of 100; 8%) experienced new high-sensitivity cardiac troponin I elevation after electroconvulsive therapy with a cumulative incidence of 3.7% (9 of 245 treatments; one patient had two high-sensitivity cardiac troponin I elevations), two of whom had a non–ST-elevation myocardial infarction (incidence 2 of 245; 0.8%). Median high-sensitivity cardiac troponin I concentrations did not increase significantly after electroconvulsive therapy. Tachycardia and/or elevated systolic blood pressure developed after approximately two thirds of electroconvulsive therapy treatments. Conclusions: Electroconvulsive therapy appears safe from a cardiac standpoint in a large majority of patients. A small subset of patients with preexisting cardiovascular risk factors, however, may develop new cardiac troponin elevation after electroconvulsive therapy, the clinical relevance of which is unclear in the absence of signs of myocardial ischemia.

Use of Ketamine in Clinical Practice: A Time for Optimism and Caution

Increasing evidence, primarily from small studies, supports the idea that the dissociative anesthetic ketamine has rapid antidepressant effects in patients with treatment-refractory major depression.1 The beneficial effects of ketamine are observed within hours of administration and can last approximately 1 week. Given that up to one-third of patients with major depression fail current treatments,2 there is a clear need for novel and more effective treatments. Results to date have led to increasing off-label use of ketamine in clinical practices, with little guidance about clinical administration. In this issue of the JAMA Psychiatry, Sanacora and colleagues3 provide a much-needed consensus statement to help guide clinical use of ketamine. Sanacora et al3 provide a thoughtful overview of ketamine use, including commentary about patient selection, risks, clinician experience, treatment setting, drug administration, and follow-up. The authors acknowledge the major limitations in the available data: limitations that should give pause to clinicians considering the use of ketamine in their practices. Sanacora and colleagues3 state that data on ketamine in psychiatric practice, especially longer-term use of ketamine, are limited or nonexistent. Thus, their recommendations are purposefully vague in places. There is little doubt that ketamine is having a major effect on psychiatry. If clinical studies continue to support the antidepressant efficacy of ketamine, psychiatry could enter an era in which drug infusions and deliveries with more rapid responses become common. Basic science studies examining the mechanisms underlying ketamine are advancing rapidly, providing hope for even better treatments in the future.4 Although ketamine is an uncompetitive antagonist of N-methylD-aspartate glutamate receptors (NMDARs), rodent studies indicate that ketamine produces its antidepressant-like effects by enhancing transmission mediated by the α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid class of glutamate receptors through modulation of intracellular signaling.4 Studies are under way to understand how ketamine alters human brain networks, as well as efforts to develop other NMDAR antagonists for use in psychiatry.4 Recent data question whether ketamine itself, and NMDAR antagonism specifically, are key mediators of antidepressant actions.5 Ketamine metabolites that are not active at NMDARs show antidepressant-like effects in rodents,5 suggesting that alternative mechanisms could be important. Determining the role of NMDARs and alternative mechanisms could perhaps lead to antidepressants that are better tolerated by patients. Despite great enthusiasm, the limitations highlighted by Sanacora et al3 are noteworthy and should be emphasized. Because of limited data to guide clinical practice, these limitations extend to almost every recommendation in the consensus statement, including, perhaps most importantly, patient selection. The bulk of the literature describes the effects of ketamine in patients with treatment-refractory major depression. The definition of treatment-refractory major depression and where treatments such as ketamine fall in the algorithm for managing treatment-refractory major depression remain poorly understood.2 Even within the literature on ketamine treatment, there is considerable variability in defining treatmentrefractory major depression (some studies required only 1 antidepressant failure, and others studied patients who failed electroconvulsive therapy). It is unclear whether patients with depression that is not treatment-refractory or patients with other psychiatric illnesses are appropriate candidates for ketamine treatment, and extreme caution must be exercised in patients with psychotic or substance use disorders. There are also major limitations in what is understood about the dose, duration of infusion, and route of administration for ketamine. Most studies examining ketamine for depression use intravenous infusions of 0.5 mg/kg for 40 minutes. This dosing derives directly from a study by Krystal and colleagues6 in the early 1990s in which they used this same dosage to induce psychotic and cognitive symptoms in healthy adults. Fortunately, psychotic symptoms last only a few hours and have not been a major problem in studies of ketamine in depression. What is unknown is whether other ketamine dosing regimens would have more or fewer beneficial and adverse effects. A major problem with ketamine is that its antidepressant effects following a single infusion are transient, usually abating in about 1 week. Efforts to prolong these effects have involved repeated infusions (several times per week with maintenance infusions) or longer durations of infusion (eg, 96 hours).7,8 The risks and benefits of such altered dosing schemes are poorly understood. As noted by Sanacora et al,3 longterm ketamine abuse is associated with cognitive impairment; whether that will be an issue with longer-term therapeutic dosing of ketamine is unknown. Several agents have been used to dampen the psychotomimetic effects of ketamine, including γ-aminobutyric acid– enhancing drugs, antimuscarinics, and α-adrenergics. It is unknown how these dampening agents influence the antidepressant effects of ketamine, although clonidine has been used effectively in 1 study8; this finding could be important because ketamine is associated with elevations in blood pressure. Most studies of ketamine in psychiatry have used intravenous infusions. Although ketamine can be administered intramuscularly, intranasally, and perhaps orally, these alternative methods remain understudied. Related article Use of Ketamine in Clinical Practice Invited Commentary