Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions.

BACKGROUND: Subanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment. METHODS: Thirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report. RESULTS: Twenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37-0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η p2 = 0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36). CONCLUSION: A short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier NCT01945047.

Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder.

BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

(Reprinted with permission from The American Journal of Psychiatry 2019; 176:401-409).

Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression.

Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen's d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

OBJECTIVE: Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions. METHODS: Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase). RESULTS: Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions. CONCLUSIONS: Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.

Optimized regimens of combined medications for the treatment of major depressive disorder: a double-blind, randomized-controlled trial.

INTRODUCTION: This study investigated if optimized dose regimens of escitalopram and bupropion combination from treatment initiation can be superior to either drug alone in speed of onset, remission rate, and maintenance of therapeutic efficacy. METHODS: Patients from a single site (N=85) within a larger double-blind 12-week trial (N=245) showed a lower dropout rate (14% vs 40%) and used higher doses; therefore, this cohort was analyzed separately. Uniquely at this single site, after 12 weeks, non-remitters on a single drug received the other one in addition and combination non-remitters underwent a switch of escitalopram for duloxetine for a 6-week period. Escitalopram could be given up to 40 mg/day and bupropion up to 450 mg/day. A 6-month prolongation was then implemented in remitters, maintaining the double-blind design throughout. Remission was defined as ≤7 on the 17-item Hamilton Rating Scale for Depression, as in the initial publication. RESULTS: At week 2, combination treatment was superior in remission rate (5/28) compared with both bupropion (0/26) and escitalopram monotherapies (0/31; P=0.03 and P=0.02, respectively). The week 12 remission rate of combination treatment showed a higher rate (15/28) relative to bupropion monotherapy (7/26; P=0.04), but not statistically different from escitalopram monotherapy (11/31; P=0.13). The 6-week augmentation produced remission in 7/21 monotherapy non-remitters and 0/6 in the switch group (P=0.13). Remission was sustained in 28/31 patients enrolled in the 6-month maintenance. CONCLUSION: These results suggest that combination of escitalopram and bupropion from treatment initiation is superior to either monotherapy in speed of onset. The addition of a second drug in non-remitters can lead to additional remissions, as shown with other combinations of medications. Treatment prolongation using optimized regimens leads to low relapse rates.

Demographic Characteristics Associated with Pregnant and Postpartum Youth Referred for Mental Health Services in a Community Outreach Center.

OBJECTIVE: Pregnancy in youth is considered high risk from a number of different standpoints. At present, limited data has explored demographic factors associated with Canadian cohorts of pregnant and postpartum youth seeking mental health services. We aimed to describe demographic characteristics associated with pregnant and postpartum youth and young adults referred for mental health services in the community and to compare this with data drawn from a hospital-based perinatal mental health clinic. METHOD: Patients were recruited at a young parents' outreach center (YPOC) in a large urban Canadian city. The patients completed questionnaires at the time of initial assessment. The number of attended and missed appointments was tracked and compared to a hospital-based control group in an effort to determine whether the community-based clinic would result in fewer missed appointments. RESULTS: A total of 28 patients were assessed at the YPOC. The mean age of all participants was 19.4 years (+/- 2.3 years) as compared to 18.57 years (± 1.81 years) for the hospital-based group. Rates of poverty were high, and high school completion and level of social support low for many patients. Patients attending the YPOC clinic missed fewer appointments overall. CONCLUSIONS: Pregnant and postpartum adolescents and young adults possess multiple risk factors across various domains that threaten short and long term health outcomes. Establishment of outreach mental health clinics may help minimize barriers to care as demonstrated in the present study by fewer missed appointments and should be investigated further as a means of improving mental health access and outcomes.

OBJECTIF: La grossesse chez les adolescentes est considérée à risque élevé d'un certain nombre de points de vue différents. À l'heure actuelle, des données limitées ont exploré les facteurs démographiques associés aux cohortes canadiennes d'adolescentes enceintes et en postpartum qui cherchent à obtenir des services de santé mentale. Nous visions à décrire les caractéristiques démographiques associées aux adolescentes et aux jeunes femmes enceintes et en postpartum adressées à des services de santé mentale dans la communauté, et à les comparer avec des données tirées d'une clinique de santé mentale périnatale en milieu hospitalier. MÉTHODE: Les patientes ont été recrutées dans un centre d'approche pour jeunes parents (CAJP) d'un grand centre urbain canadien. Les patientes ont répondu à un questionnaire au moment de leur évaluation initiale. Le nombre de rendez-vous respectés et manqués a été suivi et comparé avec celui d'un groupe témoin en milieu hospitalier en vue de déterminer si la clinique communautaire aurait moins de rendez-vous manqués. RÉSULTAT: Au total, 28 patientes ont été évaluées au CAJP. L'âge moyen de toutes les participantes était de 19,4 ans (+/− 2,3 ans) comparativement à 18,57 ans (± 1.81 an) pour le groupe en milieu hospitalier. Les taux de pauvreté étaient élevés, et ceux d'études secondaires terminées et de soutien social étaient faibles pour beaucoup de patientes. Les patientes de la clinique du CAJP ont manqué moins de rendez-vous globalement. CONCLUSIONS: Les adolescentes et les jeunes femmes enceintes et en postpartum présentent de multiples facteurs de risque dans divers domaines qui menacent les résultats de santé à court et à long terme. La création de cliniques de santé mentale d'approche peut contribuer à minimiser les obstacles aux soins comme le démontre la présente étude par le nombre réduit de rendez-vous manqués, et devrait faire l'objet de plus de recherche comme moyen d'améliorer l'accès à la santé mentale et les résultats.

Examining relations between alpha power as well as anterior cingulate cortex-localized theta activity and response to single or dual antidepressant pharmacotherapies.

Electrocortical indices may be useful in predicting antidepressant response. Greater pretreatment alpha power and high rostral anterior cingulate cortex (rACC) theta activity tend to index a favorable outcome. The predictive utility of alpha power asymmetry has been under-explored. Baseline alpha2 (10.5-13.0 Hz) power/asymmetry, rACC theta2 (6.0-8.0 Hz) activity and early (one week) changes in these measures were assessed in relation to antidepressant response by week 12 to three treatment regimens (escitalopram (ESC) + bupropion (BUP), ESC or BUP) in patients with major depressive disorder (N=51). No treatment differences in response existed at week 12. Overall, treatment responders exhibited high, and non-responders low, frontal baseline alpha2 power. Frontal alpha2 power weakly discriminated responders/non-responders overall while posterior alpha2 power and BA25-localized theta2 activity strongly discriminated ESC responders/non-responders. No associations with alpha2 asymmetry and response emerged. BUP responders exhibited high, and BUP non-responders low, baseline rACC theta2 activity. Greater early decreases in rACC theta2 activity existed in ESC+BUP non-responders versus ESC+BUP responders. BUP responders exhibited greater rACC theta2 activity decreases than ESC responders. These preliminary results indicate that baseline and early changes in alpha2 and rACC theta2 activity associate with response and have implications for tailoring antidepressant treatments.

Combination antidepressant therapy for major depressive disorder: speed and probability of remission.

INTRODUCTION: Only about a third of patients with an episode of major depressive disorder remit with a given treatment and few remissions occur within the first weeks of treatment. This study tested whether combining escitalopram and bupropion as initial treatment would result in quicker remission and a higher remission rate than monotherapy with either drug. METHOD: Two hundred forty-five outpatients aged 18-65 having non-psychotic, non-bipolar major depression were randomly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion 450 mg/d and/or escitalopram 40 mg/d for 12 weeks. A Montgomery-Asberg Depression Rating Scale score of 22 was required for randomization, while a Hamilton Rating Scale for Depression score ≤ 7 defined remission. We hypothesized that bupropion plus escitalopram would outperform both monotherapies in both earlier onset of remission and higher rate of remission. RESULTS: Primary analyses did not demonstrate that dual therapy outperformed both monotherapies in either timing of remission or remission rate. All three treatments were well tolerated. DISCUSSION: These results do not support initial use of bupropion plus escitalopram to speed or enhance antidepressant response. CLINICAL TRIALS REGISTRATION: NCT00519428.

Auditory P3 in antidepressant pharmacotherapy treatment responders, non-responders and controls.

Event-related potentials (ERPs), derived from electroencephalographic (EEG) recordings, can index electrocortical activity related to cognitive operations. The fronto-central P3a ERP is involved in involuntary processing of novel auditory information, whereas the parietal P3b indexes controlled attention processing. The amplitude of the auditory P3b has been found to be decreased in major depressive disorder (MDD). However, few studies have examined the relations between the P3b, the related P3a, and antidepressant treatment response. We tested 53 unmedicated individuals (25 females) with MDD, as well as 43 non-depressed controls (23 females) on the novelty oddball task, wherein infrequent deviant (target) and frequent standard (non-target) tones were presented, along with infrequent novel (non-target/distractor) sounds. The P3a and P3b ERPs were assessed to novel and target sounds, respectively, as were their accompanying behavioral performance measures. Depression ratings and the antidepressant response status were assessed following 12 weeks of pharmacotherapy with three different regimens. Antidepressant treatment non-responders had smaller baseline P3a/b amplitudes than responders and healthy controls. Baseline P3b amplitude also weakly predicted the extent of depression rating changes by week 12. Females exhibited larger P3a/b amplitudes than males. With respect to task performance, controls had more target hits than treatment non-responders. ERP measures correlated with clinical changes in males and with behavioral measures in females. These results suggest that greater (or control-like) baseline P3a/b amplitudes are associated with a positive antidepressant response, and that gender differences characterize the P3 and, by extension, basic attentive processes.

Response prediction to antidepressants using scalp and source-localized loudness dependence of auditory evoked potential (LDAEP) slopes.

The loudness-dependence of the auditory evoked potential (LDAEP) slope may be inversely related to serotonin (5-HT) neurotransmission. Thus, steep LDAEPs tend to predict a positive response to selective serotonin reuptake inhibitor (SSRI) antidepressants, which augment 5-HT. However, LDAEPs also predict outcome to antidepressants indirectly altering 5-HT (e.g. bupropion). Hence, the LDAEP's predicative specificity and sensitivity to antidepressant response/outcome remains elusive. Scalp N1, P2 and N1/P2 LDAEP slopes and standardized low resolution brain electromagnetic tomography (sLORETA)-localized N1 and P2 LDAEP slopes were assessed in depressed individuals (N=51) at baseline, 1 and 12 weeks post-treatment with one of three antidepressant regimens [escitalopram (ESC)+bupropion (BUP), ESC or BUP]. Clinical response was greatest with ESC+BUP at week 1. Treatment responders had steep N1 sLORETA-LDAEP baseline slopes while non-responders had shallow ones. P2 sLORETA-LDAEP slope increases at 1 week existed in responders; decreases were noted in non-responders. Exploratory analyses indicated that more BUP and ESC responders versus non-responders had steep baseline N1 sLORETA-LDAEP slopes. Additionally, slight decreases in scalp P2 LDAEP by week 1 existed for ESC treatment, while slope increases existed with ESC+BUP treatment. Only baseline N1 sLORETA-LDAEP discriminated treatment responders/non-responders. This work confirms that certain LDAEP measures are associated with treatment outcome and appear to be differentially modulated with varying antidepressant drug regimens, though this should be confirmed using larger samples.

More than just milk: a review of prolactin's impact on the treatment of anorexia nervosa.

OBJECTIVE: In completing this review, we aim to educate readers about the physiological importance of the hormone prolactin (PRL) in the treatment of patients with anorexia nervosa (AN). METHOD: A comprehensive review of PRL was undertaken using existing published literature with specific focus on domains pertinent to the treatment of AN. RESULTS: Prolactin influences multiple biological processes throughout the body. Disruption in its regulation can impact women's health issues such as menstruation and bone health, which are pertinent to AN treatment. The use of antipsychotics with high D2 receptor affinity for the augmented treatment of AN increases the potential risk of PRL-mediated adverse effects. DISCUSSION: Although not intrinsic to underlying disease underpinnings, PRL has the capacity to affect and influence multiple outcome variables in treatment of patients with AN. Improved understanding, better screening and the completion of further prospective research are necessary to help facilitate and incorporate ongoing knowledge translation.

Antenatal depression and anxiety affect postpartum parenting stress: a longitudinal, prospective study.

OBJECTIVE: Postpartum depression has been associated with parenting stress, impacting attachment and child development. However, the relation between antenatal depression or anxiety and postpartum parenting stress has not been investigated. We studied the effect of antenatal depression and anxiety and treatment with selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors (antidepressants [ADs]) on postpartum parenting stress. METHOD: Ninety-four pregnant women (part of a larger study examining prenatal AD exposure on infants) were prospectively monitored for depression and anxiety during the third trimester and 3- and 6-months postpartum using the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale. Parenting stress was assessed using the Parenting Stress Index-Short Form at 3- and 6-months postpartum. RESULTS: Both antenatal third trimester depression and anxiety were significant predictors of 3- and 6-month postpartum parenting stress, after controlling for maternal age, number of children, and exposure to prenatal ADs (all Ps < 0.001). Third trimester depression accounted for 13% to 22% of the variance in postpartum stress at 3 and 6 months. Prenatal AD use was not a significant predictor in any of the models (all Ps > 0.2). Twenty of 41 mothers on ADs achieved remission (HDRS = 7) in pregnancy and had average parenting stress scores of about 1 standard deviation lower than those who did not at 3- and 6-months postpartum (t = 3.32, df = 32, P = 0.002 and t = 2.52, df = 32, P = 0.02, respectively). CONCLUSIONS: Our findings indicate that antenatal depression and anxiety directly impact postpartum parenting stress, regardless of antenatal AD treatment. Ongoing maternal mental illness in pregnancy is an important predictor of postpartum parenting stress. Early recognition and treatment to remission is key.