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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 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

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.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).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.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.

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.

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

Zoë Zuilhof, Sandhaya Norris, Claude Blondeau, Pierre Tessier, Pierre Blier Department of Psychiatry, University of Ottawa, The Royal Ottawa Institute of Mental Health Research, Ottawa, ON, Canada 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. Keywords: antidepressant, escitalopram, bupropion, action onset, augmentation, prolongation&nbsp

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.

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. Copyright © 2011 John Wiley & Sons, Ltd and Eating Disorders Association.

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 .

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.

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.

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).A comprehensive review of PRL was undertaken using existing published literature with specific focus on domains pertinent to the treatment of AN.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.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.

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.

Background: One in five women will suffer from mental health (MH) disorders during their pregnancy or first year postpartum. These rates are even higher in adolescent mothers. In an attempt to optimize health outcomes for young mothers and their families, a multi-disciplinary clinic for pregnant and post-partum adolescents was established at a community based young parent’s outreach center in Ottawa in 2004 (St. Mary’s Home). An on-site psychiatric clinic was piloted at the center in 2013. The current study aimed to describe characteristics of patients using data obtained at initial assessment. Methods: A total of 36 patients were referred over the recruitment timeframe, of which 28 attended the first assessment and consented to participate. The patients completed a battery of psychological measures and assessment tools which screened for issues relating to mood, anxiety, attachment, level of functioning and distress, substance use, and coping skills. Our institution’s research ethics board approved the study. Results: Thirty nine percent of those assessed were adolescents (