BACKGROUND:Ketamine is a rapid-acting treatment for treatment-resistant depression (TRD), though mechanisms related to ketamine's effects remain unclear. Blood-based neurotrophic and inflammatory factors (NIFs; e.g., brain-derived neurotrophic factor, interleukin-6) have emerged as markers potentially linked to ketamine and ketamine treatment response. METHODS:In this secondary analysis of a randomized controlled trial (RCT), 133 adults with TRD received a single-dose infusion of ketamine (n = 89; 0.5 mg/kg) or saline (n = 44) and provided measures of peripheral blood NIF levels and depression severity across a five-day post-infusion period. Differences between ketamine and saline groups were examined for (1) NIF levels, (2) associations between NIF trajectories and depression score trajectories, and (3) associations between baseline NIF levels and depression score trajectories. Subgroup sensitivity analyses examined identical relationships within many (n = 28) discrete subgroups of individuals. RESULTS:No differences were found between ketamine and saline cohorts for NIF trajectories, associations of NIF and depression trajectories, or associations of baseline NIF levels and depression trajectories. On subgroup analyses, in participants with lower BMI (BMI < 25; n = 66), increasing interleukin-1 receptor antagonist (IL-1RA) trajectories post-ketamine were associated with less improvement in depression in the first day post-infusion. DISCUSSION:Associations between ketamine treatment and peripheral neurotrophic/inflammatory factors were not detected in our RCT of 133 adults with TRD. The sole exception across exhaustive sensitivity analyses was that, in individuals with low BMI, increases in IL-1RA levels may be linked to worse immediate treatment response. Future research investigating CNS-specific NIF activity is needed to more definitively test the posited role of NIFs in ketamine's antidepressant mechanisms.

Background Understanding the effects of ketamine on depressive symptoms could help identify which patients might benefit and clarify its mechanism of action in both the early (≤1 day post-infusion) and late (e.g. 2–30 days post-infusion) post-infusion periods. Symptom network analyses could provide complementary information regarding relationships between symptoms. Aims To identify the effects of ketamine on symptom-level changes in depression across both the early and late post-infusion periods and on depressive symptom network changes. Methods In this secondary analysis of 152 adults with treatment-resistant depression (with 38.8% reporting suicidal ideation at baseline), we compared symptom changes in the early and late post-infusion periods between individuals randomised to a single 40 min infusion of intravenous ketamine 0.5 mg/kg ( n = 103) or saline ( n = 49) and identified changes in symptom networks between pre- and post-ketamine treatment using network analyses. Results In the early post-infusion period, the greatest improvement (comparing ketamine with saline) was in depressive symptoms related to sadness. In network analyses, symptom network connectivity increased following ketamine infusion. Symptoms of sadness and lassitude showed persistent improvement in the first week post-infusion, whereas improvements in suicidal thoughts first emerged 3–4 weeks post-infusion. Conclusion Ketamine improved all symptoms but showed the greatest effect on symptoms of sadness, both immediately and in the initial week after treatment. Ketamine also rapidly altered the topology of symptom networks, strengthening interrelationships between residual symptoms. The efficacy of ketamine (compared with saline) regarding suicidal symptoms emerged later. Our findings suggest potentially divergent efficacy, time courses and mechanisms for different symptoms of depression.

Ketamine has shown promise in rapidly improving symptoms of depression and most notably treatment-resistant depression (TRD). However, given the heterogeneity of TRD, biobehavioral markers of treatment response are necessary for the personalized prescription of intravenous ketamine. Heterogeneity in depression can be manifested in discrete patterns of functional connectivity (FC) in default mode, ventral affective, and cognitive control networks. This study employed a data-driven approach to parse FC during positive mood processing to characterize subgroups of patients with TRD prior to infusion and determine whether these connectivity-based subgroups could predict subsequent antidepressant response to ketamine compared to saline infusion. 152 adult patients with TRD completed a baseline assessment of FC during positive mood processing and were randomly assigned to either ketamine or saline infusion. The assessment utilized Subgroup-Group Iterative Multiple Model Estimation to recover directed connectivity maps and applied Walktrap algorithm to determine data-driven subgroups. Depression severity was assessed pre- and 24-hr postinfusion. Two connectivity-based subgroups were identified: Subgroup A (n = 110) and Subgroup B (n = 42). We observed that treatment response was moderated by an infusion type by subgroup interaction (p = .040). For patients receiving ketamine, subgroup did not predict treatment response (beta = -.326, p = .499). However, subgroup predicted response for saline patients. Subgroup B individuals, relative to A, were more likely to be saline responders at 24-hr postinfusion (beta = -2.146, p = .007). Thus, while ketamine improved depressive symptoms uniformly across both subgroups, this heterogeneity was a predictor of placebo response.

This secondary analysis of a randomized clinical trial examines whether automated self-association training can prolong the antidepressant effect of a single infusion of ketamine beyond 1 month in patients with treatment-resistant depression.

BackgroundIntravenous (IV) ketamine has emerged as a rapid and effective treatment for TRD. However, the specific neural mechanisms of ketamine's effects in humans remains unclear. Although neuroplasticity is implicated as a mechanism of action in animal models, relatively few randomized controlled trials (RCTs) in TRD patients have examined ketamine's impact on functional connectivity, a posited functional marker of neuroplasticity—particularly in the context of a mood-induction paradigm (termed miFC).Methods152 adults with TRD (63% female; 37% male) were randomly allocated to receive a single infusion of ketamine or saline in a 2:1 ratio. We examined changes in connectivity (from baseline to 24-h post-infusion) that differed by treatment, and whether clinical treatment response at 24-h post-infusion was uniquely related (among patients allocated to ketamine relative to saline) to (1) pre-treatment connectivity and (2) changes in connectivity. We examined both miFC and rsFC, using prefrontal cortex and limbic seed regions. We also conducted a multiverse analysis to examine findings most robust against analytic decisions.FindingsAcross both miFC and rsFC, ketamine was associated with greater in prefrontal/limbic connectivity compared to saline, and lower baseline connectivity of limbic and prefrontal regions predicted greater treatment response in patients receiving ketamine. Greater connectivity increases in participants receiving ketamine was uniquely related to greater treatment response. In addition, certain findings were identified as being reproducible against different analytic decisions in multiverse analyses.InterpretationOur findings identify specific neural connectivity patterns impacted by ketamine and were uniquely related to outcomes following ketamine (relative to saline). These findings generally support prominent neuroplasticity models of ketamine's therapeutic efficacy. These findings lay new groundwork for understanding how to enhance and optimize ketamine treatments and develop novel rapid-acting treatments for depression.FundingThis research was supported by NIH grant R01MH113857 and by the Clinical and Translational Sciences Institute at the University of Pittsburgh (UL1-TR-001857).

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016–0.082). In the right BA10, these associations generalized to both infusion arms ( p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032–0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.

OBJECTIVE Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response. METHODS A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [β]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (β=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: β=0.015, 95% CI=0.003, 0.03; t=2.35, df=568). CONCLUSIONS After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Major depression (MDD) is a common and disabling disorder. Research has shown that most people with MDD receive either no treatment or inadequate treatment. Computer and mobile technologies may offer solutions for the delivery of therapies to untreated or inadequately treated individuals with MDD. The authors review currently available technologies and research aimed at relieving symptoms of MDD. These technologies include computer-assisted cognitive-behavior therapy (CCBT), web-based self-help, Internet self-help support groups, mobile psychotherapeutic interventions (i.e., mobile applications or apps), technology enhanced exercise, and biosensing technology.

Dementia, once described as the "silent epidemic," is now well known and greatly feared. Although the total number of dementia cases will increase worldwide because of increased life expectancy, eight population-based studies of dementia incidence or prevalence have suggested a declining age-specific risk in the United States and Europe during the past three decades. Many different psychotropic drugs have been introduced since the mid-1950s, and their clinical use has broadened and increased dramatically over time. Antidepressant drugs, second-generation antipsychotic drugs, lithium, valproate, carbamazepine, lamotrigine, electroconvulsive therapy, and exercise have all been found to activate or regulate various intracellular neurotrophic and neuroprotective processes. They promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. Because of their neurotrophic and neuroprotective effects, the widespread use of psychotropic drugs provides a plausible explanation for declining rates of dementia that have been observed.

Background We report the neuropsychological outcome of 25 patients with treatment-resistant major depressive disorder (TRD) who participated in an Institutional Review Board (IRB)-approved randomised double-blind trial comparing active to sham deep brain stimulation (DBS) in the anterior limb of the ventral capsule/ventral striatum (VC/VS). Methods Participants were randomised to active (n=12) versus sham (n=13) DBS for 16 weeks. Data were analysed at the individual and group levels. Group differences were analysed using repeated measures ANOVAs. Relationships between depression severity and cognition were examined using partial correlations. The false discovery rate method controlled for multiple analyses. Results No significant interactions comparing active versus sham stimulation over time were evident. Change in depression was unrelated to change in neuropsychological measures. Twenty patients declined by ≥1 SD on at least one measure (41.3% of declines occurred in active group participants; 63.0% in older participants regardless of stimulation status). Twenty-two patients exhibited improvements >1 SD on neuropsychological measures (47.7% in the active group; 63.1% in younger participants). Conclusions These data suggest that VC/VS DBS in patients with TRD does not significantly affect neuropsychological function. Age at surgery, regardless of stimulation status, may be related to cognitive outcome at the individual patient level. Trial registration number NCT00837486; Results.

Distinguishing itself from other benzodiazepine drugs, oxazepam has an interesting pharmacological and clinical profile, including binding effects on the translocator protein (TSPO) and a relatively favorable safety and abuse liability profile. TSPO is found in the brain (where it is involved in neurosteroid synthesis), but is also expressed in the heart and other peripheral tissues. Oxazepam is potentially useful in the treatment of substance abuse, especially in conjunction with the cortisol synthesis inhibitor metyrapone, and can be considered an appropriate medication to use in the treatment of depression. The oxazepam/metyrapone combination has been piloted in cocaine-dependent patients and should be investigated in patients with depression. Expression of cardiac TSPO is altered by different stress conditions, and drugs binding to TSPO may have cardioprotective effects. The possibility of oxazepam, alone or together with antidepressant drugs, having a positive effect on cardiac function in patients with depression should also be studied. [Journal of Psychosocial Nursing and Mental Health Services, 54(5), 21-24.].

Antidepressant, atypical antipsychotic, and hallucinogen drugs mediate their actions in part by interactions with the serotonin-2A (5HT2A) receptor. Serotonergic hallucinogen drugs, such as psilocybin, bind most potently as agonists at the 5HT2A receptor, producing profound changes in perception, mood, and cognition. Some of these drugs have been or are currently being investigated in small Phase 2 studies for depression, alcoholism, smoking cessation, anxiety, and posttraumatic stress disorder. However, unlike the synergistic effects of combining antidepressant and atypical antipsychotic drugs, the potential therapeutic effects of hallucinogen drugs may be attenuated by the concurrent use of these medications because antidepressant and atypical antipsychotic drugs desensitize and/or down-regulate 5HT2A receptors. This finding has important implications for optimizing the potential therapeutic use of hallucinogen drugs in psychiatry. [ Journal of Psychosocial Nursing and Mental Health Services, 54 (7), 21–24.]

Methylene blue, first discovered and used as a dye in the textile industry, has long been used for biological staining in histology, bacteriology, and hematology. Because of its unique physiochemical properties, it was the first synthetic drug used in medicine, having been used to treat malaria more than one century ago. Methylene blue was also one of the first drugs used for the treatment of patients with psychosis at the end of the 19th century and was the lead drug in the serendipitous development of phenothiazine antipsychotic drugs in the mid-20th century. It was studied in bipolar disorder in the 1980s and has been investigated in neurodegenerative disorders in recent years. The history of methylene blue from its discovery as a dye to its use as a stain and then its therapeutic application in medicine is an example of how a drug's use can evolve over time through careful observation, clinical needs, serendipity, and the integration of concepts from different disciplines. [Journal of Psychosocial Nursing and Mental Health Services, 54(9), 21-24.].

Listening to music may be thought of as noninvasive and nonpharmacological, but music should be considered a drug therapy. Music exposure has measurable neurobiological effects that are linked to systems regulating reward, motivation, and pleasure; stress and arousal; and immunity. Functional neuroimaging and lesion studies demonstrate that music-evoked emotions are associated with modulation of linked limbic and paralimbic brain regions. Some of these regions are involved in reward, motivation, and pleasure, and there are additional projections to brain structures regulating autonomic, emotional, and cognitive function. Controlled clinical studies have found significant benefits with the use of music for depression and anxiety, pain relief, stroke recovery, schizophrenia, and behavioral and psychological symptoms of dementia. Because music is not associated with significant adverse effects, it is a viable adjunctive treatment option for patients in many different clinical settings. [ Journal of Psychosocial Nursing and Mental Health Services, 54 (12), 23–27.]

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Polypharmacotherapy is a commonly used, but frequently criticized, clinical practice. Deprescribing is the process of discontinuing inappropriate or unnecessary medications, with the goals of decreasing adverse events and drug-drug interactions, simplifying medication regimens to enhance adherence, and reducing costs associated with medication use while maintaining or improving clinical outcomes. Studies of groups of patients suggest that deprescribing medication is feasible and safe, but individual experiences are masked by group data. Although deprescribing can decrease medication exposure, evidence of the effectiveness of deprescribing medication on improving clinical outcomes is conflicting or lacking. Medication necessity or appropriateness should be assessed on a case-by-case basis and from visit to subsequent visit over time. Deprescribing medication should be accompanied by vigilant monitoring for adverse drug withdrawal effects or relapse of an underlying condition. [Journal of Psychosocial Nursing and Mental Health Services, 54 (11), 21-24.].

Trifluoperazine, developed in the mid-1950s and introduced in 1959 as an anxiolytic and antipsychotic agent, has been an extensively studied drug molecule that has been used as a calmodulin inhibitor. Regulation of calmodulin has important roles in cellular proliferation, inflammation, neurodegeneration, and other pathological processes. Trifluoperazine also inhibits P-glycoprotein, a protein that transports organic compounds across cell membranes and the blood-brain barrier. Trifluoperazine is currently approved for the treatment of schizophrenia as well as for the treatment of non-psychotic anxiety, but has other potential clinical uses based on calmodulin and P-glycoprotein inhibition.

Benzodiazepine drugs are controversial because of safety and abuse liability concerns, although they have clinically relevant pharmacological differences. The current article reviews studies pertaining to the pharmacology, safety, and abuse liability of oxazepam. Compared to other benzodiazepine drugs, oxazepam has a favorable safety and abuse liability profile, which may be related to its pharmacology. Oxazepam is more slowly absorbed and enters the brain more slowly than other benzodiazepine drugs; it does not have active metabolites and does not accumulate with chronic dosing; its metabolism is not affected by age or by mild/moderate liver disease; and it is not prone to drug-drug interactions. Oxazepam also binds to the translocator protein, which stimulates the synthesis of neurosteroids, and this effect may contribute to its reduced abuse liability.