Improved implicit self-esteem is associated with extended antidepressant effects following a novel synergistic intervention.

INTRODUCTION: In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment's effects on implicit self-associations and their relation to symptom improvement. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30-40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial. RESULTS: The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: ß = -0.201; p = 0.049). DISCUSSION: Our findings suggest that changing implicit self-worth during a post-ketamine 'plasticity window' is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention's impact on implicit cognition, as this mechanism appears linked to the intervention's enduring clinical benefits.

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression.

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.

One-Year Outcomes Following Intravenous Ketamine Plus Digital Training Among Patients with Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

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.

A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial.

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 [ß]=-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 (ß=-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: ß=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.

Use of Computer and Mobile Technologies in the Treatment of Depression.

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.

Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression.

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.

Hey Mister Tambourine Man, Play a Drug for Me: Music as Medication.

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.].

Deprescribing to Reduce Medication Use: Will This Help Your Patient?

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.].

Methylene Blue: The Long and Winding Road From Stain to Brain: Part 2.

Methylene blue was the first synthetic drug ever used in medicine, having been used to treat clinical pain syndromes, malaria, and psychotic disorders more than one century ago. Methylene blue is a cationic thiazine dye with redox-cycling properties and a selective affinity for the nervous system. This drug also inhibits the activity of monoamine oxidase, nitric oxide synthase, and guanylyl cyclase, as well as tau protein aggregation; increases the release of neurotransmitters, such as serotonin and norepinephrine; reduces amyloid-beta levels; and increases cholinergic transmission. The action of methylene blue on multiple cellular and molecular targets justifies its investigation in various neuropsychiatric disorders. Investigations of methylene blue were instrumental in the serendipitous development of phenothiazine antipsychotic drugs. Although chlorpromazine is heralded as the first antipsychotic drug used in psychiatry, methylene blue is a phenothiazine drug that had been used to treat psychotic patients half a century earlier. It has also been studied in bipolar disorder and deserves further investigation for the treatment of unipolar and bipolar disorders. More recently, methylene blue has been the subject of preclinical and clinical investigations for cognitive dysfunction, dementia, and other neurodegenerative disorders. [Journal of Psychosocial Nursing and Mental Health Services, 54(10), 21-26.].

Antidepressant Drugs and the Risk of Intracranial Bleeding: Parsing an Observational Study.

Observational studies have suggested that antidepressant drug use is associated with a small but increased risk of intracranial bleeding. Because of the widespread use of antidepressant drugs and the potential public health significance of this finding, the current article critically evaluates the methodology and findings of a recently published observational study. Observational studies reveal associations, but cannot establish causality. Establishing causality from observed associations requires evidence from different scientific perspectives. Claims arising from observational studies are likely to be wrong, especially for small effects, because of bias and confounding. Statistical testing does not prove the validity of an association, nor does a meta-analysis of multiple observational studies. A valid association may not be clinically meaningful if the magnitude of the effect is small or the outcome is rare. Based on a critical analysis of these observational studies, it is concluded that the risk of intracranial bleeding associated with antidepressant drugs is likely to be a false alarm. [Journal of Psychosocial Nursing and Mental Health Services, 54(2), 21-24.].

Methylene Blue: The Long and Winding Road from Stain to Brain: Part 1.

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.].

Antidepressant, Antipsychotic, and Hallucinogen Drugs for the Treatment of Psychiatric Disorders: A Convergence at the Serotonin-2A Receptor.

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.].

Pimavanserin: An Inverse Agonist Antipsychotic Drug.

Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications. Whether pimavanserin can treat psychotic symptoms in schizophrenia, psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, pimavanserin may have potential for treating symptoms associated with the use of hallucinogen drugs and for treating akathisia associated with antipsychotic medications. [Journal of Psychosocial Nursing and Mental Health Services, 54 (6), 21-24.].

Oxazepam for the Treatment of Substance Abuse and Depression: Is it Appropriate?

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.].

Safety and Abuse Liability of Oxazepam: Is This Benzodiazepine Drug Underutilized?

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.

Can Declining Rates of Dementia Be Explained by the Increased and Widespread Use of Psychotropic Medications?

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.

Trifluoperazine: A Sprightly Old Drug.

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.