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.

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.

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.

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.].

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.

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.

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.].

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.].

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.].

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 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 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.].

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.].

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.

"I Want a New Drug": Exercise as a Pharmacological Therapy.

Skeletal muscle can be considered a secretory organ that produces myokines and other humoral factors having autocrine-, paracrine-, and endocrine-like signaling effects throughout the body. Exercise has such profound pharmacological and physiological effects that it should be considered a drug therapy. Exercise has documented benefits for preventing or treating many physical and mental disorders or their sequelae, and it has a potential role in managing adverse effects associated with drug therapies. If exercise were a drug evaluated by the Food and Drug Administration, it might be approved for a large number of therapeutic indications. Exercise can be appropriately prescribed for virtually anyone for primary, secondary, or tertiary prevention of many mental and physical disorders.

Deuterated Drugs.

Many drugs are carbon-based, and carbon-hydrogen bonding is particularly relevant for understanding important properties of drug molecules. Deuteration refers to the selective replacement of protium hydrogen isotope atoms in small-molecule drugs with deuterium hydrogen isotope atoms. Deuteration of a drug is most likely to affect pharmacokinetic properties, such as metabolism, rather than its pharmacodynamic effects. For this reason, the metabolism of certain drugs may be favorably influenced when deuterium is substituted for protium, resulting in improved safety, tolerability, or efficacy. Examples of deuterated drugs that have been evaluated in clinical studies include paroxetine, tetrabenazine, and dextromethorphan.

Odds and ends in psychopharmacology from the past 10 years.

Seven topics previously described in this column are revisited. The use of quantitative electroencephalography has been shown in a prospective study to be effective for predicting antidepressant treatment response. A novel antidepressant drug, agomelatine, has generated much controversy, and its development for the U.S. market was discontinued. A long awaited revised system for categorizing the safety of medications during pregnancy and lactation has finally been published by the Food and Drug Administration. Dextromethorphan/quinidine, eslicarbazepine acetate, levomilnacipran, and esketamine are recent examples of drugs that were developed based on the complex concepts of chirality and stereochemistry. Lisdexamfetamine, a stimulant drug, failed to show benefit as an augmentation therapy for the treatment of depression. The combination drug naltrexone/bupropion was finally approved as a therapy for obesity, after its cardiovascular safety was confirmed in a prospective premarketing study. Further development of the glucocorticoid receptor antagonist drug mifepristone as a treatment for psychotic depression was stopped based on a large negative trial, but the drug continues to be investigated for other potential psychiatric indications. These examples illustrate how the field of psychopharmacology continues to evolve.

Psychiatric medications and sudden cardiac death: putting the risk in perspective.

A potential adverse effect of some psychiatric medications is an abnormally prolonged corrected QT (QTc) interval and an increased risk of developing Torsade de Pointes (TdP), which is associated with sudden death. Because antidepressant and antipsychotic drug use is increasing and rates of sudden cardiac death are decreasing, the proportion of sudden cardiac death cases that may be attributed to these drugs is likely to be exceedingly small compared to other risk factors. A comprehensive review of the published literature has concluded that there is little evidence that psychotropic drug-associated QTc interval prolongation by itself is sufficient to predict TdP.

Aspergillus, angiogenesis, and obesity: the story behind beloranib.

Fumagillin, an antimicrobial compound first isolated in 1949 from the fungus Aspergillus fumigatus, four decades later was unexpectedly found to inhibit angiogenesis. Interest in developing angiogenesis inhibitor drugs as possible treatments for cancer led to the synthesis of analogs of fumagillin. Preclinical studies of various analog drugs confirmed that they inhibited angiogenesis, but they also were associated with weight loss as an adverse effect. Because adipose tissue can grow and regress throughout adulthood, is highly vascularized, and has angiogenic properties, interest in investigating anti-angiogenic agents in animal models of obesity found that fumagillin analogs caused dose-dependent reversible weight reduction and adipose tissue loss. Beloranib, a fumagillin analog that is an angiogenesis inhibitor and associated with decreased adiposity in animals, has been studied in phase I clinical trials for cancer. It is currently being investigated for the treatment of obesity and related conditions. Three phase I and three phase II studies found significant degrees of weight loss and acceptable tolerability for beloranib compared to placebo, justifying further clinical development of the drug for obesity.

"Evidence" and the treatment of alcohol use disorder.

Alcohol use disorder is an important public health problem for which evidence-based treatments should be used. In the current article, two recent publications related to this topic (i.e., a featured article from The Atlantic and a brief guide from the Substance Abuse and Mental Health Services Administration [SAMHSA]) are critically evaluated. Both publications emphasize that evidence-based medications are underused for the treatment of alcohol use disorder. The featured article was critical of faith-based Alcoholics Anonymous(®) 12-step programs, but the critique was not based on a sound evaluation of research pertaining to their use. The brief guide prepared for SAMHSA was developed by a scientific consensus panel reviewing current evidence of the effectiveness of available medications, but focused only on those that have been approved by the U.S. Food and Drug Administration (FDA) for this indication, neglecting to describe potentially effective off-label use of other FDA-approved medications.