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.

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.].

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.].

Melatonin, Liraglutide, and Naltrexone/Bupropion for the Treatment of Obesity and Medication-Related Weight Gain.

Overweight and obesity are associated with significant morbidity and mortality. This is a known problem among individuals with psychiatric illness, which may be partly due to the adverse metabolic effects of certain psychotropic drugs. Melatonin, liraglutide, and naltrexone/bupropion are examples of drugs with different mechanisms of action that have favorable effects on obesity or medication-related weight gain. Melatonin is appropriate to consider for any patient who will be started on a psychotropic drug that is potentially associated with weight gain or other adverse metabolic effects. Liraglutide should also be considered appropriate for use in overweight or obese psychiatric patients, including those with medication-associated weight gain. The use of naltrexone/bupropion may be problematic in patients with bipolar disorder or schizophrenia because of the potential adverse effects of the bupropion component of the combination. All three drugs deserve further dedicated studies in psychiatric patient populations.

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.

Down the hatch: is prescribing medication really that simple?

Drug absorption and metabolism is influenced by age, sex, pharmacogenetic variability, medical comorbidity, concurrent drug use, drug formulation, and route of administration. Drug dissolution typically begins in the stomach, but absorption occurs mainly in the small intestine. Malabsorption syndromes, previous gastrointestinal (GI) surgery, or decreased GI blood flow impair or delay the absorption of orally administered drugs. Decreased drug absorption can occur with certain gastric bypass procedures when the stomach or proximal small intestine is an important absorption site. Drugs undergoing extensive first-pass hepatic metabolism can have increased concentrations and greater systemic effects when administered directly into the jejunum. Non-oral routes of drug administration ordinarily bypass first-pass hepatic metabolism, leading to greater bioavailability and higher concentrations compared with oral administration of the same dose. Metabolic activity is variably reduced with increased age or liver disease severity, but declines in liver function cannot be quantified to determine drug metabolizing capacity.

A "glucose eater" drug as a therapeutic agent in psychiatry.

Metformin, currently approved for the treatment of type 2 diabetes, is an interesting drug that has various cellular and molecular mechanisms. These mechanisms have justified other off-label clinical and investigational uses for diabetes prevention in high-risk patients, for polycystic ovary syndrome, non-diabetic obesity, non-alcoholic fatty liver disease, and for prevention or treatment of cancer. A large number of controlled and uncontrolled studies have generally found metformin to be effective, well tolerated, and safe for preventing or treating antipsychotic-related weight gain and for improving metabolic abnormalities in psychiatric patient populations. Metformin has the potential effect of inducing hippocampal neurogenesis, and additional studies of this drug are warranted in patients with mood or cognitive disorders.

Therapies for obesity and medication-associated weight gain.

Compared to the general population, individuals with psychiatric illness, especially serious and chronic mood and psychotic disorders, are more likely to be overweight or obese, have higher rates of weight-related medical conditions, and have greater non-suicide mortality rates. Lorcaserin (Belviq(®)), phentermine/topiramate combination (Qsymia(®)), and bupropion/naltrexone combination have been demonstrated to be effective for the treatment of obesity, as an adjunct to a reduced-calorie diet and physical activity, although their absolute safety has yet to be established with more widespread use or longer use. Bariatric surgery is an effective approach for morbid obesity, but careful psychiatric assessment before and follow up after surgery is necessary. Behavioral lifestyle interventions to promote weight loss are effective and should be implemented along with or instead of drug therapies or surgery.

Quantitative electroencephalogram biomarkers for predicting likelihood and speed of achieving sustained remission in major depression: a report from the biomarkers for rapid identification of treatment effectiveness in major depression (BRITE-MD) trial.

OBJECTIVE: Clinical trials in major depressive disorder (MDD) commonly assess remission at a single endpoint. Complementary, clinically relevant metrics include the likelihood and speed of achieving sustained remission. A neurophysiologic measure, the Antidepressant Treatment Response (ATR) index, previously predicted 8-week outcomes of pharmacotherapy. We retrospectively examined data from the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD) trial to evaluate this biomarker's properties in predicting sustained remission and time to achieve sustained remission. METHOD: In the BRITE-MD trial, 67 adults with DSM-IV MDD received escitalopram continuously for 13 weeks. The 17-item Hamilton Depression Rating Scale (HDRS17) was used to define sustained remission as achieving remission (HDRS17 score ≤ 7) at a series of consecutive assessments, including week 13. The onset of sustained remission was defined as the earliest time from which all subsequent HDRS17 assessments were ≤ 7. The ATR was evaluated by using frontal quantitative electroencephalogram recordings at baseline and week 1. Subjects were stratified based on ATR status (ie, ATR+/ATR-). Kaplan-Meier survival analysis evaluated group differences in time to sustained remission. Higher ATR was hypothesized to predict sustained remission and time to sustained remission. Subjects participated between January 2006 and July 2007. RESULTS: Of 67 subjects, 36 achieved remission by week 13, and ATR predicted this single endpoint in receiver operating characteristic analyses (P = .016; sensitivity, 52.8%; positive predictive value, 76.0%). Remitters had a higher mean (SD) ATR value than those who did not remit (57.9 [10.0] vs 51.9 [8.7], P = .012). Sixteen of the 31 individuals with sustained remission had ATR+ status, while 28 of the 36 who were not sustained remitters had ATR- status (P = .012). The mean time to reach sustained remission was significantly shorter among ATR+ subjects than ATR- individuals (38 vs 53 days, P = .038). CONCLUSIONS: The ATR index predicted remission at 13 weeks as well as the speed of achieving sustained remission with antidepressant monotherapy. This finding suggests that the ATR biomarker may predict stable longer-term outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00289523.

Dietary supplement drug therapies for depression.

Many dietary supplements are readily accessible and commonly used for the treatment of depression. A dietary supplement is a product intended to supplement the diet but is not intended to treat, diagnose, prevent, or cure disease. The U.S. Food and Drug Administration can take action against dietary supplement manufacturers for products only after they are marketed, mainly if the product is found to be unsafe or if false or misleading claims are made about the product. Few dietary supplement products have been adequately studied for their safety and efficacy. Of the five products reviewed in this article (L-methylfolate, S-adenosyl-L-methionine [SAM-e], omega-3 fatty acids, L-tryptophan, and inositol), only omega-3 fatty acids and SAM-e have sufficient supporting evidence for their efficacy to warrant safe use.

Effect of concurrent substance use disorder on the effectiveness of single and combination antidepressant medications for the treatment of major depression: an exploratory analysis of a single-blind randomized trial.

BACKGROUND: The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD. METHODS: In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12- and 28-week endpoints. RESULTS: The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment. CONCLUSIONS: Although significant baseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD.

Drug therapies for tardive dyskinesia: Part 1.

Blocking dopamine (DA) receptors in the basal ganglia can cause parkinsonian symptoms, acute dystonia, akathisia, tardive dyskinesia (TD), and neuroleptic malignant syndrome. TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. Many drug therapies have been tried for TD, but none are approved by the U.S. Food and Drug Administration. The second-generation antipsychotic drugs should be considered as a treatment of first choice for clinically significant TD, because they will also be potentially effective as a primary treatment for the underlying disorder. Dopamine-depleting drugs are effective for TD, but their practical use is severely limited because of tolerability and safety concerns. Various DA-modulating drugs have been tried; clinical evidence of efficacy suggests that amantadine (Symmetrel®) and naloxone (Narcan®) are worthwhile to try. Although efficacy evidence for buspirone (Buspar®) in TD is limited, this drug is safe and well tolerated and would be reasonable to try. Bromocriptine (Parlodel®), selegiline (Deprenyl®), and cholinergic-modulating drugs are not considered effective for TD.

Alternative drug therapies for dementia.

Drugs currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease include acetylcholinesterase inhibitor (i.e., tacrine, donepezil, rivastigmine, and galantamine) and glutamate-modulating (i.e., memantine) drugs. Because these drugs have modest benefits, various alternative drug therapies have been of interest. Drugs with vasodilator activity were originally tried in dementia when it was hypothesized that the condition was due to cerebrovascular insufficiency. Isoxsuprine and ergoloid mesylates are FDA approved for the treatment of dementia, although they have limited evidence of benefit and are rarely used. The hypothesis that free radicals may initiate and maintain mechanisms responsible for neurodegeneration in dementia has stimulated interest in investigating various antioxidant and anti-inflammatory drugs. There is no evidence that other drug therapies, including vitamin E, selegiline, nonsteroidal anti-inflammatory drugs, statin drugs, omega-3 fatty acids, estrogen or combined estrogen plus progestin therapy, or B vitamins, are sufficiently effective and safe to justify their clinical use for the treatment of dementing disorders.

Potential adverse effects of discontinuing psychotropic drugs. Part 3: Antipsychotic, dopaminergic, and mood-stabilizing drugs.

Abrupt discontinuation of antipsychotic drugs in patients with schizophrenia is associated with earlier, and often more severe, illness episodes than are seen with gradual discontinuation. Antipsychotic drugs can cause various abnormal motor syndromes, but abruptly stopping them has been associated with the seemingly paradoxical development of similar motor syndromes, such as withdrawal dyskinesias, parkinsonian symptoms, dystonias, and neuroleptic malignant syndrome. Dopamine-releasing and dopamine-agonist drugs are used to treat some of the motor syndromes caused by antipsychotic drugs, but their abrupt discontinuation can also be associated with abnormal syndromes. When antipsychotic drugs, lithium, or certain anticonvulsant drugs are used for treatment of bipolar disorder, rapid versus gradual discontinuation is more likely to lead to greater mood instability and manic relapse. If necessary, these medications should be gradually tapered to minimize all types of adverse discontinuation effects. Patients should be educated about the possible adverse effects of abrupt medication discontinuation.

When is a "generic" medication not really a generic?

The distinction between pharmaceutical equivalent and pharmaceutical alternative drug products can lead to considerable confusion, especially with the proliferation of various branded, alternative, and generic medications that contain the same active ingredient. To illustrate this problem, four examples of medication products containing the active ingredients paroxetine, venlafaxine, bupropion, and valproate will be described. Understanding these differences is important for nurses providing patient care. Only generic drugs can be freely substituted for a brand-name product. Switching to a pharmaceutical alternative requires a change in prescription. Finally, the use, labeling, and cost of branded, alternative, and generic medications may be different.

Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder.

We examined the Antidepressant Treatment Response (ATR) index as a predictor of differential response and remission to escitalopram, bupropion, or a combination of the two medications, in subjects with major depressive disorder (MDD). Three hundred seventy-five subjects had a baseline quantitative electroencephalographic (QEEG) study preceding 1 week of treatment with escitalopram, 10 mg, after which a second QEEG was performed and the ATR index was calculated. Subjects then were randomized to continue escitalopram, switch to bupropion, or receive a combination of the two. Clinical response was assessed using the 17-item Hamilton Depression Rating Scale at 49 days of treatment. Accuracy of ATR in predicting response and remission was calculated. There were no significant differences between response and remission rates in the three treatment groups. A single ATR threshold was useful for predicting differential response to either escitalopram or bupropion monotherapy. Subjects with ATR values above the threshold were more than 2.4 times as likely to respond to escitalopram as those with low ATR values (68% vs. 28%). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone as those who remained on escitalopram treatment (53% vs. 28%). The ATR index did not provide a useful prediction of response to combination treatment. The ATR index may prove useful in predicting responsiveness to different antidepressant medications.

How are drugs approved? Part 1: the evolution of the Food and Drug Administration.

The discovery, development, and marketing of drugs for clinical use is a process that is complex, arduous, expensive, highly regulated, often criticized, and sometimes controversial. In the United States, the Food and Drug Administration (FDA) is the governmental agency responsible for regulating the development and marketing of drugs, medical devices, biologics, foods, cosmetics, radiation-emitting electronic devices, and veterinary products, with the objective of ensuring their safety and efficacy. As part of a broad overview of the drug development process, this article will describe the historical evolution of the FDA. This will provide background for two subsequent articles in this series, which will describe the ethical foundations of clinical research and hethe stages of drug development.