Adolescent angst or true intent? Suicidal behavior, risk, and neurobiological mechanisms in depressed children and teenagers taking antidepressants.

Suicide is one of the major causes of morbidity and mortality amongst children and adolescents. In 2004 the Food and Drug Administration (FDA) issued a "black-box" warning for antidepressants in children and adolescents, stating that these drugs may increase suicidality, a term encompassing both suicidal thoughts and behavior, especially in the first few weeks of treatment. The warning was extended in 2007 to antidepressants prescribed to adults aged 25 and under. The evidence behind this decision stemmed from meta-analyses of antidepressant clinical trials that demonstrated a slight increase in suicidality in those receiving antidepressants versus those treated with a placebo. Due to methods of this pooled data compilation, the relationship between antidepressants and suicidality remains controversial. This report investigates a case where a 14 year old with major depressive disorder (MDD) developed suicidal ideation shortly after being prescribed a selective serotonin reuptake inhibitor (SSRI). Investigating the role antidepressants may play in suicidality suggests the need to explore the neurobiological mechanisms within the serotonin system. This case and its theoretical explanations attempt to bridge the gap between neurobiology and pharmacology in order to better delineate the etiology of this adverse effect.

A neuroscientific update on monoamine oxidase and its inhibitors.

The goal of this brief review is to explain the role of monoamine oxidase enzymes in the neurobiology, etiology, and presentation of psychiatric illnesses, primarily major depressive disorder. This article will initially focus on the basic science and function of the monoamine oxidase system and some proposed neuropsychiatric symptoms that may arise if this enzyme system is altered by genetic predisposition. These findings and theories will next be translationally discussed in regard to clinical application pertaining to enzyme inhibition and the treatment of major depressive and other psychiatric disorders.

Obesity in adults with serious and persistent mental illness: a review of postulated mechanisms and current interventions.

BACKGROUND: An epidemic of overweight and obesity in the United States has had profound effects on the health of the general population, with consequent development of metabolic syndrome and related morbidity and mortality. However, these effects have been more widespread among adults with serious and persistent mental illness. METHODS: A literature search was conducted using the PubMed and Ovid databases. Terms used, in varying combinations, were schizophrenia, schizoaffective disorder, bipolar disorder, obesity, atypical antipsychotic, diabetes mellitus, hyperlipidemia, and metabolic syndrome. Of 103 articles generated, 71 were deemed pertinent to the current study. One reference was decided upon based on personal communication. RESULTS: Both nonpharmacologic and pharmacologic factors contribute to obesity development in adults with serious and persistent mental illness. Consequently, similarly targeted nonpharmacologic and pharmacologic interventions have been used to mitigate against body weight gain. Although the results obtained thus far are promising, effect sizes only in the low to medium range have been realized, with nonpharmacologic interventions demonstrating slight superiority. CONCLUSIONS: Improved therapeutic methods are needed to address the effects of obesity on individuals with serious and persistent mental illness. Factors that will likely contribute to such advancement are a better understanding of the mechanisms involved, earlier intervention, and adequately powered, randomized controlled trials of sufficient duration, with baseline body weight as a covariate.

Acamprosate calcium as augmentation therapy for anxiety disorders.

BACKGROUND: Glutamate is a major excitatory neurotransmitter, while γ-aminobutyric acid (GABA) is a predominant inhibitory neurotransmitter in the central nervous system. This GABA-glutamate imbalance is thought to play a role in the development of anxiety. Acamprosate calcium is thought to restore this chemical imbalance in alcohol withdrawal. OBJECTIVE: To examine acamprosate calcium as augmentation therapy for treatment of anxiety. METHODS: This 8-week, open-label study was designed to evaluate patients with anxiety who were stable on current medications (selective serotonin-reuptake inhibitors and serotonin-norepinephrine-reuptake inhibitors) but still symptomatic. Acamprosate was dosed at 1998 mg/day. Assessments included the Hamilton Rating Scale for Anxiety (HAM-A) and the Hospital Anxiety and Depression Scale. RESULTS: Thirteen patients enrolled in the study and received study medication. Acamprosate reduced anxiety symptoms (mean HAM-A score reduction to 8.87 from a baseline of 20). Sixty-two percent of patients receiving acamprosate achieved remission (HAM-A score ≤ 7). Modal dose was 1998 mg/day (range 999-1998). The most commonly reported adverse events were nausea (n = 1), gastrointestinal upset (n = 1), and increased dream activity (n = 1). CONCLUSIONS: Acamprosate calcium may be effective augmentation therapy in patients with treatment-resistant anxiety.

Ketamine as treatment for post-traumatic stress disorder: a review.

Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.

Mifepristone, a glucocorticoid antagonist for the potential treatment of psychotic major depression.

Corcept Therapeutics Inc is developing mifepristone (as C-1073, Corlux), an orally available progesterone and glucocorticoid antagonist originally launched as an abortifacient by Aventis Pharma AG, for the potential treatment of the psychotic features of psychotic major depression (PMD) and for Alzheimer's disease (AD). In August 2004, a pivotal phase III trial was initiated in the US for psychotic features of PMD, a second trial began in October 2004 and these were followed by a European phase III trial in May 2005. However, in August 2006, September 2006 and March 2007, respectively, these phase III trials failed to meet their endpoints. A further phase III trial was to commence later in 2007. By August 2006, Corcept expected to file an NDA for PMD in 2007. In addition, in March 2005 a phase II study of mifepristone as a cognitive enhancer in AD was underway, and in May 2006 a proof-of-concept study in alleviating the weight gain associated with olanzapine had begun.

Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole.

BACKGROUND: Brexpiprazole and cariprazine are the latest US Food and Drug Administration approved atypical antipsychotics available in the United States. Both function as partial agonists of the dopamine-2 receptor (D2R), a mechanism of action shared with aripiprazole. However, all three differ in their affinities for the D2R as well as for serotonin receptors (5-HTRs). This paper seeks to delineate these pharmacodynamic and clinical differences amongst the three dopamine partial agonist atypical antipsychotic drugs. METHODS: PubMed and clinicaltrials.gov searches were used to generate preclinical and clinical evidence for review. Data derived from animal models and human subjects were used to provide insight on clinical mechanisms and adverse effect potentials. Clinical trial data were reviewed to compare clinical efficacy and adverse effects. RESULTS: Efficacies among the three drugs are comparable for their shared indications. Side-effect profile and underlying pharmacodynamic mechanism of action for each drug may differ. CONCLUSION: Partial agonism of the D2R is a similarity of the three drugs reviewed. Each drug varies in affinity for both the D2R and a diverse group of 5-HTRs, generating a distinct profile of clinical indications and adverse effects for each.

A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality.

OBJECTIVE: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. METHOD: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. RESULTS: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). CONCLUSIONS: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.

Why is mechanism of action important in antidepressant treatment?

Antidepressants are one of the most common treatment strategies for patients diagnosed with major depressive disorder (MDD). However, antidepressant medications have different mechanisms of action that can theoretically and in practice affect how patients respond. Clinicians should assess their patients' symptoms and response to medication at every visit to determine whether or not the treatment is fully effective. Here, follow the case of Maria, a 42-year-old teacher who is experiencing her first depressive episode.

Effectiveness, tolerability and practical application of the newer generation anti-obesity medications.

OBJECTIVE: Comparison of the efficacy and tolerability of five newer anti-obesity medications to guide clinical decision making, examining bupropion-naltrexone combination, liraglutide, lorcaserin, orlistat, and phentermine-topiramate combination. METHODS: A brief literature review and internet search for high-powered, randomized and placebo-controlled drug trials was conducted. Drug trial information was established for five currently approved anti-obesity medications. Secondarily, a statistical comparison of medications through Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses were attempted as a way to provide a clinical analysis across these varied medications. Finally, a commentary about clinical application is issued for each agent accounting for typical side-effects, serious side-effects, mechanism of action and ease of use. RESULTS: All five agents are currently approved oral medications to lower weight. The NNT range was 3-12, and NNH range was 4-17. The agent with the best NNT is phentermine-topiramate combination (NNT=3) and the agent with the best NNH is bupropion-naltrexone combination (NNH=17). CONCLUSION: When considering each patient's clinical presentation, knowledge of each drug's mechanism of action, side-effect profile, efficacy, and NNT and NNH values can help in selecting an anti-obesity medication to augment his or her weight loss efforts.

Neural Implications of Psychotherapy, Pharmacotherapy, and Combined Treatment in Major Depressive Disorder.

Numerous clinical trials have been conducted to determine the utility of antidepressant treatment (ADT), psychotherapy, and combined psycho-pharmaco-psychotherapy (PPPT) in treating major depressive disorder (MDD). While all approaches have shown benefit over placebo to varying degrees, the parallel neurophysiological mechanisms that underlie their efficacy have received little attention. The authors will review and discuss a growing body of literature that relates the factors of treatment selection and response to the principles of neuromodulation, with emphasis regarding how neuroimaging and other experimental data reinforce the need for personalized MDD treatment. This manuscript and its theoretical approaches were supported by conducting relevant literature searches of MEDLINE and PubMed electronic databases, prioritizing systemic reviews, and randomized clinical trials using selected MeSH terms. The authors conclude that ADT, psychotherapy, and PPPT all create potentially observable neurofunctional changes and argue that additive and synergistic potentiation of these effects in PPPT may produce more sustained symptom relief than with monotherapy alone.

Open-label treatment with citalopram in patients with irritable bowel syndrome: a pilot study.

BACKGROUND: This open-label pilot study investigated whether the selective serotonin reuptake inhibitor (SSRI) citalopram improves symptoms of irritable bowel syndrome (IBS), a functional gastrointestinal disorder with frequent psychiatric comorbidity. METHOD: Fifteen patients meeting Rome I criteria for IBS were administered open-label citalopram (20-40 mg/day) for 12 weeks. The study was conducted from October 2000 to August 2001. RESULTS: Twelve (80%) of the 15 subjects reported a > or = 50% decrease in the presence of abdominal pain, 10 (67%) reported a > or = 50% reduction in the severity of the symptom, and 12 (80%) reported a > or = 50% reduction in the frequency of the symptom. Approximately one half of the patients met criteria for remission (> or = 70% improvement) of abdominal pain. CONCLUSION: Results of this pilot study suggest that large controlled trials are needed to further evaluate the efficacy of SSRIs such as citalopram for the treatment of IBS.

Antidepressant efficacy and side-effect burden: a quick guide for clinicians.

Prescribing of antidepressant treatment (ADT) for major depressive disorder (MDD) has increased in quantity and popularity over the last two decades. This is likely due to the approval of safer medications, better education of clinicians and their patients, direct-to-consumer marketing practices, and less stigma associated with those taking ADT. This trend has also been met with some controversy, however, as the ongoing safety and effectiveness of these treatments have at times been called into question. This paper discusses the differing levels of evidence that support the use of ADT based on (A) Food and Drug Administration approvals, (B) data from randomized controlled trials or meta-analyses and, where these are not available, the authors discuss and apply, (C) theoretical pharmacodynamic principles to justify antidepressant choice in the treatment of MDD patients. The final section discusses standard psychopharmacology guideline approaches to better alert the reader as to which practices are commonplace compared with those which are more outside of the standard of care.

Using mechanism of action to choose medications for treatment-resistant depression.

Remission rates for depression continue to be low, and for many patients, complex treatment regimens are needed for optimal response. Many physicians do not fully understand how and why depression medications work or which ones will complement each other. This CME Webcast covers the different mechanisms of action of current pharmacotherapeutic options for depression, both monotherapy and adjunctive medications, and shows clinicians how to use their understanding of mechanisms of action to choose the most effective treatment strategy for their patients, especially those with treatment-resistant or difficult-to-treat depression.

Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder.

Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD) is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA)-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and symptoms of hyperarousal often persist. This article specifically reviews the literature on alpha-2 receptor agonist use for the treatment of PTSD and concludes that while the evidence base is limited, these agents might be considered useful when SSRIs fail to treat symptoms of agitation and hyperarousal in patients with PTSD.

Tramadol for the treatment of fibromyalgia.

Tramadol is a novel, synthetic opioid receptor agonist with serotonin-norepinephrine reuptake inhibitor properties that is often prescribed acutely for painful conditions. Fibromyalgia (FM) is a chronic painful condition that is difficult to treat and until more recently has had no approved medical treatments. Currently, the only US FDA-approved medications for FM include duloxetine, milnacipran and pregabalin. No opioid is approved for use in the treatment of FM. This paper specifically reviews the literature on tramadol use in FM and concludes that there is a fair evidence base to support its use as a second-line treatment for more resistant cases.

A critical appraisal of the selegiline transdermal system for major depressive disorder.

The selegiline transdermal system (STS) is the first antidepressant transdermal medication approved by the US FDA for the treatment of major depressive disorder. Its unique antidepressant delivery system allows for steady release of selegiline over 24 h with minimal fluctuation in drug serum levels. It is able to deliver high enough central nervous system concentrations required for an antidepressant effect without substantially inhibiting Monoamine oxidase-A in the gastrointestinal and hepatic system, thereby reducing the risk of tyramine hypertensive crises especially at the lowest doses. Patient adherence theoretically could be improved due to ease of use and once-daily dosing when compared to oral counterparts' need for multiple daily doses. Clinical trials have established that doses between 6 and 12 mg over 24 h have been effective for major depressive disorder and tolerated among patients. Episodes of hypertensive crisis with STS have been minimally reported thus far. Overall, STS appears to be an effective agent for major depressive disorder when held to regulatory standards and post marketing analyses. This paper reviews the pharmacologic characteristics of STS and results of studies investigating its clinical efficacy and safety.