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.

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.

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.

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.

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.

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.

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.

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.

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.

Tardive dyskinesia in patients treated with atypical antipsychotics: case series and brief review of etiologic and treatment considerations.

Tardive dyskinesia (TD) is a disfiguring side-effect of antipsychotic medications that is potentially irreversible in affected patients. Newer atypical antipsychotics are felt by many to have a lower risk of TD. As a result, many clinicians may have developed a false sense of security when prescribing these medications. We report five cases of patients taking atypical antipsychotics who developed TD, review the risk of TD, its potential etiologic mechanisms, and treatment options available. The goal of this paper is to alert the reader to continue to be diligent in obtaining informed consent and monitoring for the onset of TD in patients taking atypical antipsychotics.

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.

Psychopharmacological Practice: The DSM Versus The Brain.

In 1952, the Diagnostic and Statistical Manual of Mental Disorders (DSM) system of creating, validating, studying and employing a diagnostic system in clinical psychiatric practice was introduced. There have been several updates and revisions to this manual and, regardless of its a theoretical framework, it actually does have a framework and presupposition. Essentially the DSM dictates that all psychiatric disorders are syndromes, or a collection of symptoms that commonly occur together and impair psychosocial functioning. These syndromes allow for homogenous groups of patients to be studied and psychotherapies and pharmacotherapies to be developed. This editorial will examine the DSM system with regards to its applicability to central nervous system dysfunction where psychiatric disorders are concerned. Specifically, the brain does not follow categorical, or syndromal, constructs. In fact, the psychiatric patient likely inherits several risk genes that promote abnormal proteins along several neuropathways in the brain. These abnormalities create dysfunctional neurocircuits which create individual psychiatric symptoms, but not a categorical syndrome or diagnosis. The concept that the DSM may be excellent for clinical diagnostic purposes, but less correct in its assumptions for a psychopharmacologist's treatment approaches will be discussed.

Managing insomnia: an overview of insomnia and pharmacologic treatment strategies in use and on the horizon.

This review explores basic sleep physiology, the mechanism of action for each class of hypnotic agents, their clinical application based on pharmacodynamic and pharmacokinetic factors, and potential pharmacologic sleep-inducing mechanisms of future hypnotics. The paper challenges the reader to understand the neuroscientific basis of insomnia and use this knowledge to guide prescription of hypnotic agents. Currently indicated hypnotic agents are discussed with regard to their mechanism of drug action and clinical application. A broader discussion is developed throughout this paper regarding other non-indicated agents that may improve sleep and describing newer pharmacological treatments that may become available in the future for use in sleep disorders and their comorbid conditions.

Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects.

BACKGROUND: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD). OBJECTIVE: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD. METHODS: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 µs pulse width), MEDIUM (0.5-1.0 mA, 250 µs), or HIGH (1.25-1.5 mA, 250 µs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase). RESULTS: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose. CONCLUSIONS: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.

Glutamate neurocircuitry: theoretical underpinnings in schizophrenia.

The Dopamine Hypothesis of Schizophrenia is actively being challenged by the NMDA Receptor Hypofunctioning Hypothesis of Schizophrenia. The latter hypothesis may actually be the starting point in neuronal pathways that ultimately modifies dopamine pathways involved in generating both positive and negative symptoms of schizophrenia postulated by the former hypothesis. The authors suggest that even this latter, NMDA receptor-based, hypothesis is likely too narrow and offer a review of typical glutamate and dopamine-based neurocircuitry, propose genetic vulnerabilities impacting glutamate neurocircuitry, and provide a broad interpretation of a possible etiology of schizophrenia. In conclusion, there is a brief review of potential schizophrenia treatments that rely on the etiologic theory provided in the body of the paper.

Memantine as an augmentation therapy for anxiety disorders.

Objective. Glutamate, an excitatory neurotransmitter in the central nervous system (CNS), may play a role in the development of anxiety. Memantine partially blocks N-methyl-D-aspartate (NMDA) receptors' glutamate channels located in the CNS. This paper evaluates memantine as an augmentation therapy for treatment of anxiety. Methods. 15 consecutive partially responding anxious patients were treated with adjunctive memantine for 10 weeks. Memantine was dosed 5-20 mg/day. Result. Memantine augmentation resulted in clinically relevant reduction in anxiety symptoms when compared to baseline. Forty percent of patients achieved remission (HAM-A ≥ 7). Memantine improved sleep quality. Mean dose was 14 mg/d (range 5-20 mg/d). Typical adverse events included nausea and headache. Conclusion. The NMDA receptor antagonist memantine may be an effective augmentation therapy in patients with treatment-resistant anxiety.