The World Health Organization estimates that depression is the fourth leading cause of disability worldwide with a lifetime prevalence of ∼15% to 20%. While the antidepressants currently on the market will be effective in most patients, a significant number of patients will experience residual symptoms, treatment-resistance, and relapse. The recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study has shed some light on the reality of antidepressant treatment. At first, only one-third of patients on citalopram monotherapy remitted. The other two-thirds who failed to remit saw their likelihood of remission decrease with each successive trial of another antidepressant monotherapy. Thus, after four successive monotherapies were tried over the course of one year, (ie, after four treatments each lasting 12 weeks), only two-thirds of patients achieved remission (Figure 1). Besides this poor prognosis, the patients who required more treatment cycles to get better also had a higher likelihood of relapsing. Once patients reach that point, they are considered treatment-resistant.

Case-based learning is often considered a new innovation in medical teaching, but it is actually as old as clinical medicine. Physicians have always consulted with their peers on difficult cases and utilized the case-based form of discussion as an educational tool, as a means of understanding new diagnoses, and as a method of determining the best treatment for a particular patient. Fibromyalgia syndrome (FM), a common clinical disorder with a world-wide distribution, has been unrecognized and/or ignored for years. FM can be likened to a volcano, with pain at the very top and insomnia and depression as key, but less common, manifestations (Slide 1). However, many physicians are insecure about the diagnosis and treatment of patients with FM, because they simply do not know enough about the disorder.

Mr. Jones, 30 years of age, presents to the office for the first time with symptoms of mania. He had gone through a period of increased spending during which he purchased thousands of dollars worth of audio and video equipment in addition to other items he could not afford. He is currently living with his parents due to his inability to meet these financial obligations. When his parents starting receiving packages at their house, they decided to have Mr. Jones evaluated. They note that he is awake much of the night talking on the phone and browsing the Internet. His bills indicate large charges for phone sex and pornography.

Oxytocin and vasopressin are highly conserved neuropeptides that play a key role in social attachment and affiliation, including parental care and pair-bonding. Oxytocin attenuates neural responses to aversive pictures and has been associated with reduced coupling of amygdala to brainstem regions involved in the fear response. Differential activation of the amygdala has been found to be associated with different genetic variants of the vasopressin receptor. There is growing evidence that oxytocin and vasopressin receptor variants are associated with individual differences in prosocial behavior. It is humbling that differences in complex human behaviors may be partially explicable on the basis of relatively simple neuropeptide systems. Nevertheless, such findings potentially allow for targeted interventions for a range of psychiatric disorders in which such systems play a role.

In discussion of the best practices for patients with fibromyalgia (FM), it is key to Introduce commentary about what FM is as a clinical condition, how clinicians should assess for FM, and the pharmacologic approaches to management.

The first widely accepted criteria for the classification for FM were published in 1990 as the American College of Rheumatology criteria for FM. However, the condition has long been described in medical history. In the 1800s, a condition similar to FM was labeled “neurasthenia” and was further defined by researchers in the medical literature. During the early 1900s, symptoms associated with FM were labeled “fibrositis,” which was based on the mistaken idea that there were inflammatory changes in peripheral connective tissue. It was not until the mid-1970s when pioneering work by Smythe and Moldofsky defined central nervous system abnormalities, including significant sleep pathology, in patients with this condition that led to the increased recognition by researchers and clinicians that FM was a central pain phenomenon.

Following this critical development, use of the term “fibromyalgia” began and was codified in the 1990 criteria, intended for use in research settings to standardize classification of FM. The 1990 criteria classify the condition as involving chronic widespread pain for at least 3 months. Patients must also exhibit tenderness of at least 11 of 18 tender points.

A growing body of evidence suggests that mitochondrial abnormalities are involved in aging and in age-related neurodegenerative diseases as well as cancer, diabetes, and several other diseases known to be affected by mitochondria. Causal factors for most age-related neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA)—are largely unknown. Genetic defects are reported to cause a small number of neurodegenerative diseases (Slide 1), but cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. However, based on several cellular, molecular, and animal model studies of Alzheimer's disease, Parkinson's disease, ALS, FRDA, cancer, and diabetes, aging may play a large role in cell death in these diseases. Age-dependent, mitochondrially-generated reactive oxygen species (ROS) have been identified as important factors responsible for disease progression and cell death, particularly in late-onset diseases, in which genetic mutations are not causal factors.

There are a several therapies available for the treatment of primary insomnia, most notably cognitive-behavioral therapy (CBT) and pharmacologic treatment. The benzodiazepines are a group of chemically related compounds represented by medications such as triazolam, temazepam, and lorazepam. Non-benzodiazepines, such as zaleplon, zolpidem extended-release (ER), eszopiclone and zopiclone, act via a mechanism similar to the benzodiazepines but have a different chemical structure. Also available is the melatonin receptor agonist, ramelteon, as well as several antihistamines such as diphenhydramine, doxylamine, hydroxyzine.

Medications, such as the antidepressants trazodone, mirtazapine, doxepin, and amitriptyline as well as the antipsychotics, quetiapine, olanzapine, and risperidone, have been used off-label for the treatment of insomnia. Patients often turn to alcohol, over-the-counter agents, and melatonin for relief of their sleep problems (Slide 1).

Given these treatment options, there are several questions faced in clinical practice concerning when to treat patients for insomnia, what treatments should be used, and how long treatment should continue. CBT is typically continued for a fixed length of time. Generally, the greater the functional impairment a person experiences, the more there is to be gained from treatment. The decision about whether to treat and which treatments should be used, should consider the risks and expected benefits of all treatment options. CBT for insomnia has relatively minimal risks, with the only downsides being cost, access, and convenience. CBT should always be a therapeutic option.

With the increasing number of new brain stimulation techniques now available and on the horizon, does electroconvulsive therapy (ECT) still have a role? As clinicians and researchers we say most definitely “yes”. ECT is the most effective and rapidly acting treatment for severe forms of depression and other disorders. Transcranial magnetic stimulation has shown promise but mainly for less severely ill and less treatment resistant patients. Deep brain stimulation (DBS) has shown promise for the more resistant cases but its invasiveness limits its use. Results from only ∼50 patients treated worldwide are available and at present it is not approved by the United States Food and Drug Administration for depression. Vagus nerve stimulation, less invasive than DBS but still a surgical procedure, is presently FDA approved for acute treatment resistant depression but published efficacy rates fall short of those seen with ECT. Therefore, there continues to be an important role for ECT in the treatment of severe psychiatric disorders. But will ECT always be there when our patients need it? Somewhat unexpected recent developments at the FDA may impact the future availability of ECT to severely depressed patients. Here we provide background on the classification of ECT devices, the FDA reclassification process, and the process for providing FDA input in these critical deliberations.

The presentation of attention-deficit/hyperactivity disorder (ADHD) in adolescence is often complex, but clinicians will attest multiple and complex comorbid conditions in adolescence are by no means unusual. Given that this is often the typical presentation, this article will describe a case to illustrate the multiple pathways to treatment of an adolescent with myriad distinct but interacting issues. Although all clinicians attempt to practice evidence-based medicine, the evidence is often limited to circumscribed disorders, and management and sequencing of treatment of adolescents with a combination of different conditions has not be adequately researched.

Treatment-resistant depression (TRD) may be defined, both pragmatically and clinically, as the failure of an episode of major depression to respond fully to the adequate administration of a treatment that is known to be effective (Slide 1). It is important for the clinician, in terms of not inadvertently reinforcing stigma, to bear in mind, as the definition indicates, that it is the disease state or episode of depression that is treatment resistant, and not the patient, per se. The treatment that has failed must be a valid one and must also have been delivered effectively before one can conclude that this episode of major depression is resistant to any particular level of treatment.

For clinicians, primary care physicians (PCPs), and other health professionals treating patients with any ailment, including depression, the first task in addressing nonadherence to treatment is to detect it. Patients conceal treatment nonadherence because it is a socially undesirable behavior, and patients want their clinicians or PCPs to think that they are “good” patients. They may hope that their clinicians will be understanding, but assume that clinicians will adopt a judgmental attitude. There is evidence that, as a result of these psychological barriers, self-report and physician interview assessments have poor correlation with adherence as measured by virtually any other methodology. Three studies have been conducted that dramatically indicate the force of this need to conceal nonadherence.