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.

Evidence-based guidelines for the pharmacologic management of patients with generalized anxiety disorder (GAD) recommend initial treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). However, response rates to initial treatment with an SSRI or SNRI can be disappointing, and it remains impossible to predict reliably which patients will respond positively or negatively to treatment. Due to the dearth of longitudinal studies of outcome in GAD and the relatively small number of placebo-controlled relapse prevention studies, the optimal duration of treatment after a satisfactory response to acute treatment is still uncertain. Furthermore, there have been few studies on the management of patients who do not respond to initial treatment. Also, there is a clear need for further randomized controlled trials of augmentation treatment in patients who do not respond to SSRI, SNRI, or other initial pharmacologic approaches. Future guidelines will be influenced by emerging data with both established and novel drug treatments, and through better identification of patient groups that are likely to respond preferentially to particular interventions.

In 1990, The American College of Rheumatology laid out several sets of criteria for the diagnosis of fibromyalgia syndrome (FM). The first criterion required patients to report at least 3 months of widespread pain. Pain was considered widespread if it was present in four quadrants of the body—the right and left side as well as above and below the waist. Axial skeleton pain is also very commonly present in FM and is often considered a fifth “quadrant.” The second diagnostic criterion was widespread pain in response to a tender point examination. In this assessment the clinician presses on 18 specific areas with enough pressure to blanche his fingertip (∼4 kg). The patient's report of pain and not pressure on such testing in at least 11 of the tender points completes the requirements for the diagnosis of FM (Slide 1). Although these criteria were established to standardize patients for research studies, many physicians follow them for diagnostic purposes as well. However, these criteria must be viewed in the same context as the definition of hypertension (ie, blood pressures ≥140/90). Patients who do not quite attain these criteria should still be considered to have probable hypertension; and the same applies to FM. A patient who has three-quadrant pain and 9 tender points does not meet the criteria for FM, but the therapeutic approach to this patient is the same as it is for the patient with definitive FM.

During the past decade, a similar composite has emerged for both bipolar disorder and adult attention-deficit/hyperactive disorder (ADHD). First, both conditions have a relatively high prevalence, a low case detection, a protracted illness course, a high rate of comorbidity, multifactorial ideology, substantial heritable liability, and tremendous burden of illness in economic cost as well as interpersonal and vocational maladjustments. What has also been interesting along with these reports is that there has been emerging scientific studies implicating common brain regions and neural circuits subserving essential features of both conditions.

Despite significant progress in the development of antidepressant therapies, tolerability remains an important factor associated with the selection of appropriate antidepressant treatment. Side effects commonly reported by depressed patients taking antidepressants include weight gain, sexual dysfunction, and gastrointestinal effects. Tolerability issues associated with antidepressants can negatively impact treatment outcomes for patients with major depressive disorder. In addition, a drug's tolerability profile substantially influences a physician's choice of specific antidepressant therapy. Despite the availability of many antidepressants, empirical clinical evidence to guide physicians in making the best choice is limited and not always clear. Thus, it is key for clinicians to understand the short- and long-term outcomes and side effect profiles of the available antidepressants.

Bipolar disorder is a lifelong condition, and pharmacotherapy is essential to its long-term management. Once a comprehensive diagnostic assessment for acute or mixed mania has been completed, it is important to look at an evidence-based data set to guide treatment selection for mood stabilization.

For most patients, lifetime adherence to pharmacotherapy is necessary for maximal mood stability. Pharmacotherapy is the primary treatment for bipolar disorder, as it has been found to be efficacious in treating acute episodes and preventing future episodes of bipolar I disorder. Combination therapy, including at least one mood stabilizer, may be necessary to treat acute depression and mania and to further prevent both depressive and manic recurrences. The goal is to minimize frequency, duration, and severity of depressive and manic symptoms with a treatment regimen, ideally a combination of pharmacotherapy and psychotherapy, that is positioned to maximize treatment adherence and minimize side effects.

This discussion reviews some treatment guidelines for acute manic and mixed episodes associated with bipolar I disorder. Through the context of a case study, this discussion will attempt to provide an understanding and appreciation of Food and Drug Administration-approved and non-FDA-approved treatments for acute mania. In addition, the impact of alcohol as an example of drugs of abuse and its impact on the presentation of acute mania will be discussed.

Mixed episode is one of the more difficult-to-treat conditions in bipolar disorder. The presence of mixed features (symptoms of both depression and mania in a single acute episode) is associated with both poorer acute treatment response and poorer longitudinal outcomes, including shorter subsequent inter-episode periods and greater suicidality. Mixed features are indicative of an overall greater severity of both acute and chronic illness (Slide 1).

Efficacy, safety, and tolerability are primary parameters for evaluation of any pharmacologic treatment. However, in order to evaluate the effectiveness of a new treatment in everyday clinical practice, these parameters must be assessed in the context of a number of societal, patient, and methodological variables.

Morality may be innate to the human brain. This review examines the neurobiological evidence from research involving functional magnetic resonance imaging of normal subjects, developmental sociopathy, acquired sociopathy from brain lesions, and frontotemporal dementia. These studies indicate a “neuromoral” network for responding to moral dilemmas centered in the ventromedial prefrontal cortex and its connections, particularly on the right. The neurobiological evidence indicates the existence of automatic “prosocial” mechanisms for identification with others that are part of the moral brain. Patients with disorders involving this moral network have attenuated emotional reactions to the possibility of harming others and may perform sociopathic acts. The existence of this neuromoral system has major clinical implications for the management of patients with dysmoral behavior from brain disorders and for forensic neuropsychiatry.

The optimal management of fibromyalgia (FM) is comprised of both pharmacologic and nonpharmacologic approaches. This multidimensional approach is preferred given that FM is not only a pain condition, but involves a number of other symptoms as is reflected in the new clinical criteria being developed by Wolfe and colleagues. Proper management of FM should be informed through multidimensional assessment of the clinically relevant domains described previously in this supplement. Pharmacologic and nonpharmacologic approaches work together to provide the broadest possible coverage of these domains, minimize the impact of each domain on functioning and well-being, and facilitate long-term adaptations to one's lifestyle.

The use of nonpharmacologic strategies in the management of FM has varying levels of evidence. The strongest evidence currently exists for aerobic exercise, cognitive-behavioral therapy (CBT), and for patient education or self-management. Moderate evidence exists for strength training, acupuncture, hypnotherapy, and biofeedback modalities. Weaker evidence exists for manual massage therapy. Currently, there is no evidence of long-term benefit for tender point injections or flexibility exercise modalities, although these options may be beneficial in the short term. This article will focus on the three areas that have the strongest evidence base: patient education, exercise, and CBT.

Educational programs are typically offered in the context of primary care or in specialty practices. In their simplest form, these programs try to dispel myths about FM and provide patients with the most up-to-date knowledge about the condition.

The 2001 Institute of Medicine Report “Crossing the Quality Chasm,” summarized the current care of chronic illness in the United States by emphasizing “Between the health care we have and the health care we could have lies not just a gap, but a chasm.” Across multiple chronic illnesses within primary and specialty care systems, this summary statement illustrates that clinicians and other health professionals are not adequately providing patients guideline levels of treatment–levels that can lower the risk for complications of those illnesses.

There are many new findings in the area of comorbid insomnia. Almost 50% of all cases of chronic insomnia are due to a mental disorder, with depressive illness explaining the majority of cases related to mental disorder (Slide 1). Other common causes of comorbid, or secondary, insomnia include chronic respiratory disease such as asthma and chronic obstructive pulmonary disease, chronic pain, degenerative neurological disease, and some medications such as glucocorticoids and serotonin reuptake inhibitors. A general principle of management of insomnia related to mental or medical disorders is that the principal disorder must be fully treated as part of the insomnia treatment plan. If there is an offending medication, it must be discontinued if possible.