Traditional guidelines call for treatment of major depression with a sequence of single antidepressants. Augmentation with a second agent generally only occurs when the first agent is well tolerated and when it also provides at least some symptomatic improvement on its own. Since this standard approach leads to low rates of attaining and sustaining remission by the first agent, with diminishing returns for each subsequent agent, there is growing dissatisfaction with this approach to the treatment of major depression. One new trend is to attempt to enhance the rates of sustained remission from a major depressive episode by combining two therapeutic agents from the very initiation of treatment of a major depressive episode.

Traditional treatment of major depression begins with a single “first line” antidepressant, and if it does not work or is not tolerated, trying another and then another. Unfortunately, this strategy results in disappointing remission rates for the first antidepressant (Figure 1), and disappointing rates of maintaining any improvement that is attained by this first agent because of high relapse rates over the next year despite continuing treatment with the first antidepressant (Figure 2A). And that is the good news. The bad news is that with each subsequent antidepressant treatment administered remission rates are progressively reduced (Figure 1). For those patients who do improve, they are progressively less likely to sustain their therapeutic gains despite continuing to take the drug that led to their initial improvement (Figure 2).

Major depression is the most common serious brain disorder with a lifetime prevalence of up to 17%. Despite numerous options currently available for the treatment of depression, ~2 million people in the United States may experience an inadequate response to treatment (treatment-resistant depression [TRD]) at some point in their lives. The definition of TRD is variable, ranging from a failure to respond to two or more trials of antidepressant monotherapy to a failure to respond to four or more trials of different antidepressant therapies, including augmentation, combination therapy, and electroconvulsive therapy. It has been reported that as many as one-third of patients experience only a partial response to initial therapy, while nearly one-fifth are considered nonresponders. In addition to the obvious quality of life issues for the patient with TRD, the economic cost of TRD is significant. Annual healthcare costs increase significantly for patients with TRD with each successive change in antidepressant medication. Early in treatment (two medication changes), the annual costs are <$7,000/Year. By the eighth medication change, annual costs double to nearly $14,000/year.

There is a well-documented need for better long-term treatments for TRD, as witnessed by multiple efforts to establish treatment algorithms and best treatment steps when first and subsequent treatment measures prove inadequate. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which analyzed outcome following several standardized antidepressive treatment steps, reported that 33% of patients did not respond even after four evidence-based treatment steps. A substantial proportion of patients are inadequately treated and some of these will go on to suffer from chronic, debilitating, and life-threatening symptoms.

Our spirits may be regulated by the methylation of our genes. Methylation, acetylation, and other biochemical processes are the molecular switches for turning genes on and off. There is evidence now that certain behaviors, feelings, and psychiatric symptoms may be modified by turning various genes on or off. If classical genetics is the sequence of DNA that is inherited, then epigenetics is a parallel process determining whether a given gene (ie, a sequence of DNA coding for transcription) is expressed into its RNA or is silenced. Epigenetics is now entering psychiatry with the hypothesis that normal genes as well as risk genes can both contribute to a mental disorder. That is, it has long been hypothesized that when “abnormal” genes with an altered sequence of DNA are inherited as risk genes for a mental illness, these risk genes will make an abnormal gene product in neurons, contributing to inefficient information processing in various brain circuits and creating risk for developing a symptom of a mental illness. Now comes the role of epigenetic actions in mental illnesses.

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hey) are implicated in the pathogenesis of Alzheimer's disease (AD). They noted that Hey is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphoryalation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase β-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-β production in in vitro models; elevated Hey levels in rates are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hey levels in vitro increase amyloid-β protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hey induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

Regarding the treatment of patients with bipolar disorder, positive findings have shown that patients engaged in treatment may live longer. Angst and Sellaro studied standardized mortality ratios for patients with bipolar disorder and found a significant reduction in mortality ratio in our bipolar patients who were actively in treatment (Slide 1). Data from the Collaborative Depression Study by Judd and colleagues showed that bipolar patients are quite symptomatic. Judd and colleagues followed bipolar patients over a 13-year period and found that these patients were symptomatic ~50% of the study period. What were these patients most likely to be symptomatic with: bipolar depression (Slide 2). Thus, it is important to focus on bipolar depression and examine placebo-controlled trials that were adequately powered in its treatment.

Over the last decade, there have been positive trials studying lamotrigine, quetiapine, olanzapine, and olanzapine-fluoxetine combination. Two of these medications are United States Food and Drug Administration—approved in bipolar disorder treatment: quetiapine and olanzapine-fluoxetine. There are a number of negative trials in bipolar depression, including a number of antidepressant monotherapy trials and antidepressants in combination with mood stabilizers (Slide 3). However, what is the most frequent pharmacotherapy treatment used for bipolar depression? It is the use of antidepressants alone; antidepressant monotherapy is twice as commonly prescribed as mood stabilizers (Slide 4). Thus, it is necessary for clinicians to possess knowledge of the evidence and results from both positive and negative antidepressant trials for bipolar disorder.

Conventional antipsychotics have a substantial literature of >30 placebo-controlled studies supporting their use in depression. Reports describing the use of antipsychotic treatment in depression appeared as early as 1959. In the 1970s, combination products of perphenazine and amitrip-tyline were quite popular. Antipsychotic agents were effective for selected symptoms or in selected patients; yet, these agents were not viewed as “true” antidepressants, perhaps because of their lack of effects on loss of interest. The use of antipsychotics in patients with nonpsychotic depression declined rapidly in the 1980s when tardive dyskinesia (TD) surfaced as a potential adverse effect of this class of medications. Depressed patients were thought to be at increased risk. Interest in the potential utility of antipsychotics in depression resurfaced with the availability of the second-generation antipsychotics (SGAs), which possess a considerably lower risk for TD.

Most of the SGAs are inhibitors of the serotonin (5-HT)2A receptor and the dopamine (D)2 receptor. In fact, the ratio of these effects has been considered one attribute of an SGA. The SGAs have a variety of other receptor actions that might contribute to antidepressant effects but which vary substantially among the drugs. These include agonist effects at the 5-HT1A serotonin receptor, inhibition of the 5-HT2C receptor, and partial D2 agonism of aripiprazole (Slide 1). In addition, ziprasidone blocks 5-HT and norepinephrine (NE) reuptake and the metabolite of quetiapine has NE reuptake blocking effects.

A key consideration in the discussion of maintenance treatment in schizophrenia is how to first help bring patients to the point where acute psychopathology is sufficiently controlled, so that we can focus on consolidating the gains achieved and prevent a recurrence of illness.

The different phases of treatment and response in schizophrenia include the acute phase, wherein we look for response and resolution; remission, where we control symptoms to levels of mild or less and work toward preventing relapse or any exacerbation of psychopathology; and recovery, meaning the ability to function in the community in the workplace, school, family roles, etc.

In preparing patients with schizophrenia for maintenance treatment, clinicians must ensure that they have done everything possible to alleviate the acute signs and symptoms of illness to the extent possible.

There are several questions to consider at this stage: How much improvement is enough? When do we change treatments, and why? What about adverse effects and the locus of care? In the context of this process of deciding how to bring about the best possible treatment response, we must consider that, if a patient is not responding, the diagnosis may need to be reevaluated. Adherence must be assessed and blood levels should be done (if feasible) to ensure that patients have an adequate amount of medication in their system. If blood levels are unavailable and adherence is an issue, the use of long-acting injectable medication should be considered. The clinician might decide to alterthe medication dose—to increase it, or perhaps decrease it if significant side effects are impeding therapeutic response. Adjunct medications or a switching strategy may be employed. Non-pharmacologic therapy, such as cognitive behavioral therapy, which can be effective at reducing symptoms of schizophrenia, should also be considered.

Mr. A is 24 years of age with a history of schizophrenia (Slide 1). He has been living with his parents and has been ill for a few years. Police saw him on the street in a state of crisis and brought him to the emergency room (ER). He was very anxious and his delusions of being in great physical danger had worsened. He reported a history of asthma, but it was noted that his asthma occurred a long time ago and was inactive; however, due to his anxiety, his smoking had increased to where it was continuous. At the time he was brought to the ER, Mr. A was triaged to psychiatry and became agitated in the waiting area; hence, security was called. He was about to be restrained and given an intramuscular dose (IM) of lorazepam, but the psychiatrist noted that he was having trouble breathing and stopped the IM before it was given. The psychiatrist noticed that Mr. A was wheezing, had a rapid respiratory rate of 25/minute, was tachycardic, and sweating. His pulse oximeter measurement was 90% saturated, which is considered low.

Mr. A was re-interviewed and reported that he previously had asthma. His parents were contacted and agreed that he had active asthma, had stopped his psychiatric treatment several months ago, and, more recently, stopped his asthma medications when his prescriptions were not refilled ∼1 week prior to this episode. An emergency arterial blood gas showed a pH of acidosis at 7.27; a Po2 of 60 (normal is 80); and a Pco2 of 48 (normal is 40). The Pco2 was of particular concern because if he was retaining CO2, respiratory failure was imminent.

Medication is the mainstay of treatment for bipolar disorder. However, no medication will be effective if patients do not take it, and the rates of medication compliance in bipolar disorder are very low. Johnson and McFarland found that the modal length of compliance with a mood stabilizer was only 2 months. Keck and colleagues found that 50% to 66% of patients with bipolar disorder exhibit poor compliance within the first 12 months of treatment. In addition, even with adequate medication compliance, high rates of relapse persist.

Adjunctive psychosocial treatments can help reduce relapse and provide patients as well as their families with tools to manage bipolar disorder more effectively. Several forms of intensive psychotherapy have shown promise for the treatment of bipolar disorder. In the Systematic Treatment Enhancement Program for Bipolar Disorder, Miklowitz and colleagues compared three forms of intensive interventions: cognitive-behavioral therapy (CBT), interpersonal and social rhythm therapy, and family-focused treatment. These were compared to a brief, 3-session psychoeducational intervention known as collaborative care. A total of 293 depressed patients with bipolar type I or type II disorder were treated with protocol pharmacotherapy and were randomly assigned to either one of the three intensive interventions or the brief psychoeducational intervention.

The three intensive interventions provided up to 30 sessions of treatment over a 9-month period. The collaborative care intervention consisted of three sessions administered over a 6-week period. The authors found that patients who received one of the intensive interventions had a median time to recovery 110 days earlier than patients who had received the collaborative care conditions. Patients who received one of the three intensive psychotherapies also had significantly higher year-end recovery rates, and are more than 1 to 1.5 times more likely to be clinically well during any study month. No statistically significant differences were found between the 3 intensive treatments.