Advances Seen in Mood Disorders ResearchAdvances Seen in Mood Disorders Research

Toronto—Growing recognition of bidirectional links between mood and medical disorders lends urgency to efforts to speed recognition of mood disorders in the primary care setting. Surveys show 8 of 10 patients later diagnosed with depression initially present with a physical symptom.

Mood disorders carry a hefty medical burden. They boost patients' risks for obesity, cardiac and cerebrovascular disease, diabetes mellitus, thyroid disease, and other medical illnesses, and also exacerbate the severity of these disorders, said David Kupfer, MD, chair of psychiatry at the University of Pittsburgh School of Medicine.

Individuals with mood disorders are more apt to smoke and to abuse alcohol and other drugs than are people who do not have such illnesses. They have higher rates of coexisting anxiety disorders, eating disorders, and motor vehicle crashes. They also are more likely to die by suicide, added Kupfer.

Co-occurring mood and medical disorders may stem from a shared vulnerability, suggested Kupfer, who chaired a symposium on advances in mood disorders at the annual meeting of the American Psychiatric Association (APA) here in May.

“Mood disorders should be managed in the same way as diabetes, hypertension, and other chronic illnesses,” said Kupfer, a coeditor of the The American Psychiatric Publishing Textbook of Mood Disorders (Washington, DC: American Psychiatric Publishing Inc; 2006; http://www.appi.org/book.cfm?id=62151). That means both primary care physicians and psychiatrists should use patient self-report scales along with their own assessments and objective tests to measure patients' progress over time, he said.

At the APA meeting, Kupfer and others discussed new perspectives on bipolar disorder, algorithms to assist measurement-based management of mood disorders, and brain stimulation techniques that may benefit patients with difficult-to-treat depression.

Recent epidemiologic studies show bipolar spectrum disorders affect an estimated 3% to 4% of the population, or 10 million to 12 million people in the United States, Kupfer said. These disorders range from severe full-blown mania to milder hypomania, both alternating with longer-lasting bouts of major depression (Kupfer D. JAMA, 2005;293:2538-2530).

Bipolar disorder often emerges before age 20 years, earlier than previously suspected. This fact calls for heightened vigilance to identify symptoms in adolescents and young adults, especially in those who may have experienced hypomania but not a manic episode and who have a positive family history, he said.

In contrast to major depressive disorder, which occurs about twice as often in women as men, bipolar disorder has a nearly equal sex distribution, Kupfer said, although women enroll in clinical studies more often than men do.

Among all people with mood disorders, those with bipolar disorder exhibit the highest rates of behaviors often used to self-medicate mood disturbances, such as smoking, drinking, drug abuse, and overeating. For example, 3 of 4 people with bipolar disorder smoke, he said.

About 20% of people with bipolar disorder remain chronically depressed, a state that may hinder motivation to take medication and follow other prescribed regimens. Existing medications can alleviate mania relatively quickly, but they have been less successful in combating depression and bringing people with bipolar disorder to complete recovery, Kupfer said. Residual symptoms make relapses more likely. Anticonvulsants and other mood stabilizers, he suggested, may benefit some people with persistent bipolar symptoms.

Psychotherapy, given short shrift in the treatment of bipolar disorder until about a decade ago, can increase adherence to medications, benefit social and occupational functioning, and enhance a person's capacity to manage stressors in daily life, Kupfer said.

Recent studies explore interventions targeting bipolar disorder subgroups, such as people vulnerable to circadian rhythm disruption. A combination of interpersonal and social rhythm therapy, an approach devised at Pittsburgh, aims to regularize timing of meals, sleep, and other daily routines and has been shown to reduce the likelihood of recurrence of affective episodes (Frank E et al. Arch Gen Psychiatry. 2005;62:996-1004).

Evidence-based algorithms for the treatment of depression provide prescriptive advice that goes beyond practice guidelines, said John Rush, Jr, MD, professor of clinical sciences and psychiatry at the University of Texas Southwestern Medical Center in Dallas. They recommend when and how to implement specific treatment options.

“Algorithms are not recipes. They also are not handcuffs,” Rush said. Physicians need to tailor recommendations to individual patients, according to age, concomitant medical illnesses, prior history, and other factors. Physicians also need to respect patients' preferences, he said, as patients will have to live with adverse effects, if any. When medications are clinically equivalent, he suggested, one should let the patients choose.

Algorithms ideally provide faster and more sustained benefits than a less programmatic approach, he said. In one study, Rush and colleagues compared treatment using algorithms with treatment as usual in 547 patients with major depressive disorder in a public-sector population treated for 1 year by psychiatrists. The researchers found algorithms superior to standard treatment, as reflected in clinician-rated and patient self-reported symptoms and overall mental functioning. They included the algorithms in their report (Trivedi MH et al. Arch Gen Psychiatry. 2004;61:669-680).

All 10 studies conducted to date of enhanced care using varying degrees of algorithmic guidance have yielded positive findings, Rush said.

Psychiatrists historically have relied less on measurements than have primary care physicians, and patient self-report rating scales have gained currency in psychiatric clinical practice only recently. Inventories of depressive symptoms developed by Rush and colleagues, which can be completed by either patient or physician, are available in long and short forms, in the public domain, as free downloads (http://www.ids-qids.org).

Showing patients where they are on a scale helps keep them in treatment, Rush said. “I might tell a patient that most people respond to a specific medication in 4 to 6 weeks, but one third do not,” he said, “and then say, ‘If you do not, let's hang in there for a few more weeks, and then reevaluate.’”

Rush and colleagues also developed a self-administered scale to assess the impact of adverse events in people receiving treatment for depression. The 2876 outpatients with nonpsychotic major depressive disorder participating in the 6-year Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project (http://www.star-d.org) used this 3-question inventory, called the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) Scale.

Participants in the STAR*D project, funded by the National Institute of Mental Health and for which Rush is principal investigator, initially received the antidepressant citalopram, with care provided in 23 psychiatric and 18 primary care “real-world” settings. They were assessed by clinicians and completed the FIBSER at 2, 4, 6, 9, and 12 weeks, and, in some instances, 14 weeks, after starting on medication. The FIBSER proved to be a reliable and valid self-report measure, Rush said; it also is in the public domain (Wisniewski SR et al. J Psychiatr Pract. 2006;12:71-79) and is available at http://www.star-d.org under “clinician resources.”).

In the first phase of the STAR*D trials, about 30% of participants achieved a remission, defined as a virtual absence of symptoms. About 10% to 15% more showed substantial improvement. Patients treated in primary care settings did as well as those treated in psychiatric settings.

In the second phase of the project, the original medication was either augmented or replaced by other treatments, including cognitive therapy, with treatment proceeding according to algorithms. Approximately 1 in 4 patients who switched to another antidepressant had a remission (Rush AJ et al. N Engl J Med. 2006;354:1231-1242). Overall, a little over half of the patients achieved remission with their first or second course of treatment, Rush noted.

For those who did not reach remission in the first 2 rounds, switching to a third medication enabled about 1 in 5 to become symptom-free (Fava M et al. Am J Psychiatry. 2006;163:1161-1172). Ongoing STAR*D analyses will examine effects of different medications, dosage, timing, and other treatment options that may affect remission rates.

Remission is the goal of treatment, Rush said: “We don't always get there, but we should try.”

Somatic treatments benefit some people whose depression persists after treatment with medication, psychotherapy, and a combination of these two, said Mark George, MD, professor of psychiatry and director of the brain stimulation laboratory at the Medical University of South Carolina, in Charleston.

Refinements of electroconvulsive therapy that use a shorter pulse width yield efficacy comparable with older techniques, with less cognitive dysfunction, George said.

In 2005, the US Food and Drug Administration approved vagus nerve stimulation for treatment-resistant depression. This technique requires implantation of a pacemaker in the neck to stimulate the left vagus nerve.

Repetitive transcranial magnetic stimulation (rTMS) has generated the most excitement among researchers in therapeutic neuromodulation, George said, as rTMS is non-invasive, and, in studies to date, has not been shown to have deleterious cognitive effects. This still-investigative technique involves external application of magnetic fields that stimulate the cortex.

A 20-site study of 301 patients with difficult-to-treat depression who received either rTMS or sham rTMS as outpatients for 35 min/d, 5 d/wk, for up to 6 weeks, followed by a 3-week taper phase, found greater improvement on standard depression rating scales in the active treatment group than in the sham treatment group, according to a report at another symposium at the Toronto meeting. John O'Reardon, MD, assistant professor of psychiatry at the University of Pennsylvania School of Medicine, Philadelphia, principal investigator at that site, described findings from this study, funded by Neuronetics Inc, a TMS device manufacturer. A replication trial sponsored by the National Institutes of Health is now in progress.