Psychiatric Dispatches

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Primary Psychiatry. 2006;13(8):15-18

Patients with Treatment-Resistant Depression Maintain Improvement after Vagus Nerve Stimulation

Previous studies have shown that vagus nerve stimulation (VNS) is an effective long-term therapy for patients with chronic or recurrent depression who have not responded to ≥4 antidepressant treatments. A team of researchers recently investigated the durability of symptom improvement due to this therapy in patients who either responded early to VNS or responded at a later period.

In two studies led by Harold Sackeim, PhD, of Columbia University in New York City, and Stephen Brannan, MD, at Cyberonics, Inc. in Houston, Texas, the research team studied patients with treatment-resistant depression (TRD) following implantation of VNS therapy. Patients were then placed into subgroups depending on response to VNS and assessed after 12 months and 24 months for durability of improvement. Fifty-nine patients participated in a pilot study and 205 patients participated in the study that followed.

Patients in an early response group met response criteria 3 months after implantation and patients in a late response group met criteria after 12 months. Researchers also studied patients who had no response to VNS. Response criteria were identified as patients who has at least a 50% reduction in symptom scores at 3 or 12 months, measured by the 24-item Hamilton Rating Scale for Depression, the Beck Depression Inventory, and the Inventory of Depressive Symptoms-Self Report.

Findings showed that those patients who either responded to VNS earlier or later both had strong durability of improvement through the 12- and 24-month assessment periods. In the pilot study, 72.2% and 61.1% of early responders were responders at 12 and 24 months, respectively. Of late responders, 78.8% maintained response to the therapy at the 24-month interval. In the second study, 63.3% and 76.7% of early responders maintained response after 12 and 24 months and a majority of late responders were responders after 24 months.

Researchers also studied potential differences in severity of TRD between patients who responded at different times. Findings of the second study showed that there were no significant differences between either group. In addition, medication changes among participants did not account for any differences between groups.

The study authors said these findings show that VNS therapy is beneficial for patients who have had difficulty achieving sustained improvement with other treatment methods or medications. The researchers cite the extreme treatment-resistant conditions of the study sample as a further indication of the efficacy of VNS.

Funding for this research was provided by Cyberonics, Inc. (Poster 187, APA 2006). —CP

SSRI Comparison in Efficacy and Safety From Naturalistic Data

While randomized clinical trials are considered the “gold standard” for evaluating the efficacy, safety, and tolerability of medications, their findings are not always applicable to clinical practice. Kenneth R. Gersing, MD, and Bruce Burchett, PhD, at Duke University Medical Center in Durham, North Carolina, studied the comparative efficacy, treatment duration, and rates of adverse events of selective serotonin reuptake inhibitors (SSRIs) in patients with depressive disorders using a large-scale naturalistic database.

Data from the Clinical Management Research Information System at Duke University Medical Center Department of Psychiatry from July 1999 to November 2004 were included in the study. From the data, 2,292 patients were included who presented with major depressive disorder (MDD), dysthymia, or depression not-otherwise-specified for a new episode of treatment in outpatient, inpatient, or emergency room settings.

“Our motivation was to understand whether all of the SSRIs are the same in a real world setting and to see what people are really using and what they are saying the side effects and dose effects are,” said Dr. Gersing.

Patients received monotherapy with one of five SSRIs (citalopram [n=431], escitalopram [n=298], fluoxetine [n=499], paroxetine [n=345], sertraline [n=719]). The researchers identified a subgroup of patients who were experiencing their first episode of MDD (n=444) and were therefore likely to be antidepressant-naïve, to ensure that they did not have pre-existing sensitivities to the medications. Psychiatric comorbidities were common; patients who received concurrent treatment with more than one SSRI were excluded from the study. Concomitant psychiatric medications other than SSRIs did not result in exclusion, but were documented. Assessments included the Clinical Global Impressions-Improvement scale (CGI-I) to measure safety and efficacy.

Median total daily doses were: citalopram 40 mg, escitalopram 20 mg, fluoxetine 40 mg, paroxetine 30 mg, and sertraline 100 mg. Clinical response was measured as a CGI-I score of 1 (“very much improved) or 2 (“much improved”) and approximately 64% of patients overall and 65% of MDD-naïve patients were CGI-I responders. Treatments were found to be statistically similar in overall response rates: citalopram 64%, escitalopram 58%, fluoxetine 66%, paroxetine 64%, and sertraline 66%. Treatment duration was defined as the time from monotherapy initiation to the last visit in the treatment episode. The median duration in days was: citalopram=136, escitalopram=85, fluoxetine=199, paroxetine=168, and sertraline=164.

“We found that the drugs are pretty comparable in their effectiveness—it was the reactions and the side effects and the tolerability that had the significant difference,” said Dr. Burchett.

Adverse side effect rates were reported as citalopram 27%; escitalopram 19%; fluoxetine 19%; paroxetine 23%; and sertraline 16% (Table). These effects included sexual dysfunction, headache, nausea, increased appetite/weight gain, diaphoresis/flushing, anxiety, and sedation. The differences between sertraline and citalopram (regarding sedation and sexual dysfunction) and sertraline and paroxetine (regarding sexual dysfunction) reached statistical significance.

"This is a very granual electronic record that is physican-reported, not patient-reported, and therefore the side effects as expected are underreported,” Dr. Gersing added. “The database records side effects that the clinician needs to address over a long-term period.”

Drs. Gersing and Burchett intend to expand their research by comparing their data to the databases of other universities to have a larger sample size and gain a regional significance to the study.

Funding for this research was provided by Pfizer. (Poster 191, APA 2006). —SW

Patients and Physicians Both Contribute to Underdiagnosis of ADHD

In a recent study, researchers at New York University School of Medicine found that complications in diagnosing adult attention-deficit/hyperactivity disorder (ADHD) often arise from both the discomfort of many primary care physicians (PCPs) in forming the diagnosis without a specialist’s assistance and patients who exhibit ADHD symptoms, such as poor planning, which can hinder their ability to seek medical advice.

Lenard Adler, MD, and colleagues, gathered these findings from two separate surveys: one examining physicians’ attitudes toward and experience with adult ADHD as compared to other well-known disorders, such as generalized anxiety disorder (GAD), and a second survey, which screened adults for the disorder and assessed rates of patient diagnosis and treatment.

Utilizing a public release survey available online, Adler and colleagues compiled 400 completed responses by PCPs who were currently in a family, general, or internal medicine practice. Plus, physicians had to have practiced for ≥2 years and treat at least 30 adult patients per week with any combination of various disorders, including ADHD, for the review of PCPs attitudes toward the disorder.

Researchers found that a majority of PCPs felt uncomfortable diagnosing adult ADHD without consulting a specialist or referring a patient directly to a specialist, such as a psychiatrist or psychologist. Despite reporting that there is a significant adult ADHD population, many PCPs indicated that they are more comfortable with their knowledge and experience in depression and GAD.

“The study indicates that PCPs feel that they need additional training in adult ADHD,” Dr. Adler said. “The reason that the lack of recognition by PCPs is critical is that only 25% of the 8 million adults with ADHD in the United States are diagnosed and treated. The approximately 6 million adults who are not diagnosed and treated obviously cannot all see specialists. Many would need to be treated by PCPs.”

In addition, physicians, who mostly treated patients with depression and GAD, reported that training with an easy-to-use, validated screening tool for adult ADHD would prompt them to diagnose and treat the disorder in patients.

Researchers also utilized responses from 51 out of 330 adults who each screened positive for ADHD at a New York University Adult ADHD Screening Day and completed a 32-question follow-up survey about the screening 2 years later, for a study of patient diagnosis and treatment. The 6-item Adult Symptom Rating Scale Screener was used to determine the disorder in participants.

A majority of the sample did not receive medical diagnosis and treatment for ADHD after the screening day. Participants reported that symptoms of the disorder–including disorganization, procrastination, and trouble planning–were causal factors in their not seeking treatment from a PCP or other healthcare provider.

Adler and colleagues contend that these findings show that a vast number of adults with ADHD remain undiagnosed and untreated, while symptoms of the disorder contribute to those low rates of treatment. The authors believe clinicians should actively follow-up with patients identified through screenings.

Funding for this research was provided by an unrestricted educational grant from Eli Lilly. (Poster 621, APA 2006). —CP

Comparison of the Standard Scales and CGI Scores in MDD, Panic Disorder, SAD, and GAD

The Clinical Global Impression (CGI) scale is often used as a global measure for disease severity and treatment-induced improvement in a variety of medical and psychiatric disorders. Clinicians administering the CGI rate the overall severity of the patient’s illness at time of assessment relative to previous patients with the same diagnosis. The CGI-severity scale rates all aspects of the disorder, and the CGI-improvement (CGI-I) scale rates the patient’s overall improvement compared to baseline.

A recent study by Borwin Bandelow, MD, PhD, at the University of Göttingen in Germany, and colleagues, compared CGI measures with standard disorder-specific scales. The objective of the study was to define levels for response and remission for the standard scales by referring to the CGI definitions. In a post-hoc analysis, randomized, double-blind, placebo-controlled, acute treatment studies with patients treated with escitalopram for major depressive disorder (MDD; n=5), panic disorder (n=1), generalized anxiety disorder (GAD; n=4), or social anxiety disorder (SAD; n=2) were compared with regard to the standardized effect sizes in the CGI score as well as the standard rating scales for each disorder. The disorder-specific scales included the Montgomery-Asberg Depression Rating Scale (MADRS) for MDD, the Panic and Agoraphobia scale (P&A) for panic disorder, the Hamilton Rating Scale for Anxiety (HAM-A) for GAD, and the Liebowitz Social Anxiety Scale (LSAS) for SAD.

 Treatment with escitalopram showed high standardized effect sizes on all efficacy measures in all indications. Moderate to high correlations were found between the CGI and standard scales. The CGI was a consistent measure of disease severity and was sensitive to change. Response to treatment on a standard rating scale is defined as a ≥50% decrease from baseline scale score; however, in this analysis, the CGI-I definition of at least “much improved” corresponded to only 39%, 23%, 42%, and 31% reduction in the MADRS, P&A, HAM-A, and LSAS, respectively (Table). Thus, the comparison of the standard scales and CGI scores suggest that the traditional definition of response may be too conservative.
Funding for this research was provided by H. Lundbeck A/S. (Poster 626, APA 2006). —DC

STAR*D Study Offers Third-Round Results

Findings from the third round of reports from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study—the largest randomized clinical trial in depression ever conducted—show that patients who switch to a different class of antidepressants after failing on two prior antidepressants have only a minimal chance of achieving remission.

In a study led by Maurizio Fava, MD, at Massachusetts General Hospital in Boston, 235 patients who opted for a switch in their medications were randomly assigned to nortriptyline or mirtazapine, antidepressants they had not taken in two prior medication treatments for depression. The rates of remission after 14 weeks were statistically insignificant—20% for nortriptyline and 12% for mirtazapine.

Patients in the STAR*D study who failed with the first two medications were treated according to real-world practice, where a clinician might switch to an antidepressant from a different pharmacologic class. That the rate of remission for depression continues to be low underscores the persistence of depression and its resistance to current treatments.

Funding for this study was provided by the National Institute of Mental Health. (Am J Psychiatry. 2006;163:1161-1172). —DC

Posters were drawn from the 159th Annual Meeting of the APA (May 20-25, 2006, Toronto, Canada). Psychiatric Dispatches is written by Dena Croog, Carlos Perkins, Jr., and Shelley Wong.