The Year In Psychiatry

ROCKVILLE, Md., Jan. 5 -- Clinical and regulatory developments in psychiatry during the year included extended black box warnings about suicide for antidepressants, new insights for treating schizophrenia gleaned from an old trial, and the possibility of a "taste test" for selecting the best medicine.

After much debate between critics and supporters of the black box warnings about suicidality risks associated with antidepressant use in children and adolescents, an FDA advisory committee recommended in December that the agency extend the warnings to include young adults.

Also, researchers continued to mine data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for insights into improving treatment of schizophrenia.

The year also saw the emergence of a once-daily patch for treating attention-deficit hyperactivity disorder (ADHD) and evidence supporting a novel antipsychotic for schizophrenia.

The following summary reviews some of the highlights of the year in psychiatry. For fuller accounts, links to the individual articles published in MedPage Today have been provided.

Black Box Suicide Warning

Last month, an FDA advisory panel voted six to two in favor of extending the black box warning for antidepressants about suicide risk in children and adolescents to include young adults up to their middle 20s.

The recommendation was based on an FDA analysis of 372 randomized, placebo-controlled antidepressant trials involving nearly 100,000 adult patients.

The analysis found that the suicidality risk previously found with children and adolescents also applied to young adults up to about age 25. However, after that age, the phenomenon reversed and antidepressants conferred a protective effect against suicidality, said Thomas P. Laughren, M.D., director of the FDA's division of psychiatry products.

To address concerns that the black box warnings might discourage some depressed individuals from seeking treatment, the FDA said it might reword the current warning in an effort to ensure that "physicians are not frightened into not treating patients who should be treated."

• FDA Advisers Want Antidepressant Suicidality Black-Box Warning for Young Adults

Just one week before the FDA committee's recommendation, a large Finnish study found that antidepressants were linked with increased attempted suicides in both children and adults.

The study, published in the December issue of Archives of General Psychiatry, included all 15,390 patients hospitalized in Finland for a suicide attempt from 1997 to 2003. Average follow up was 3.4 years.

Although the risk of completed suicide tended to be slightly lower among patients on any antidepressant (relative risk=0.91, 95% confidence interval=0.75 to 1.11, P=0.36), suicide attempts were significantly more common (RR=1.64, 95% CI= 1.54 to 1.74, P<0.001) than among those not on antidepressants, the study found.

Interestingly, the adjusted relative risk death of was significantly lower among those taking any antidepressant (RR=0.64, 95% CI=0.56 to 0.73, P<0.001). The main factor in reducing mortality appeared to be the lower cardiovascular- and cerebrovascular-related mortality for patients taking antidepressants (RR=0.48, 95% CI=0.34 to 0.68, P=0.002), the authors said.

• Antidepressants Increase Suicide Attempts But Not Suicides

Pediatric antidepressant prescriptions fell by about 10% after the FDA ordered the black box warnings, according to a study reported at the American Academy of Child and Adolescent Psychiatry meeting in San Diego.

"While not intended to discourage appropriate prescribing, concerns have arisen that the warning would result in hesitance to use potentially effective treatments," said Christine Thomason, Ph.D., of i3 Research in Basking Ridge, N.J., in a poster presentation.

In 2004, the FDA found an increased risk for suicidal thoughts or behavior (average risk 4% versus 2% placebo) associated with some antidepressants. In October of that year, the agency mandated black box warnings on all antidepressant labels.

After the warnings appeared, overall prescriptions dropped by 9.7% (68,121 versus 61,561, P<0.0001), and new prescriptions declined by 19.6% (54,902 versus 44,150, P<0.0001). The largest decline in new prescriptions occurred in 15- to 17-year-olds: a 23.2% drop, the study found.

• AACAP: Black Box Warnings Decreased Pediatric Antidepressant Use

In August, a case control study was reported suggesting that severely depressed adults did not seem susceptible to additional suicide risk from antidepressants.

While conflicting with results of a subsequent FDA analysis presented in December, this study, published in the Archives of General Psychiatry, confirmed the increased suicide risk with antidepressants in younger patients reported by the FDA in 2004.

The Archives study analyzed the medical records of nearly 5,500 Medicaid patients who were hospitalized for depression at least once in 1999 or 2000. The researchers selected all cases of completed suicides (eight children and adolescents and 86 adults) and suicide attempts (263 children and adolescents, 521 adults).

Though no increased risk was found for adults, antidepressants appeared to increase the risk for suicide attempts in severely depressed children and adolescents by more than 50%, the study found.

• Increased Antidepressant Suicide Risk Not Found for Adults

Attention-Deficit Hyperactivity Disorder (ADHD)

In contrast to the black box warning recommendation for antidepressants, an FDA advisory panel voted against a black box warning about potential cardiovascular and psychiatric risks of stimulant drugs for attention deficit hyperactivity disorder (ADHD).

The pediatrics advisory panel met in March after a surprise Feb. 9 recommendation by the Drug Safety and Risk Management Advisory Committee. By a narrow margin, this committee voted for placing a black box warning on stimulants used to treat ADHD in adults.

Explaining the panel's vote against the committee's earlier recommendation, Robert M. Nelson, M.D., the committee chairman said, "A black box is really meant for situations where the risk-benefit analysis would suggest you shouldn't do something, but in the light of ADHD -- at least in pediatrics -- the evidence is pretty strong and convincing that it's effective, and we didn't think that the risk of these adverse events rose to the level of a black box warning for pediatrics."

Instead, the committee recommended a labeling change in the highlights section of the package insert for stimulants used to treat ADHD. These included Ritalin (methylphenidate), Adderall (mixed salts of a single-entity amphetamine product), and Concerta (extend release methylphenidate).

• FDA Pediatric Advisers Say Nay to ADHD Drug Black Box

The labeling change went into effect on August 23.

The new language warned that sudden death "has been reported in association with central nervous system stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems."

Additionally, the labels now warn that although "some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at an increased vulnerability to the sympathomimetic effects of a stimulant drug."

• Cardiovascular Safety Warning Added for Stimulants for ADHD

Elsewhere on ADHD, Ritalin appeared less effective in treating ADHD in preschoolers than in school-age children, according to a complex NIH-sponsored trial reported in five separate papers in the November Journal of the American Academy of Child and Adolescent Psychiatry.

The trial found a smaller effect size on symptoms in three- to five-year-old children than has been reported for school-age children.

In addition, tolerability was lower than expected in preschoolers. For example, 11% of preschoolers discontinued due to adverse events compared with a previously reported rate of less than 1% in school-age children, the study found.

To improve tolerability, researchers suggested that preschoolers with ADHD need to start with low doses, probably 2.5 mg twice daily moving up to 7.5 mg three times daily over the course of a week.

• Ritalin Less Effective for ADHD in Preschoolers Than Older Children

On a more positive note, the FDA approved the first transdermal patch for treating ADHD in April. The patch is called Daytrana (methylphenidate transdermal system).

The once-daily patch is offered in doses of 10 mg, 15 mg, 20 mg, and 30 mg, according to an announcement by Shire PLC, which was licensed to market Daytrana by Noven Pharmaceuticals.

The patch is designed to withstand normal daily activities of children without falling off, including swimming, exercising and bathing. In addition to this convenience, the patch allows physicians to manage the duration of effect and potential side effects by having patients wear the patch for a shorter time period than the recommended nine hours per day, the company said.

• FDA Approves Daytrana Transdermal Patch for ADHD

Schizophrenia

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, published in September, still gave researchers much data to chew on and to debate in secondary analyses this year.

CATIE was a prospective randomized trial that compared Trilafon (perphenazine), an older antipsychotic drug, with four so-called second generation antipsychotics in treating chronic schizophrenia. The second generation antipsychotics were Zyprexa (olanzapine), Geodon (ziprasidone), Seroquel (quetiapine fumarate), and Risperdal (risperidone).

CATIE found that Zyprexa had the lowest rate of discontinuation, but that Trilafon was comparable to the other three and "not that much less effective than olanzapine," said Jeffrey Lieberman, M.D., of Columbia University, the principal investigator.

A secondary analysis published this year went further than Dr. Lieberman in support of Trilafon. It said Trilafon is significantly cheaper and no less effective than the four newer medications for treating chronic schizophrenia.

The older drug is more cost-effective than the newer drugs in terms of their "human benefit," said Robert Rosenheck, M.D., of Yale University, author of one of two secondary analyses of the CATIE data published in the December issue of the American Journal of Psychiatry.

Using a range of measures of quality of life derived from interviews of participants during the study, Dr. Rosenheck and colleagues found that all five drugs were roughly equivalent in improving patients' well-being, but that Trilafon cost between and less per month.

"The bottom line of the study is that the older drug is substantially less expensive -- by between ,600 and ,000 a year -- and no less effective," Dr. Rosenheck said.

• Older Schizophrenia Drug Called More Cost-Effective Than Newer Ones

That view was echoed by a presentation given at the U.S. Psychiatric & Mental Health Congress in New Orleans in November. The presentation, based on an interpretation of CATIE data, also suggested that Trilafon could sometimes work as well as the newer antipsychotics.

The times to discontinuation because of intolerable side effects were similar among all five drugs in the trial. However, Zyprexa was associated with more discontinuation for weight gain or metabolic effects, and Trilafon was associated with more discontinuation for extrapyramidal effects, Rajiv Tandon, M.D., of the University of Florida in Tallahassee, told meeting attendees.

Zxprexa was the most effective drug in terms of the rates of discontinuation, but it was the "worst offender" in terms of metabolic side effects, Dr. Tandon said.

Furthermore, the efficacy of Trilafon appeared similar to that of Seroquel, Risperdal, and Geodon in patients at low risk for extrapyramidal side effects, he said.

The CATIE study suggested that in schizophrenic patients with a low risk for extrapyramidal side effects, older antipsychotics such as Trilafon may work as well as the newer ones "if you can get the dosing just right," Dr. Tandon said.

• USPSYCH: Newer Antipsychotics Not Always Better

In other CATIE news, the common practice of switching antipsychotic drugs to improve symptom control is likely to backfire in patients already doing well on a particular medication, according to another secondary analysis of CATIE published in the December issue of the American Journal of Psychiatry.

This analysis found that many patients who were randomly assigned to stay with the same medication they were already using did better than those who were switched, reported Susan Essock, Ph.D., of Mount Sinai in New York, and colleagues.

"The stayers did better, which underscores the risk associated with changing anti-psychotic medications," Dr. Essock said. However, the urge to change medications is understandable, because most patients are "partial responders," and the new study shouldn't discourage physicians from trying new avenues, she added.

But, she said, doctors "should make all efforts to optimize the current regimen for patients" before switching.

• Switching Drugs No Panacea in Schizophrenia

Physicians should also be aware that large numbers of schizophrenics have co-morbidities such as diabetes or heart disease but aren't being treated for them, according to a secondary analysis of CATIE data presented at the annual meeting of the American Psychiatric Association in Toronto in May.

About 42% of the 1,460 patients in the CATIE trial already met the criteria for the metabolic syndrome when they entered the study, but the treatment rate for this and other comorbidities were "shockingly low," said Henry Nasrallah, M.D., of the University of Cincinnati. For example:

• 40% of patients with frank diabetes were not under treatment.
• 65% of those with hypertension were not getting any anti-hypertensive drugs.
• 90% of those with high cholesterol and triglycerides were not being treated, the analysis found.

"The take-home message for a clinician is that among patients with schizophrenia who are presenting for treatment there are a substantial proportion who have hypertension, hyperlipidemia, diabetes, overweight, and obesity," said John Kane, M.D., of Zucker Hillside Hospital in New York.

One reason for the under-treatment may be that psychiatrists tend to focus on mental illness, assuming that physical illness will be taken care of by a family doctor or other physician, Dr. Kane said.

• APA: Schizophrenia Patients Go Untreated For Comorbidities

The year also saw the emergence of promising evidence about a novel antipsychotic drug for schizophrenia. The drug Abilify (aripiprazole) proved well tolerated and effective in both the acute and maintenance setting for schizophrenia, according to two company-sponsored studies presented at the American Psychiatric Association meeting.

The Schizophrenia Trial of Aripiprazole (STAR) compared Abilify to Zyprexa, Seroquel, and Risperdal.

At every time point during the 26-week trial, Abilify showed superior effectiveness compared with the other drugs as assessed by the Investigator Assessment Questionnaire (IAQ) Total Score (P<0.001), beginning as early as three weeks. Patients taking Abilify were also more likely to report that their current medication was better than the one they had been taking before the trial (P<0.001).

A second study explored the efficacy of Abilify when used as a maintenance drug for schizophrenia. This 52-week study compared Abilify to Haldol.

A greater proportion of patients on Abilify achieved symptomatic remission (32%) during the trial, compared with patients taking Haldol (22%, P<0.001). Moreover, among the patients who achieved remission in either group, the Abilify patients got there faster than did those taking Haldol (P=0.0024 by log-rank test), the study found.

• APA: Abilify Shows Benefits in Schizophrenia and Bipolar Disorder

Another company-sponsored study presented at the American Psychiatric Association called into question the established wisdom that Zyprexa increased cardiovascular risk for schizophrenics compared with Haldol.

The study found that after six months on Haldol, patients' average 10-year Framingham heart percentage risk was 4.58, while after six months of Zyprexa, that risk was 4.12. The difference was non-significant, the study found.

Of the six variable Framingham criteria, only blood pressure changed notably: It was slightly lower in the Zyprexa patients, the study found.

• APA: Zyprexa No Booster of Framingham Heart Risk Compared With Haldol

Autism

A major story in autism was the FDA approval in October of the adult antipsychotic Risperdal for symptomatic treatment of irritability in autistic children and adolescents.

Risperdal was the first drug approved for this indication, which includes aggression, deliberate self-injury, and temper tantrums. The drug's effectiveness was established in two eight-week, placebo-controlled trials including 156 patients ages five to 16.

Children taking Risperdal achieved significantly improved scores for certain behavioral symptoms of autism compared with children on placebo. The most common side effects associated with Risperdal were drowsiness, constipation, fatigue, and weight gain.

• FDA Approves Antipsychotic Drug for Irritability in Autistic Children

Depression

Compared with experienced mothers, first-timers are at increased risk of schizophrenia, depression, and bipolar disorder in the 10 to 19 days after the birth of their child, a Danish study reported.

The study, published in the Dec. 6 issue of the Journal of the American Medical Association, supported universal screening for postpartum major mood episodes as early as two weeks after childbirth, the authors said.

Compared with women who had given birth before, primiparous women had an increased risk of incident hospital admission with any mental disorder through the first three months after childbirth, regardless of age (relative risk=1.68; 95% confidence interval=1.23-2.30). At 10 to 19 days postpartum, the risk was seven times greater (RR=7.31; 95% CI=5.44-9.81), the study found.

• First-Time Mothers at Risk for Postpartum Mental Disorders

On a more positive note, treating mothers with depression can help their children as well, according to results reported this year from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study.

When depressed mothers achieve remission after three months on medication, the diagnoses and symptoms in their children of anxiety, disruptive behaviors, and depressive disorders also diminishes significantly, according to a report in the March 22 issue of the Journal of the American Medical Association.

Among children whose mothers had remission of symptoms, there was an overall 11% decrease in rates of diagnoses of children, according to DSM-IV criteria for depressive disorders, anxiety disorders, and disruptive behavior disorders.

In contrast, children whose mothers did not have a remission after three months on medication had about an 8% increase in rates of diagnosis of any of the disorders. The differences between the two groups remained significant even after controlling for the child's age, gender, and possible confounding factors (P=0.01).

"The bottom line message is: mothers who are depressed, go get treated for your depression," said study author A. John Rush, M.D., of the University of Texas Southwestern Medical Center in Dallas. "It will help not only you, but your child."

• Treating Depressed Moms Brightens Children's Lives

In other depression news, deep brain stimulation may be useful for some patients with treatment-refractory depression, according to research presented at the American Psychiatric Association annual meeting in Toronto in May.

Of 12 patients with treatment-resistant depression who underwent the experimental treatment, six responded after six months with a reduction of 50% or more in their rating on the Hamilton Depression Scale (HAM-D17), said Sydney Kennedy, M.D., of the University of Toronto.

However, all six patients who responded (as well as three non-responders) had disease that was classified as melancholic. None of the three participants whose illness was classed as atypical responded, Dr. Kennedy said.

The treatment involves delivering a small electrical current though electrodes implanted in the subgenual cingulate region (Brodmann Area 25). This area of the brain has been shown to be metabolically overactive in patients with depression and to become less active if treatment succeeds.

• APA: Melancholic Depression Responds Better to Deep Brain Stimulation

The possibility of tailoring antidepressant treatment to one's genetic makeup moved a little closer to reality in 2006.

The presence of certain polymorphisms in the serotonin transporter and norepinephrine transporter genes may determine whether patients are likely to benefit more from a selective serotonin reuptake inhibitor (SSRI) or norepinephrine reuptake inhibitor (NRI), according to a Korean study published in the Oct. 4 issue of Journal of the American Medical Association.

The researchers found that patients who responded to Aventyl (an NRI) were nearly eight times more likely to carry the NET G1287A polymorphism (odds ratio, 7.54, 95% confidence interval, 2.53-22.49, P<0.001). An even stronger association was seen between an SSRI response and the presence of the 5-HTT intron 2 s/l variation (odds ratio 20.11, 95% CI, 4.27- 94.74, P<0.001).

"Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment," the authors wrote.

• Genes Influence Response to Antidepressants

If a genetic test doesn't work, a "taste test" may help match the right class of antidepressant to the right patient, according to a British study in the Dec. 6 issue of Journal of Neuroscience.

In the study of 20 healthy adult volunteers, those who were exposed to the selective serotonin reuptake inhibitor Paxil (paroxetine) had significantly lower thresholds for sweet and bitter tastes than they normally did, wrote Lucy F. Donaldson, Ph.D., of the University of Bristol, and colleagues.

Similarly, volunteers given the norepinephrine reuptake inhibitor Edronax (reboxetine) were able to detect much smaller concentrations of bitter and sour tastes than they normally could, although neither drug appeared to affect taste thresholds for salt, the investigators found.

"Because we have found that different tastes change in response to changes in the two different neurotransmitters, we hope that using a taste test in depressed people will tell us which neurotransmitter is affected in their illness," said Dr. Donaldson.

• There Is Accounting for Taste in Treatment of Depression