Antidepressants shown ineffective for bipolar depression.
The largest and most rigorous study to date on the treatment of bipolar depression was just published in the New England Journal of Medicine. The study, conducted as part of the NIMH-funded Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), enrolled a total of 366 subjects with either bipolar I or II disorder during a major depressive episode. These patients, all of whom were already taking a mood stabilizer, were randomly assigned to two groups: 179 received their current mood stabilizer plus an antidepressant (paroxetine or bupropion), and 187 received their mood stabilizer plus placebo. The investigators found that the addition of either paroxetine or bupropion did not improve either response or remission rates compared to a placebo control group. On a somewhat reassuring note, antidepressants did not increase rates of either suicidal ideation or switches to mania (Sachs GS et al., NEJM 2007;356:1-12).
TCPR’s Take: These disappointing results argue against the standard practice of adding antidepressants to mood stabilizers in bipolar depression. These findings will likely cause a boost in prescriptions of atypical antipsychotics in bipolar depression, particularly in light of Seroquel’s (quetiapine) recent FDA approval for this indication (see TCPR Feb 2007 for details).
FDA orders consumer medication guides for stimulants.
On February 21, the FDA directed all manufacturers of stimulants to develop Medication Guides for patients, spelling out, in non-technical language, the dangers of taking these medications. Last year, the FDA required an additional black box warning for stimulants warning of the risk of sudden death due to cardiac complications. This new directive responds to concerns that the black box information wasn’t filtering down to consumers. You can view the drafts of these medication guides at http://www.fda.gov/cder/ drug/infopage/ADHD/default.htm. Don’t worry, you won’t have to keep a stack of these in your office; the pharmacist who fills the script will hand them to your patients.
TCPR’s Take: This will certainly lead to many questions from patients and family members, as well as fewer stimulant prescriptions overall – which is either a good or a bad thing depending on your pharmaco-politics. Some psychiatrists believe that ADHD is severely under-treated, while others believe that the current wave of stimulant enthusiasm has gone overboard. You can find research data to support either position if you look hard enough!
The molecular mechanism of antipsychotic-induced weight gain is found.
We’ve known for some time now that clozapine and Zyprexa (olanzapine) cause the most weight gain of any antipsychotic, but we didn’t know the actual mechanism – until now. Researchers from Johns Hopkins and the University of Vermont found that both clozapine and Zyprexa increase levels of a specific enzyme in the hypothalamus that boosts the appetite. The enzyme, AMPK (AMP-protein kinase), is one of the brain’s major fuel-sensors, and leads to various biochemical reactions that eventually cause weight gain and metabolic abnormalities. Atypical antipsychotics that cause little weight gain, such as Risperdal, Abilify, and Geodon, increase AMPK levels only minimally. Interestingly, the way clozapine and Zyprexa stimulate AMPK appears to be via histamine-1 receptor antagonism, a neurotransmitter pathway that has long been a prime suspect as a mediator of weight gain (Kim SF et al., Proc Nat Acad Sci 2007:104(9): 3456-3459).
TCPR’s Take: It’s rare to find a clear molecular explanation for anything in psychiatry, so this finding is intriguing for that reason alone. Are there any clinical implications? Not really, since we already knew which antipsychotics caused the most weight gain. But researchers will use these findings to develop more targeted medications, both to prevent and to treat obesity in our psychotic patients.
TRANSCRANIAL MAGNETIC STIMULATION
TMS for the treatment of auditory hallucinations.
In the February issue of TCPR, we reported a recent FDA panel’s opinion that rTMS (repetitive transcranial magnetic stimulation) was relatively ineffective for treatment-resistant depression. The type of rTMS that has been tested for depression generally involves 10 Hz (ten pulses per second). But when the pulse of magnetic coils is slowed down to only 1 Hz, this reduces neuronal excitability, temporarily “stunning” those neurons subjected to the magnetic field. Researchers have been using this property to try to turn off the parts of the brain responsible for auditory hallucinations in schizophrenic patients. In a recent meta-analysis of such studies, the authors reviewed 10 TMS controlled trials (with sham-TMS as the control), and reported a robust average effect size of 0.88 (Aleman A et al., J Clin Psychiatry 2007;68:416-421). In the largest of the studies they reviewed, the anti-hallucination effect lasted about five months.
TCPR’s Take: This is potentially exciting stuff, but as is always the case with research, the devil is in the details. Most of these studies use specially created auditory hallucination scales to demonstrate a benefit of rTMS. These scales yield “hallucination scores” that decrease significantly with treatment, and are great for statistical testing, but not so helpful for clinicians trying to divine the applicability of the results to their patients. In fact, this meta-analysis found that while slow rTMS appears to decrease AH, it does not improve overall ratings of positive symptoms, making it debatable how useful this expensive treatment is likely to be for our patients.