November 2009

And a One, and a Two… Exercise for Depression
As an adjunct to medication and psychotherapy or by itself, exercise can be an effective treatment for depression.

Milnacipran (Savella)
Milnacipran (Savella) is the third compound to be approved in the United States for the treatment of fibromyalgia syndrome.

Preventing Depression in Adolescents
Current depression in parents negates the positive effects of a group cognitive behavioral prevention program in preventing depression in adolescents.

Anticholinergic Medicines and Cognitive Decline in the Elderly
Anticholinergic medications can impair cognition and memory, especially in elderly patients.

In Brief
Predictors of Mortality in Depressed Patients following Cardiac Events; Disruption of Dopamine Neurotransmission in ADHD

Raising the SSRI Dose: Does It Help?
Selective serotonin reuptake inhibitors (SSRIs) do not appear to have an obvious relationship of dose to likelihood of benefit.

Generic Antidepressants: Bioequivalent?
Generic formulations of antidepressants may not have the same pharmacokinetics and clinical effects as the original brand-name versions.

Lamotrigine in Borderline Personality Disorder
Preliminary research found lamotrigine (Lamictal) superior to placebo in improving symptoms of affective instability and impulsivity in patients with borderline personality disorder.

Raising the SSRI Dose: Does It Help?

November 2009

Some antidepressants, such as imipramine (Tofranil and others) and venlafaxine (Effexor), seem to have a positive dose-effect relationship. In other words: raising the dose increases the likelihood of a good clinical outcome (albeit at the risk of increasing side effects). For selective serotonin reuptake inhibitors (SSRIs), by contrast, the evidence for a relationship of dose to efficacy is murkier. Still, prescribers often increase the dose when the clinical effect is insufficient. Ruhé and coworkers in the Netherlands studied a dose escalation strategy for the SSRI paroxetine (Paxil and others), examining a possible role for serotonin transporter occupancy.1

Investigators performed a 6-week, multicenter study of 107 nonpsychotic patients, aged 18 to 70 years, with major depressive disorder (MDD), funded by a grant from the Netherlands Organisation for Health Research and Development. After 6 weeks of open-label treatment with paroxetine, 20 mg/day, about one-quarter of the subjects were deemed "responders" and removed from the trial. The remaining 60 patients ("nonresponders") were randomly assigned in double-blind fashion to continue taking the same dose of paroxetine or to have their doses raised to 30 to 50 mg/day as tolerated.

Response rates (at least a 50% decrease on the 17-item Hamilton Depression Rating Scale total score) were nonsignificantly different between the elevated-dose group (33.3%) and the 20-mg/day group (37.0%). Raising the paroxetine dose led to increased paroxetine serum concentrations but no significant increase in serotonin transporter occupancy in the midbrain or in the diencephalon. In the authors' opinion, the lack of clinical benefit from the dosage escalation resulted from serotonin transporter occupancy already being maximally reached at the 20-mg/day dose.

Of course, individual patients may vary, and conceivably some patients will not receive maximal benefit from paroxetine until they take a higher dose. Perhaps the same may apply to the other five SSRIs. Nonetheless, the best available science does not support an SSRI dosage escalation strategy for most MDD patients.

1Ruhé HG, Booij J, v Weert HC, Reitsma JB, Fransen EJ, Michel MC, Schene AH: Evidence why paroxetine dose escalation is not effective in major depressive disorder: A randomized controlled trial with assessment of serotonin transporter occupancy. Neuropsychopharmacology 2009;34:999–1010.