February 2008

Rimonabant Causes Depression and Anxiety
Rimonabant works as a weight loss agent but may cause depression and anxiety.

Selegiline Augmentation for Negative Symptoms of Schizophrenia
Patients with schizophrenia who take selegiline (Eldepryl, Emsam) in addition to antipsychotic drugs may have greater improvement in negative symptoms.

Managing Psychosis in Parkinson's Disease and DLB
Psychosis in Parkinson’s disease or dementia with Lewy bodies is difficult to treat, and patients are sensitive to side effects of drugs used for these conditions.

New Medicines for GAD: Duloxetine and Quetiapine
Duloxetine (Cymbalta) and quetiapine (Seroquel) are effective in treating generalized anxiety disorder.

In Brief
FDA Warns About Varenicline Psychiatric Adverse Effects; Index Ranks States on Prevalence of Depression and Suicide

Norepinephrine Uptake Inhibition
Atomoxetine (Strattera) inhibits norepinephrine uptake at lower doses than does venlafaxine (Effexor and others) or paroxetine (Paxil and others).

Norepinephrine Uptake Inhibition

February 2008

For about half a century, psychopharmacology has categorized antidepressants by which monoamine neurotransmitter they inhibit—most often, serotonin or norepinephrine. We have six different selective serotonin reuptake inhibitors (SSRIs), and now two drugs said to inhibit the uptake of both serotonin and norepinephrine (SNRIs).

Aldosary and associates used the tyramine pressor test to measure norepinephrine uptake inhibition by three drugs in vivo in depressed humans.1 In this test, a small bolus of tyramine is injected intravenously. Norepinephrine release from peripheral norepinephrine terminals, which is believed to parallel the same release centrally, increases systolic blood pressure. Attenuation of this response is used to measure central norepinephrine reuptake inhibition.

Thirty depressed patients received either escalating doses of venlafaxine (Effexor and others), 75 mg to 300 mg/day; paroxetine (Paxil and others), 20 to 50 mg/day; or atomoxetine (Strattera), 25 to 80 mg/day, over 4 to 6 weeks. Each subject received the tyramine pressor test.

Atomoxetine is a selective norepinephrine reuptake inhibitor labeled by the US Food and Drug Administration (FDA) to treat attention deficit hyperactivity disorder (ADHD) but used off-label as an antidepressant. It showed norepinephrine uptake inhibition (by inhibiting the tyramine response) at only 25 mg/day. (The starting adult dose for ADHD is 40 mg/day.) Not surprisingly, paroxetine did not demonstrate norepinephrine uptake inhibition at the doses used. Venlafaxine did—but only at 225 mg or 300 mg/day—consistent with clinical impressions.

We still don't completely understand how antidepressants work. Most likely, inhibition of serotonin or norepinephrine uptake begins a neurobiological cascade, which somehow allows healing of mood circuits. Atomoxetine, even at low doses, inhibits norepinephrine's reuptake into neurons. Paroxetine does not. Perhaps venlafaxine's benefits come from the inhibition of both serotonin and norepinephrine, but it seems norepinephrine uptake inhibition begins only at higher doses. This may be one reason more patients respond and remit at higher doses of this antidepressant.

1Aldosary F, Tremblay P, Norris S, Hébert C, Blier P: Venlafaxine daily dose of 225 mg and atomoxetine block norepinephrine reuptake in depressed patients, but not paroxetine or lower doses of venlafaxine. Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.