by John McManamy

Augmenting an antidepressant with another drug is an important option in helping achieve remission for depression, a number of speakers pointed out at the American Psychiatric Association annual meeting held in Philadelphia in May 2002. Augmenting carries forward a partial response from an antidepressant and buys time, Andrew Nierenberg MD of Harvard and Associate Director of the Mood Disorders Program at Massachusetts General Hospital noted in one symposium. It also helps avoid discontinuation, may achieve a more rapid response, and can be used to treat breakthrough symptoms. Holly Swartz MD of the University of Pittsburgh in addition observed that augmentation may result in synergy while Richard Shelton MD, chief of the Adult Psychiatric Division at Vanderbilt, mentioned the possibility of lowering doses and expanding therapeutic effect. On the minus side are cost issues, the uncertainties of dosing, and the possibility of drug-drug interactions.

Unfortunately most of what we know is based on a small number of open studies and anecdotal reports. "There is not enough data," Dr Swartz cautioned. Dr Nierenberg alluded to the phenomenon of the "augmentation of the month club" where once you have a study involving five patients, "everyone does it."

Antidepressant Augmentation Strategies

Augmentation strategies include:

Lithium - 60 published studies, all but three involving tricyclics, slow onset of action, side effects "burdensome." A 2003 meta-analysis of 10 placebo-controlled trials of treatment-resistant patients found 45 percent responded to the addition of lithium.

Thyroid (T3) - Three 2003 studies muddy the waters. An Israeli study of 44 nonresponders to Prozac after four weeks found that raising the dose from 20 mg to 40 mg was effective in only five patients, but adding thyroid T3 was effective in 10 of 16 women, while none of the nine males responded. A Dutch study found T3 added to Paxil only had the effect of worsening side effects while another Dutch study of 113 depressed patients on SSRIs found that the response rate was 46 percent, irrespective of whether the drug was augmented by the thryroid T3, and that remission rates did not differ significantly (32 percent for T3 vs 36 percent for SSRI-only).

Buspar - Very little data, may improve sexual dysfunction, may speed up response of SSRI.

Pindolol - A University Hospital Lewisham (London) study of 78 patients with moderate to severe depression found that those given pindolol - used to treat high blood pressure - added to their antidepressant (an SNRI milnacipran, available in Europe) found improved depression scores at week one and that the drug was well-tolerated over six weeks, leading the authors of the study to conclude that augmenting an antidepressant with pindolol "represents a rational strategy for the possible acceleration or potentiation of antidepressant action."

Viagra - May counter SSRI sexual dysfunction side effect.

Stimulant and Dopamine Agonists (Mirapex, etc) - A University of Pisa study of 31 non-responders to antidepressants (both unipolar and bipolar depressed) found that the Parkinson's drug pramipexole (Mirapex) added to their meds resulted in 21 responding after 16 weeks.

Anticonvulsants - Evidence for bipolar depression.

Provigil - Novel psychostimulant, three studies finding the drug useful as an adjunct.

Ritalin - Some psychiatrists are treating their geriatric patients with low doses of Ritalin to augment their antidepressants. Ritalin can have an energizing effect in 72 hours, but its benefit is short-lived. By then, hopefully, the antidepressant is beginning to kick in. It is also being used to clear up the thinking and concentration difficulties that occur with depression

Zyprexa - Eli Lilly was the first to get in the act with its blockbuster antipsychotic, with a series of studies presented at the 2002 American Psychiatric Association annual meeting looking at Symbyax (combination six or 12 mg [low dose] Zyprexa and 25 or 50 mg [low-mid dose] Prozac) for psychotic depression, treatment-resistant depression, and bipolar depression. At the 2003 APA meeting, Eli Lilly presented three large Symbyax studies, the first showing a 64.8 percent response for bipolar depression after eight weeks, with eight days to partial response. The second found a 77.8 percent response after eight weeks for depressed rapid-cyclers. A third study followed those depressed bipolar patients who had remitted on Symbyax through an open label maintenance phase over six months, finding 62.5 percent remained free from relapse. In late Dec 2003, Eli Lilly received FDA approval to market the drug for treating bipolar disorder.

Other Antipsychotics - Lilly's competitors are looking to hop on the Zyprexa bandwagon. A 2004 open-label Janssen study of 386 patients with major depression who failed to respond to Celexa found that adding low dose Risperdal resulted in 59.3 percent remission after six weeks. A double-blind relapse prevention study is in progress.

Preliminary results from a 2004 AstraZeneca study of 16 depressed patients who hadn’t responded to their antidepressant found the addition of full dose Seroquel resulted in a 88 percent response and remissions vs 50 percent response/38 percent remission for those with high dose lithium as an add-on.

A 2004 Bristol-Myers-Squibb open-label study of five patients who failed to respond to their antidepressant found four of them responded two weeks after adding low to full dose Abilify. In another study, 14 of 30 responded to low doses of the drug.

Estrogen - Case reports of women responding.

Inositol - A Massachusetts General Hospital study of 16 depressed bipolar patients found a 33 percent response in those who augmented their lithium or Depakote with the simple carbohydrate, inositol, vs zero in the placebo group. Inositol naturally occurs in the body, is necessary for the formation of lecithin, and may reverse desensitization of serotonin receptors.

Potential augmenters - SAMe, EPA (found in omega-3), folate.

Antidepressant Combinations

Combinations tend to involve two different classes of antidepressants, such as an SSRI with an antidepressant that works on norepinephrine (such as Effexor, with a dual serotonin-norepinephrine action, plus a weaker dopamine action). One controlled study of patients who had not responded to an SSRI showed a 64 percent response when treated with an SSRI-Remeron combination (Remeron has a unique action that works on both serotonin and norepinephrine).

Essential Pharmacology of Depression and Bipolar Disorder (Cambridge University Press, 2002) by Stephen Stahl of the University of California at San Diego describes "California rocket fuel," a combo of Remeron and Effexor which can give a triple boost to the serotonin system, a double boost to the norephinephrine system, and a single boost to the dopamine system.

With triple combinations, Dr Nierenberg reported at the APA meeting, "we’re in No Man’s Land," with no data. The NIMH STAR*D trials involving several thousand patients currently underway should yield more information on combinations, he promised. In the meantime: "A lot of time I make my patients better by getting rid of the drugs [the pharmaceutical companies] give out."

Adding Talking Therapy to Antidepressants

Antidepressant Treatment for Co-Occurring Illnesses

Depression is a constant traveling companion with anxiety and sleep disorders, not to mention a feature of bipolar disorder, borderline personality disorder, and schizophrenia. Accordingly, it is not unusual to combine an antidepressant with any one or more of a whole array of medications. "Essential Pharmacology" describes combining an SSRI with Trazodone (a novel antidepressant that works on a different serotonin receptor), which improves the agitation and insomnia many people experience on SSRIs, thus allowing the SSRI to be administered in a higher dose, as well as boost the efficacy of the SSRI in treating OCD or other anxiety disorders.

Conclusion

Augmentation and combination treatment works on the synergy principle, where one plus one can hopefully equal three, or, even better, zero plus zero can equal ten as one drug or treatment either kickstarts the other or exploits some hidden chemical benefit. Thus, if a number of individual antidepressants have let you down, you may wish to ask your doctor or psychiatrist to start you on some kind of augmentation or combination treatment. Beware, however, of what some practitioners call "exotic polypharmacy," of patients being prescribed a virtual cornucopia of pills for no apparent reason. We are still very much in the dark about these treatments, so to a certain extent you will be a guinea pig. You have a right to ask exactly why a certain medication is being added to your existing one - the mechanism of action of the combination, its intended effect, possible drug-drug interactions, whether your doctor or psychiatrist has had success with this combination, whether this is temporary, and so on. Two medications should be par for the course for treating treatment-resistant depression, and two or three for depression plus another mental illness or related disorder such as sleep. There may be sound medical reasons for going higher, but the final decision should be the result of an enlightened partnership between you and your doctor or psychiatrist.

Factor in two to any set of numbers and you will find yourself with a seemingly infinite range of combinations. Hopefully, you will find one with your name on it.

John McManamy is the publisher of McMan's Depression and Bipolar Web. He is a former financial journalist with a law degree who has struggled with bipolar disorder most of his life.

next: Augmenting and Switching Antidepressants

top . send to friend . depression site map

Reviewed: 01/2006