Treatment-Resistant Depression

Management Strategies

By James G. Barbee, MD | July 27, 2009

Dr. Barbee is George C. Dunn, MD professor of psychiatry, professor of neurology and pharmacology at the Louisiana State University Medical Center in New Orleans. The author reports that he is a consultant for Bristol-Myers Squibb (BMS) and Jazz Pharmaceuticals; and he has received research support from BMS, GlaxoSmithKline, Pfizer, PamLab, and Wyeth Ayerst.

By contrast to these relatively small studies with classical augmentation agents, there are a number of large, randomized, placebo-controlled trials of atypical antipsychotics in nonpsychotic, unipolar depression in combination with antidepressants. These studies culminated in the first-ever FDA approval of an agent specifically for antidepressant augmentation—aripiprazole. In their meta-analysis, Papakostas and colleagues³⁸ conclude that the results support the utility of atypical augmentation, even in the absence of double-blind, placebo-controlled trials with aripiprazole(Drug information on aripiprazole) (now available) and ziprasidone(Drug information on ziprasidone). Virtually all of the studies to date of atypical augmentation have been conducted with SSRIs, although there are reports that aripiprazole was effective with bupropion, tranylcypromine, and mirtazapine(Drug information on mirtazapine).^39-41

The study of tranylcypromine (an MAOI) with aripiprazole suggests the need for cautious use of some combinations. As noted in the package insert, tranylcypromine should not be coadministered with dibenzazepine-related entities because of the risk of severe interactions, including hypertensive crises and seizures.⁴² Some of the atypical antipsychotics (eg, aripiprazole, ziprasidone) have a high affinity at the 5-HT_1A-receptor; agents such as buspirone(Drug information on buspirone), which also binds at this receptor site, are not recommended for use with MAOIs. Ziprasidone also has a similar potency to imipramine(Drug information on imipramine) in terms of blocking norepinephrine(Drug information on norepinephrine) and serotonin reuptake (imipramine is al-so relatively contraindicated with MAOIs).⁴³ There is a report of 5 patients treated safely with risperidone(Drug information on risperidone) and MAOIs, and another of 12 patients exposed to olanzapine(Drug information on olanzapine) with the selegiline(Drug information on selegiline) patch.^44,45

In general, the effective dosage of atypical antipsychotics in this role seems to be lower than that used in psychosis. Data on the long-term risks in depressed patients, including tardive dyskinesia and metabolic syndrome, are urgently needed. The recent FDA approval of quetiapine(Drug information on quetiapine) as monotherapy in bipolar depression raises questions as to whether some of the atypical antipsychotics may be effective (and perhaps better tolerated) when given as a single agent for unipolar TRD.

In regard to the value of switching atypicals, if one agent fails, is it worth attempting trials of another? There are limited data that show that switching to another atypical is worthwhile.^46,47However, results from randomized controlled trials are still needed.

SUMMARY

Each of the agents listed in Table 3 may be most effective when used for augmentation purposes. The quality of the evidence varies widely, particularly in the second and third categories of the table. For example, in a pooled analysis, estrogen was effective when added to sertraline in a group of depressed women over 60 years; however, the total sample size was only 127.⁴⁸ There are small, positive, double-blind studies for agents such as testosterone, L-tryptophan, and omega-3-fatty acids.^49-51In the case of pindolol(Drug information on pindolol), there are negative studies as well, and in a recent review, the evidence supporting its efficacy was rated as a “C” (the lowest rating).^28,32

Open-label reports for buspirone were positive, but 2 randomized controlled trials were negative.^52,53Buspirone was used as an augmentation agent for citalopram in level 2 of STAR*D: remission rates were 33% by the QIDS-SR compared to 39% with bupropion at the same stage. Although the remission rates between the 2 drugs did not differ significantly, the bupropion group had a significantly greater reduction in depression scores.⁵⁴

Despite reports that suggest the efficacy of lamotrigine(Drug information on lamotrigine), this agent did not separate significantly from placebo in the only large, multicenter, double-blind, placebo-controlled trial to date.⁵⁵ Modafinil(Drug information on modafinil), used in 2 randomized, placebo-controlled trials did not show significant placebo separation on most mood-scale scores, but it did reduce sleepiness and fatigue.^56,57

The unfortunate reality is that conducting large, double-blind, placebo-controlled trials is extremely expensive and time consuming. Definitive evidence of the efficacy of these agents is likely to accrue slowly. Negative studies may not prove that a drug is ineffective because of factors such as high placebo response rates, or the more subtle reality that there may be meaningful subgroups of patients with TRD that we are currently unable to identify.

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by meck skate | March 24, 2010 4:11 AM EDT

So, if those depressed patients that simply don't get better on current medications that mainly work on 3 or so types of neurotransmitters, but do get dramatically better as soon as they receive an agent like buprenorphine, yet it gets No mentioning. No mentioning. Despite that many may be suicidal, the info about it, let alone treatment with it, is not being presented to them, despite overwhelming positive results in at least two studies, albeit small, but yet. And many anecdotal reports of its efficiency apparently exist. If everything else fails, and at least two studies show something else to be overwhelmingly helpful, shouldn't it at least be a last option?

As for buprenorphine being the 'only' agent able to correct that subgroup's biochemical deficiency. Well, at least as of currently. In the future an opioid may not be needed at all, but it seems the great majority of research still focuses on the same biochemical areas, despite wide spread knowledge that they don't cover for all depressive illnesses. What's the matter.

by meck skate | March 24, 2010 3:57 AM EDT

Ok, the millions of treatment resistant depressed patients should read articles like these with suspicion, in the cases where you've heard the story before. Try one ssri, combined with another ssri, or snri, and repeat, and repeat. Until it looks like they're just doing it to seem 'nice' not because it helps.

Read up studies on "buprenorphine"in the treatment of treatment resistant depressed patients, some that had even undergone ECT, without success. An overwhelming majority of subjects saw remission of their depressive symptoms. How hard is it to strongly suspect, in lack of any strong contradicting data, that those patients din't have any serotonin or norepinephrine deficencies? But had deficiencies that only agents like buprenorphine are able to correct.
It's just a travesty when even the top tier of the psychatric community appears to put taboo before healing.

Also in this Special Report

Introduction Underlying Causes and Implications

Chronic Eating Disorders

Treatment-Resistant Bipolar Disorder

Treatment-Resistant Depression

Borderline Personality Disorder and Resistance to Treatment

Psychodynamic Psychopharmacology

Treatment-Resistant Schizophrenia

Drugs Mentioned in This Article

Agomelatine (Valdoxan, Melitor)
Amantadine (Symmetrel)
Amibegron
Aminoglutethimide (Cytadren)
Aripiprazole (Abilify)
Atomoxetine (Strattera)
Bromocriptine (Parlodel)
Bupropion (Wellbutrin, Zyban)
Bupropion SR (Wellbutrin SR)
Buspirone (BuSpar)
Carbamazepine (Carbatrol, Tegretol, others)
Celecoxib (Celebrex)
Citalopram (Celexa)
Dehydroepiandrosterone
Desipramine (Norpramin; Pertofrane)
Dexamethasone (Decadron, others)
Duloxetine (Cymbalta)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Folic acid (Folacin, Folate, Pteroylglutamic acid, Vitamin B9)
Gabapentin (Neurontin)
Imipramine (Tofranil)
Inositol
Ketamine
Ketoconazole (Nizoral)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithane, Lithobid)
L-tryptophan
Melatonin (Bevitamel)
Memantine (Namenda)
Metyrapone (Metopirone)
Mifepristone (Mifeprex)
Mirtazapine (Remeron)
Modafinil (Provigil)
Nefazodone (Serzone)
Olanzapine (Zyprexa)
Omega-3-acid ethyl esters (Lovaza)
Paroxetine (Paxil)
Pergolide (Permax)
Pindolol (Visken)
Pramipexole
Quetiapine (Seroquel)
Riluzole
Risperidone (Risperdal)
Ropinorole (Requip)
S-adenosyl-l-methionine (SAMe)
Selegiline (Emsam, Atrapryl, Carbex, others)
Sertraline (Zoloft)
Sipatrigine
Topiramate (Topamax)
Tranylcypromine (Parnate)
Trazodone (Desyrel)
Valproate/valproic acid (Depakote, others)
Venlafaxine (Effexor)
Yohimbine (Procomil)
Ziprasidone (Geodon)

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Evidence-Based References

Barowsky J, Schwartz TL. Part 1: An evidence-based approach to augmentation and combination strategies for treatment-resistant depression. Psychiatry 2008. 2006;3:42-61.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.

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Treatment-Resistant Depression

Management Strategies

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