Practical Management of Treatment-Resistant Depression


Am Fam Physician. 1998 Dec 1;58(9):2059-2062.

Patients receiving antidepressant monotherapy may be partially or totally resistant to treatment in 10 to 30 percent of cases. In patients who have experienced only partial treatment results, the clinician should first consider optimizing antidepressant dosage or lengthening therapy. Antidepressant drug substitution should generally be reserved for use in patients who haven't responded at all (nonresponders). Combining two or more antidepressants is generally not recommended, as this approach may obscure adequate monotherapy evaluation and lead to significant adverse effects or drug-drug interactions. Use of electroconvulsive therapy is recommended in patients with psychotic and severe refractory depression. Augmentation therapy is often efficacious in patients who exhibit a partial antidepressant response. Lithium and thyroid hormone have been the most extensively studied augmentative agents but, more recently, pindolol and buspirone have also been used for this purpose.

Partial response and nonresponse to antidepressant medications are common problems in patients with depression. Between 10 and 30 percent of depressed patients taking an antidepressant are partially or totally resistant to the treatment.1,2 Recurrence of depression while still taking medication (i.e., breakthrough) can also occur.3

Several factors may contribute to treatment failure, including undiagnosed or misdiagnosed medical conditions such as hypothyroidism and anemia. Therefore, the patient who does not respond or only partially responds to an antidepressant should first be reassessed to make sure the original diagnosis of depression was correct. Also, nonpsychiatric drugs such as methyldopa (Aldomet), beta blockers and reserpine (Serpasil) can cause or exacerbate depression. In addition, comorbid disorders (e.g., eating disorders, substance abuse or dependence) may affect treatment response. Psychotic depression, bipolar depression and atypical depression are depressive subtypes that may require concurrent pharmacotherapy such as antipsychotic or augmentative psychotherapy.4 Finally, adverse effects and poor compliance may be additional obstacles to successful treatment.

Strategies for Partial Response and Nonresponse

Five strategies for treating partial response or nonresponse to antidepressant therapy are optimization, drug substitution, combination therapy, electroconvulsive therapy and augmentation therapy.


Prescribing antidepressant medication in dosages that are too low and for lengths of time that are too short are common causes of treatment failure.5,6 In a study7 conducted in a managed care environment, only 11 percent of patients requiring antidepressant therapy received either an adequate therapeutic dosage or an adequate duration of therapy. Inadequate antidepressant dosage and duration are particularly prevalent in elderly patients.8

When a patient's history suggests inadequate therapy, the clinician should maximize the dosage or duration of therapy. Some depressed patients who are resistant to treatment may benefit from antidepressant dosages that are higher than the usual recommendations.7

An adequate duration for a trial of antidepressant therapy has been defined by some clinicians as four to six weeks.2 Others assert that a minimum of six weeks is necessary.1 If the patient exhibits a partial response during this initial period, another four to six weeks of treatment should be added. Thus, a total of 10 to 12 weeks may be required in some cases to elicit a full antidepressant response.7

Drug Substitution

“Nonresponders” are most likely to benefit from drug substitution. A change from one antidepressant to another in the same class has not produced impressive response rates among depressed patients. However, uncontrolled studies suggest that switching to an antidepressant with a different mechanism of action is often associated with a better response rate.7 Uncontrolled trials suggest that switching from a tricyclic antidepressant to an alternative antidepressant class may result in a 50 to 60 percent positive response rate.1

A response rate of 30 to 50 percent has been observed when selective serotonin reuptake inhibitors (SSRIs) are substituted for tricyclic antidepressants.5 Because SSRIs are structurally diverse, switching from one SSRI to another may also be useful.7 If drug-switching is chosen as the method of therapy, patients should be closely monitored for possible drug interactions or other adverse effects. This is particularly true if the half-life of the first agent is quite long (e.g., fluoxetine [Prozac]) and another SSRI is begun before a prudent “wash-out” period has occurred. This situation may sometimes result in serotonin syndrome (toxic levels of central nervous system serotonin that result in hyperalertness, agitation, confusion, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor and, possibly, death.)9

Combination Therapy

Combination therapy involves the addition of a second antidepressant agent to the therapeutic regimen. Concurrent administration of two or more antidepressant agents (e.g., adding trazodone [Desyrel], desipramine [Norpramine] or bupropion [Wellbutrin] to fluoxetine) may result in a different therapeutic response than that produced by use of either drug alone. However, no double-blind, placebo-controlled studies recommend the usefulness of this practice. In addition, this approach does not allow for adequate evaluation of monotherapy and may lead to significant adverse effects or drug-drug interactions (Table 1).

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Pros and Cons of Combination/Augmentation Strategies


Strategy builds on therapeutic gains

Addition of second compound is generally well tolerated

More rapid onset of antidepressant effects

Response rate comparable or superior to drug substitution


Polypharmacy and the potential for increasing drug interaction

Reduced compliance

Increased adverse effects


Pros and Cons of Combination/Augmentation Strategies


Strategy builds on therapeutic gains

Addition of second compound is generally well tolerated

More rapid onset of antidepressant effects

Response rate comparable or superior to drug substitution


Polypharmacy and the potential for increasing drug interaction

Reduced compliance

Increased adverse effects

Electroconvulsive Therapy

Electroconvulsive therapy is still the most effective treatment for psychotic depression and severe refractory depression. The clinician should not hesitate to recommend it and should reassure patients as to its appropriate and safe use under medically monitored conditions.

Augmentation Therapy

Augmentation therapy involves adding a second agent, but one that is not routinely regarded as an antidepressant, to the therapeutic regimen when there is only a partial response to the antidepressant agent.1,6 Four agents frequently used in augmentation therapy are lithium, thyroid hormone, the beta blocker pindolol (Visken) and buspirone (Buspar). It is helpful to review the neurotransmitter serotonin, the 5-HT receptor and the mechanism for antidepressant actions as they relate to the 5-HT1A receptor to understand the rationale for augmentation therapy.

Serotonin. Serotonin plays an important role in sleep, appetite, memory and mood. Serotonin release is inhibited or enhanced by the activity of the 5-HT1A receptor. Stimulation of the presynaptic somatodendritic 5-HT1A receptor by high levels of synaptic serotonin results in a negative feedback mechanism that inhibits further serotonin synthesis and release. Depression is associated with a relative lack of serotonin and norepinephrine in the synaptic cleft and, thus, a lack of normal responsiveness of the postsynaptic 5-HT1A receptors to stimulate the release of more serotonin. Although this description conveys a simplistic notion of a complex process, the serotonin hypothesis of depression has recently been expanded by the discovery that the true antidepressant effect (hence the four-to-six week delay in obtaining clinical improvement) may be due to the “down regulation” of central beta-adrenergic receptors by the antidepressant agent.10

Lithium. Lithium has been the most widely used and extensively studied augmentation agent. It apparently enhances serotonin transmission by reducing the activity of post-synaptic serotonin or 5-HT receptors. This, in turn, reduces the negative feedback to serotonin-releasing cells and thereby increases serotonin levels in the synaptic cleft. Lithium may also have effects on other neurotransmitter systems and neuromodulators.11

Lithium's efficacy as an augmentation agent has been demonstrated in a series of case studies3 that produced response rates of 30 to 65 percent. In some cases, responses were noted within 48 hours, but delays of three to six weeks have also been reported.11

The potential adverse effects of lithium are well known. They include hand tremor, weight gain, increased thirst and urine production, and mild cognitive impairment.12 A starting dosage of 150 mg twice daily, with a trough serum level obtained within one week, is a practical starting point for augmentation therapy. The lithium dosage should be adjusted to result in a serum blood level between 0.4 and 0.8 mEq per L (0.4 and 0.8 mmol per L). In clinical practice, aiming for the lower limit is prudent, since there is probably equal augmentative efficacy at serum blood levels of 0.4 and 0.8 mEq per L (0.4 and 0.8 mmol per L). Attempting to enhance response by increasing the dosage to higher serum blood levels may only result in unwanted side effects.11

Thyroid hormone. The thyroid hormone triiodothyronine (T3 [Cytomel]) appears to be a more effective augmentation agent than tetraiodothyronine (T4 [Synthroid])13 and is effective in small dosages; for example, 25 to 50 μg per day [ corrected].14 T3 may be used to augment response to tricyclic antidepressants, monoamine oxidase inhibitors and SSRIs.5 Although fewer controlled studies have focused on thyroid hormone than on lithium, T3 augmentation of tricyclic antidepressants has been shown to be effective in approximately 50 to 60 percent of patients.1

Monitoring thyroid function before T3 administration (for a baseline reading) as well as after administration is important. Beyond the observation that T3 potentiates noradrenergic activity, its mechanism of action as an augmentation agent is not clearly understood.4 Although T3 is a relatively safe augmentation agent with few adverse effects or potential allergic reactions, it has the potential, if taken chronically, to interfere with thyroid metabolism. Therefore, its use should generally be limited to two or three weeks. Adverse effects associated with excess administration of T3 include irritability, sweating and the possibility of cardiac arrhythmias.

Pindolol. The 5-HT1A postsynaptic antagonist pindolol accelerates the onset of action of antidepressants by preventing negative feedback to the presynaptic 5-HT1A receptor.15 Prevention of negative feedback results in higher levels of serotonin in the synapse. On a clinical level, pindolol, at dosages of 2.5 to 7.5 mg per day for a trial period of up to six weeks, might prove to be an effective augmentor of SSRIs. Adverse effects of pindolol, which occurred in fewer than 10 percent of study participants, included nausea, diarrhea and mild heart rate reduction.16

Buspirone. In terms of clinical characteristics, buspirone's primary activity is as an anxiolytic. Although buspirone may decrease the nonspecific symptoms of depression, it has no specific or intrinsic antidepressant effects. However, when used in conjunction with an antidepressant, it may have augmentative antidepressant effects. A number of open studies1719 of dosages of 15 to 30 mg of buspirone per day for up to three months suggested that an improved antidepressant response occurred in up to two thirds of patients. Adverse effects of buspirone, including lightheadedness and nausea, usually occur early and are generally transient.

Buspirone acts as a full agonist at the presynaptic autoreceptor and as a partial agonist at the postsynaptic autoreceptor.20 Administration of buspirone decreases extracellular serotonin concentrations over the short term through activation of 5-HT1A presynaptic autoreceptors. Buspirone also activates postsynaptic 5-HT1A receptors. Chronic buspirone administration desensitizes and downregulates 5-HT1A presynaptic autoreceptors, but not postsynaptic 5-HT1A receptors, thereby encouraging further serotonin release.

Caution is necessary when prescribing buspirone with nefazodone (Serzone). Dizziness, insomnia and headaches may occur more frequently with this combination than with either drug alone. This finding is likely related to the fact that there is pharmacokinetic interaction between nefazodone (which inhibits the cytochrome P450 enzyme 3A3/4) and buspirone (which is metabolized by this enzyme). In order to avoid this potential interaction while still deriving benefits from buspirone's augmentative effects with nefazodone, a lower initial dosage of buspirone (2.5 mg, twice daily) should be prescribed.

The Author

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ROGER J. CADIEUX, M.D., is associate professor of psychiatry and director of the geriatric assessment program in the Department of Psychiatry at Pennsylvania State University College of Medicine, Hershey. He is also physician consultant to the Pennsylvania Department of Aging. Dr. Cadieux received his medical degree from Louisiana State University School of Medicine, Shreveport, and completed a residency in psychiatry at Pennsylvania State University College of Medicine....

Address correspondence to Roger J. Cadieux, M.D., Dept. of Psychiatry (C506), Penn State-Geisinger Medical Center, 500 University Dr., Hershey, PA 17033. Reprints are not available from the author.

The author is or has been a member of the speaker's bureau of the following pharmaceutical companies: Bristol-Myers Squibb Co., Pfizer Inc., Roche Pharmaceuticals and G.D. Searle & Co.


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Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.



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