Dr. Gotto is acting director of consultation-liaison psychiatry at Cedars Sinai Medical Center in Los Angeles, California.   


Dr. Rapaport is chairman of the Department of Psychiatry at Cedars-Sinai Medical Center, and vice chairman and professor in residence in the Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine at the University of California, Los Angeles.   


Disclosure: Dr. Gotto reports no affiliation with or conflict of interest in any organization that may pose a conflict of interest. Dr. Rapaport is a consultant to Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, the National Institute on Drug Abuse, National Institute of Mental Health, Neurocrine, Novartis, Pfizer, Roche, Sanofi, Solvay, Sumitomo, and Wyeth; is on the speaker’s bureaus of Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Novartis, and Pfizer; receives grant/research support from Abbott, AstraZeneca, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Janssen, the National Institute of Mental Health, Novartis, Pharmacia-Upjohn, Pfizer, Sanofi, Solvay, Stanley Foundation, UCB Pharma, and Wyeth; and owns stock in Forest.    



Please direct all correspondence to: Jennifer Gotto, MD, 8700 Beverly Blvd, Los Angeles, CA 90048; Tel: 310-423-3440; Fax: 310-423-8268; E-mail: Jennifer.Gotto@cshs.org.


 

Focus Points

•One third of patients do not respond to antidepressant monotherapy.

•After optimally dosing a medication, the clinician may choose to combine, switch, or augment the antidepressant therapy.

•Augmentation therapy works by improving on the intended neurotransmission of the antidepressant or by stimulating additional neurotransmitter systems that are pharmacologically synergistic.

•Theoretically, improved neurotransmission increases neuronal nuclear activity, which stimulates protein transcription and translation, which ultimately determines core features of mood and behavior.

•The goal of aggressive augmentation is cure, not palliation.

•Even with aggressive therapy, some patients still may not respond completely.

 

Abstract

Treatment-resistant depression, or difficult-to-treat depression is emerging as a focus of scientific endeavor. Serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are no longer “new” antidepressants, and most recent phase II and phase III studies attempting to identify agents with novel mechanisms of action have been unsuccessful. Unfortunately, 30% to 60% of patients treated with the currently approved antidepressant medications do not receive adequate relief of symptoms of major depressive disorder from the initial treatment intervention. In fact, only approximately 35% of patients in rigorously-controlled clinical research studies (those having a score of <8 on the Hamilton Rating Scale for Depression) benefit enough from initial treatment to be classified as fully remitted. Good clinicians are frequently challenged to devise alternatives for these difficult-to-treat patients. This article reviews the current treatment augmentation options
and the rationale for their use.

Introduction

The definition of treatment-resistant depression (TRD) is in evolution; a common definition for the purpose of this article is “the failure of a patient to respond to an adequate dose of two antidepressants from different classes given for at least 8 weeks.” Adequate dose means that the patient receives a maximum safe, tolerable dose. With today’s goal of psychiatric treatment being complete remission of symptoms, “partial response” and “no response” are considered together when discussing TRD. Unfortunately, 30% to 40% of patients treated in clinical practice do not receive any significant relief of signs and symptoms of major depression disorder from the first two attempts at pharmacotherapy.1 When this occurs, the clinician must have a strategy for dealing with the difficult-to treat-patient. Whether the patient is a nonresponder or partial responder determines whether to pursue switching versus augmentation or combination strategies.2 The definition of TRD is a clinical definition. Many types of practitioners with differing levels of expertise treat depression: general internists, nurse practitioners, psychiatrists, obstetricians, neurologists, and others. Thus, the definition of TRD varies from clinician to clinician. Depressive disorders are not alike, so variations in patient presentation further complicates our ability to unambiguously define a patient as suffering from TRD.

Clinical Reasons for Treatment Failure

Nonadherence is the most common cause of treatment failure. A patient’s opportunity for compliance increases if that patient takes medication once a day (7% missed doses versus 70%).3 Identifying the patient as a psychotic or a bipolar subtype of depression creates differences in the treatment strategy of the patient. Psychotic depression requires additional antipsychotic medication to avoid a very low response rate of 20%.4 Bipolar depression has typically been treated with either lithium or divalproex sodium, often with the addition of a second mood stabilizer or an antidepressant. However, more recently, several alternative options have emerged. These include the combination of olanzapine and fluoxetine; in a large-scale controlled trial, olanzapine alone produced a significant but partial antidepressant action, while the two together produced an even more robust action.5 Quetiapine has also been tested as a monotherapy in a placebo-controlled trial and was shown to have a significant antidepressant effect.6 Finally, lamotrigine has been studied in two controlled trials yielding positive results as an add-on treatment.

Accurate identification of these different depressive disorder subtypes is crucial and can facilitate earlier and more effective treatment of these complex patients. Other identifiable causes of treatment failure are undertreatment, medical illness, and comorbid psychiatric conditions such as anxiety and personality disorder diagnosis.7 A patient suffering from medical illness, substance abuse, or personality disorder may have these problems concomitantly with TRD. If these additional problems are identified early in the course of treatment, their effect on the patient’s response can be minimized. Current thinking is that these factors increase the likelihood that the response to treatment will not be straightforward. However, this is not always the case. It is not known how many TRD cases are “pure” (ie, no comorbid substance abuse, personality disorders, or medical illness) and how many are comorbid.

There are several options for TRD (Table 1):

Optimization

Patients should receive two different antidepressants from two different drug classes (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOIs], or atypical antidepressants) at the highest tolerable dose for at least 8 weeks prior to receiving the label “TRD.” Fava and colleagues8 studied 41 patients who did not respond to an 8-week open trial of fluoxetine 20 mg/day. These patients were assigned randomly to fluoxetine 40–60 mg/day, fluoxetine 20 mg and desipramine 25–50 mg daily, or fluoxetine 20 mg and lithium 300–600 mg daily. The patients receiving fluoxetine 40–60 mg/day were more responsive (53%) than either of the other two arms (25% and 29%, respectively).

In a study by Schmidt and colleagues,9 1,186 depressed patients entered a three-phase study that investigated treatment response with varying doses of fluoxetine. In phase I, all patients received fluoxetine 20 mg/day for 13 weeks. In phase II, the patients were randomized to receive fluoxetine 90 mg/week, fluoxetine 20 mg/day, or placebo for 25 weeks. The 178 patients who relapsed during phase II and chose to enter phase III were entered into three treatment cells: placebo-treated subjects received fluoxetine 20 mg/day, subjects receiving fluoxetine 20 mg/day were increased to 40 mg/day, and those receiving 90 mg once per week were increased to 90 mg twice per week. Most patients (60% to 70%) rapidly recovered and sustained improvement with this re-initiation or increase in fluoxetine levels.

Substitution

Uncontrolled studies suggest that switching to an antidepressant with a different mechanism of action improves response rate.10 Prior to the advent of SSRIs, switching antidepressant classes generally referred to switching therapy in poorly responding patients from a TCA to an MAOI. Patients with atypical depression11 or anergic bipolar patients12 seemed to respond more robustly to MAOIs. There are some older data that show that switching from a TCA to an SSRI improves response rates by 43% to 75%.13 It is doubtful that this improvement in response rates represents a true efficacy advantage. It more likely represents the benefits associated with a significant reduction in side-effect burden, allowing a more effective dose to be achieved.

There are two studies on the switch from an SSRI to a TCA. In one small study of 15 patients,14 individuals who did not have a good response to paroxetine treatment were openly switched to imipramine treatment.14 Peselow and colleagues reported a 73% response rate with imipramine treatment. Thase and colleagues15 investigated the benefits of switching individuals with chronic depression who did not respond to sertraline treatment to imipramine treatment and reported that 44% of these patients responded to the imipramine therapy. When switching from an SSRI to a TCA, one must monitor for drug-drug interactions since co-administration of certain SSRIs may result in elevated TCA drug levels.

Although not as plentiful as the TCA-SSRI data, there is evidence suggesting that a switch from an SSRI to another class of antidepressant facilitates a response in some patients with TRD. A change in class from SSRIs to the SNRI venlafaxine has been most extensively studied. Medication options for patients who do not have an adequate response to an optimal dose of an SSRI could include bupropion, trazodone, venlafaxine, nefazodone, duloxetine, or mirtazapine treatment. All of these antidepressant medications have mechanisms of action that are distinctly different from the SSRIs and from each other. Bupropion is thought to enhance dopamine (DA) and norepinephrine (NE) neurotransmitter activity, trazodone has partial serotonin-agonist (5-HT) activity, venlafaxine inhibits reuptake of NE and serotonin at higher doses, nefazodone acts as an SSRI and 5-HT2 antagonist, duloxetine inhibits reuptake of both serotonin and norepinephrine, and mirtazapine acts on NE and serotonin through α2 and 5-HT1A receptors. Similar to the logic behind the switch from an SSRI to a TCA, the theoretical rationale for the switch is to recruit additional or different neurotransmitter system interactions into the attempt to treat the depressive disorder.

There is evidence supporting and arguing against switching within the SSRI class. The argument in favor of the SSRI-to-SSRI switching strategy is that the structural diversity among the SSRIs is so great that there may be benefit either because of differences in side-effect profiles or because of actions on second neurotransmitter systems. For example, in ex vivo models, high doses of paroxetine increase noradrenergic activity, and high doses of sertraline seem to increase dopaminergic activity. The argument against switching within class is that all SSRIs work via serotonin reuptake inhibition and, therefore, have a similar, if not identical, mechanism of action. Thus an SSRI-to-SSRI switch may be conceptualized as not representing any form of treatment alternative to continuing on the initial SSRI. Additionally, if a patient does not tolerate one SSRI because of class side effects, it is unlikely that the patient will tolerate side effects of a second SSRI.

At this time there is no definitive evidence suggesting greater benefit for either of the two most commonly employed options, substitution or augmentation therapy.16 In general, it is believed that nonresponders may benefit from switching, and partial responders may benefit from augmentation, but more empirical evidence is needed to validate this viewpoint. At this time, the choice of approach is frequently determined by other factors such as cost, drug interactions, and patient compliance.17

Combination

There are a number of small studies that combine two antidepressants of different classes. Most of the work in this area involves combining TCA and SSRI antidepressants. The combination of fluoxetine and desipramine was studied in an open 4-week trial.18 Fourteen inpatients with major depression were given fluoxetine and desipramine in combination and were retrospectively compared with 52 similar inpatients that received fluoxetine alone. One week after treatment, the Hamilton Rating Scale for Depression (HAM-D) score change was 42% in the combination treatment group and 20% in the fluoxetine-alone group. After 4 weeks of therapy, 71% of the patients receiving combination therapy achieved remission, while only a few of the fluoxetine patients were completely symptom free.

Combining a TCA with an SSRI may reduce the time it takes for a patient to respond to treatment. In an open study, Rosenthal and colleagues19 found that 10 refractory patients responded within 24 hours to 2 weeks when fluoxetine was added to heterocyclic antidepressants. Studies combining buspirone with SSRI treatment have had mixed results. Buspirone acts as a full agonist at the presynaptic 5-HT1A autoreceptor and as a partial agonist at the postsynaptic autoreceptor. This acutely decreases extracellular serotonin concentrations through activation of 5-HT1A presynaptic autoreceptors. However, over a longer time period, the 5-HT1A presynaptic auto receptors downregulate, while the postsynaptic receptors do not, so that the end result is an increase in postsynaptic serotonergic tone.

Very frequently, bupropion is employed in combination strategy. Debattista and colleagues20 examined 28 SSRI-resistant depressed patients in an open study in which bupropion sustained release (SR) 150–300 mg was added to the SSRI-based treatment regimen. Fifty-four percent of patients responded (shown by a decrease in HAM-D of 50%) by week 6 of combination therapy. Bupropion’s noradrenergic action enhances the SSRIs antidepressant efficacy in addition to helping with apathy or anorgasmia induced by SSRIs. Other atypical antidepressants have been studied in combination with SSRI therapy. Carpenter and colleagues21 examined mirtazapine as a combination therapy with SSRIs. Mirtazapine 15–30 mg QHS was added to the current antidepressant regimens of 20 patients with persistent symptoms of major depressive disorder (MDD) or dysthymia. Four weeks after treatment, 11 out of 20 patients (55%) responded, 6 out of 20 (30%) did not respond, and 3 out of 20 (15%) did not tolerate the weight gain, sedation, or fatigue effects. Mirtazapine’s unique mechanism of action may account for its success in augmentation. Its noradrenergic antagonist (at the α2 autoreceptor) and serotonergic agonist increases noradrenergic and serotonergic tone. There are two case reports of both mania and hypomania resulting from the SSRI–mirtazapine combination.

Whenever antidepressants are combined, the clinician should titrate the second antidepressant carefully and monitor for drug interactions, especially if one of the drugs is an SSRI.

Somatic Therapies

Electroconvulsive therapy (ECT), light therapy, vagus-nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) are the most common somatic therapies used in patients with TRD. In general, somatic therapies, with the exception of ECT, are less well-studied and are less frequently used.

There is a report that right unilateral ECT is superior to paroxetine in 39 subjects with TRD.22 Another retrospective study comparing continuation ECT with antidepressant versus antidepressant alone in patients with chronic depression found the ECT-plus-medication combination superior to medication alone with respect to relapse, recurrence, and patient survival.23

VNS treats depression by implanting a battery device in the chest area of the patient and attaching wires to the vagus nerve. A side effect is voice hoarseness which is usually related to current intensity. The best candidate for the VNS procedure is ECT naive and has fewer than six previous antidepressant trials.24 VNS may prove to be more effective when it is administered for a longer period of time, with higher or more sustained doses.25 VNS has not been approved in the United States for TRD at this time.

rTMS is being studied as an option for TRD. The parameters for efficacy and safety of rTMS are not well-established. One study comparing sub-threshold rTMS for 2 weeks to sham therapy in treatment-resistant patients did not demonstrate superiority, but more research is needed.26

Bright-light therapy is effective in seasonal affective disorder (SAD), particularly winter depression. One study found that a 2-week course of bright-light therapy added to antidepressant medication was helpful in 7 out of 10 depressed patients who failed one trial of medication.27

Augmentation

Interest in augmentation strategies has waxed and waned over the last several decades. Prior to 1987, TCAs, MAOIs, and heterocyclic compounds were the only available medications for the treatment of MDD. There was active pursuit of trials with lithium and thyroid hormone. However, interest in augmentation research diminished with the advent of SSRIs, which were thought to be safer, better tolerated, and potentially more effective for certain types of depression. After 15 years of use, the strengths and limitations of the SSRIs and SNRIs have been realized. As previously discussed, only 40% to 70% of patients respond well to initial treatment with these agents, and only approximately 35% actually achieve remission.28 This led to a re-emergence of interest in treatment augmentation research. The advent of the atypical antipsychotic medications and atypical antidepressant medications increases our appreciation for the complex pathophysiology of mood and anxiety disorders. It is apparent that mood regulation involves multiple neurotransmitter systems, and this widens the potential for chemical manipulation and, thus, treatment options.

Augmentation therapy involves adding a second agent (one that is not routinely regarded as an antidepressant) to the therapeutic regimen when there is a partial response to the antidepressant agent. Lists of common augmentation agents (Table 2), their mechanisms of action (Table 3), and dosing strategies (Table 4), are provided.

 

Lithium

There are case reports, as well as both controlled and open studies, suggesting that lithium augmentation is effective. A group of case series reported response rates of 30% to 65% for lithium augmentation. In 22 clinical reports, the overall response to lithium augmentation was 71%.29 Overall, the response rates from double-blind studies seem to be approximately 50%.30

The usual starting dose for lithium is 150 mg BID. Lithium is adjusted upward to a blood level of 0.4–0.8 mEq/L. It is not clear how long lithium augmentation should continue if the patient responds to treatment. Time of response to lithium augmentation varies with some reports of response occurring in 48 hours, and other responses up to 2–4 weeks.31 It is not known how long the clinician is to keep trying in cases of no response, but general practice is to discontinue the lithium in the nonresponsive patient after 2 weeks.

Lithium enhances serotonergic transmission by reducing the activity of postsynaptic 5-HT1 serotonin receptor, thus reducing the negative feedback to the presynaptic 5-HT1 receptor that regulates serotonin release into the synaptic cleft. Common side effects of lithium therapy include polyuria, polydipsia, mild tremor, and weight gain.

Thyroid Hormone

The benefits of augmentation with triiodothyronine (T3) are well-documented for TCAs and MAOIs, but less well-documented for SSRIs. The combination of T3 with TCA is effective augmentation strategy. T3 increases response to antidepressants by 60% in patients with TRD.32 There is much less evidence for a SSRI-plus-T3 combination, but anecdotal evidence is promising. Lithium 900 mg/day and T3 37.5 mg/day were compared with placebo in patients who failed to respond to a trial of TCA. Both lithium and T3 showed 50% of patients responded with a decrease in HAM-D by 50%, and both were superior to placebo.33

The most common dose range for T3 is 25–50 mcg/day. Thyroid function tests are obtained prior to administration, and the patient is monitored for signs of hyperthyroidism. Response usually occurs within the first 14 days. Typically, if there is no response by 3 weeks, T3 is discontinued. It is not known how long a patient that responds to treatment should be maintained on T3, though, in most of the studies, maintenance lasted 2–3 weeks.

Thyroid augmentation potentiates noradrenergic activity in the central nervous system. The specific mechanism of how this benefits mood is not clear. Untoward side effects are cardiac irritability, interference with thyroid function, nervousness, and sweating. T4 is not effective, and T3 is not effective alone as antidepressant therapy.

Atypical Antipsychotics

There are several theories postulated as to the exact mechanism of SSRI augmentation by the atypical antipsychotic medications.34 One theory is that the antiserotonergic activity of the atypicals actually improves NE function in the prefrontal cortex, thus increasing the number of neurotransmitter systems activated. When both serotonin and norepinephrine systems are activated, there may be an increase in neuronal nuclear activity, affecting second-messenger systems and protein production that ultimately affects functions of energy, mood, and cognition. This translates clinically into recovery, and, hopefully, remission.

There may be a specific unique effect on the NE, DA, and 5-HT neurotransmitter systems with the olanzapine-fluoxetine combination. With fluoxetine treatment, serotonin increases, and, with the addition of olanzapine, extracellular NE and DA concentrations increase in the prefrontal cortex.35

The evidence for efficacy of the atypical antipsychotic augmentation in TRD is promising. There are a series of open-label trials looking at the use of ziprasidone, risperidone, and olanzapine augmenting SSRI antidepressant response.

Twenty patients with TRD who failed SSRI therapy had ziprasadone 40–160 mg added to SSRI medication over 6 weeks. Out of the 13 patients completing the trial, 8 responded and 5 remitted.36

In another open trial, risperidone was added for eight depressed patients undergoing SSRI therapy. All 8 patients responded and specifically improved in sleep and sexual dysfunction.37

In another open study,38 patients received a combination of risperidone and fluvoxamine. Eighty-nine percent of the depressed patients responded within 4 weeks.

The olanzapine-fluoxetine combination has been studied in both open and controlled settings. In a large open-label study of 560 depressed patients, not all treatment-resistant, patients received olanzapine and fluoxetine in combination for 76 weeks. Response and remission rates for the TRD study population were 53% and 44%, respectively.39 Only 25% of the TRD population relapsed during the 76-week period of treatment.

In a double-blind, controlled study by Shelton and colleagues,40 28 patients with recurrent resistant MDD were randomized to 1 of 3 treatments: olanzapine 5–20 mg/day plus placebo, fluoxetine 20–60 mg/day plus placebo, or olanzapine plus fluoxetine. The group receiving combination therapy did better than either of the groups treated with monotherapy. Furthermore, the combination treatment group experienced improvement within 1 week of therapy.

Olanzapine may do more than simply augment the antidepressant effect of fluoxetine. Marangell and colleagues41 treated 21 patients with remitted SSRI-treated MDD, with olanzapine  2.5–5 mg/day for 8 weeks for SSRI-induced apathy. Apathy was defined as a score of =31 on the Apathy Evaluation Scale (AES) and a Montgomery-Asberg Depression Rating Scale (MADRS) item 8 (inability to feel) =2. Following the addition of olanzapine, both the apathy and the depression scores improved.

Inositol

There is not much evidence supporting the use of inositol (a simple isomer of glucose that precurses phosphatidyl-inositol (PI) second messenger cycle) as an augmentation agent. There is a double-blind, controlled 4-week trial by Levine and colleagues42 comparing SSRI and placebo to SSRI with inositol, which found no significant difference between the two treatment groups. Inositol may have benefit for bulimia nervosa and anxiety disorders. A double-blind crossover trial using inositol 18 g versus placebo was performed with 12 patients for 6 weeks. Inositol was significantly better than placebo as determined by scores on the Global Clinical Impressions scale.43 Inositol 18 g was comparatively better than fluvoxamine 150 mg/day in reducing the number of panic attacks per week (4 versus 2) in patients with panic disorder.44 In rats, inositol increases activity levels, reduces immobility time in the forced swim test, and reduces anxiety in the elevated plus-maze.45

Inositol is frequently prescribed as myo-inositol 12–18 g/day. The dose range for antidepressant augmentation is not established. Inositol appeals to patients inclined to use “natural” remedies since it is a simple sugar.

Psychostimulants

There are case reports and case series investigating methylphenidate or dextroamphetamine augmentation of TCA, MAOI, and SSRI antidepressants in patients with TRD. Methylphenidate is thought to work by releasing catecholamines, blocking their reuptake, and possibly inhibiting amine oxidase. It is particularly useful in targeting the somatic symptoms of the medically ill, such as fatigue, decreased appetite, decreased cognitive function, and pain.

There is one case report of methylphenidate augmentation of SNRI where a mildly demented, depressed patient’s mood symptoms did not respond to venlafaxine 225 mg. After methylphenidate 15 mg/day was added, the patient’s mood and activity levels improved.46 There are two case series47,48 in which methylphenidate was added to either a second-generation antidepressant or SSRI, and depressed patients clinically improved. There is one 10-week, open-label trial examining treatment response time in elderly depressed patients treated with a combination of citalopram 20–40 mg and methylphenidate 5–20 mg. In this trial, six out of nine patients met criteria for accelerated response (HAM-D <10 by treatment day 14).49

The usual starting dose for methylphenidate is 5–10 mg 2–3 times daily. Blood pressure and heart rate is monitored with initiation and dose change. Doses are increased by 5 mg increments at each dose until a clinical response occurs. If the patient does not respond at 60 mg/day, it is not likely he will respond to a higher dose. The last dose of the day is given before 4PM to avoid insomnia. Stimulants are avoided in patients with active substance abuse or those who have a history of abusing stimulants.

Side effects are hypotension, hypertension, heart rate variability, agitation, irritability, nervousness, shakiness, tremor, headache, and gastrointestinal (GI) upset. Response is rapid and occurs in a few days of initiation and titration.

Modafinil

Modafinil is indicated for the treatment of narcolepsy but is clinically used for medication-induced sedation. The exact mechanism of action is unclear; however, it is postulated to act in the hypothalamus to stimulate wakefulness. Modafinil acts on multiple neurotransmitter systems; it has weak dopamine-releasing activity, and it inhibits the reuptake of noradrenaline, particularly in the ventrolateral preoptic nucleus. It also regulates cortical serotonergic transmission by amplifying the electroneurosecretory coupling mechanism.50 There is one double-blind placebo-controlled study of modafinil as augmentation of SSRI-refractory patients. Patients were randomized to receive either modafinil 200 mg/day or placebo plus their SSRI. Modafinil improved overall clinical condition in the subset of severely depressed patients (HAM-D > 14) and overall had a 63% response rate compared to a 45% response rate for placebo.51 In a double-blind, placebo-controlled trial that studied modafinil 100–400 mg as an adjunctive treatment for depression, DeBattista and colleagues52 found that modafinil helped treat symptoms of fatigue, but did not differ from placebo in terms of a significant antidepressant effect. Side effects of modafinil therapy include headache, nausea, dizziness, dry mouth, nasopharyngitis, and jitteriness.

Estrogen

Estrogen can positively affect mood in perimenopausal, postmenopausal, and postpartum females. The exact mechanism of action is unknown; estrogen has a complex interaction with the central nervous system and effects ?-aminobutyric acid (GABA), serotonergic, noradrenergic, and cholinergic function. One open study of the estrogen as augmentation agent randomly assigned depressed perimenopausal women to one of three treatment groups: 0.1–0.2 mg estrogen patch, fluoxetine 20 mg, or estrogen plus fluoxetine. At the end of treatment, the estrogen-fluoxetine combination was the most effective, followed by fluoxetine alone, and the estrogen patch.53 The use of estrogen alone as an antidepressant agent has not proved to be helpful. One randomized, controlled study of estrogen versus placebo in depressed postmenopausal women did not find any significant difference between the two treatment groups.54 There are no consistent findings of a correlation between any serum hormone level and severity or presence of mood symptoms.55

While there may be benefit to estrogen therapy for bone, heart, and brain, there may also be substantial risk for certain women who are susceptible to diseases such as uterine or breast cancer. Any woman receiving hormonal therapy as antidepressant augmentation should be aware of her individual risk for these problems.

Omega-3 Fatty Acids

There is general evidence linking omega-3 fatty acids (polyunsaturated fatty acids [PUFAs]) with depressive illness. For example, geographic areas where docosahexaenoic acid (DHA) is prominent in the diet have lower rates of depression.56 Depressed patients are reported to have abnormally low polyunsaturated fatty acids in cell tissue contents.57 There is mixed evidence supporting the use of PUFAs in the treatment of depression. There is one 8-week double-blind placebo-controlled study comparing PUFAs to placebo in depressed patients. Twenty-eight patients with MDD were assigned to receive either placebo or PUFA 9.6 g/day. Patients treated with PUFAs had a significantly decreased HAM-D score compared to the placebo group.58 However, in another double-blind, placebo-controlled study by Marangell and colleagues,59 35 patients with MDD were assigned either placebo or DHA 2 g/day. This study found no difference between placebo and DHA for depression; the response rates were 27% and 23% for DHA and placebo, respectively.

Amantadine

In theory, amantadine works by modulating dopaminergic, MAO, and N-methyl-D-aspartate systems. In the past, it was used with haldol to prevent the occurrence of extra pyramidal symptoms. More recently it has been used as an augmentation agent in TRD.

There is one 4-week open trial60 in which amantadine 300 mg/day was used to augment antidepressant therapy in eight patients with TRD. All eight patients improved by 49% by the end of the study. Females responded more dramatically and in a shorter period of time.60 Side effects of amantadine therapy include dry mouth and sedation.

Pramipexole

 Pramipexole is used in Parkinson’s disease, and acts in the striatum as a dopamine agonist. There is little evidence supporting its efficacy as augmentation therapy for TRD. In one retrospective chart review of 20 patients with either bipolar or unipolar depression treated with antidepressant medication and adjunctive pramipexole, 50% of the bipolar patients and 40% of the unipolar-depressed patients reported some improvement in depressive symptomatology.61 Sixty percent of patients discontinued pramipexole due to either side effects or lack of response.

Steroids

There are two open, small studies evaluating the use of steroids in TRD. In one study, prednisone 7.5 mg was given to patients in addition to their antidepressant. Five of six patients improved.62 In the second study, 10 patients with TRD treated with either sertraline or fluoxetine received dexamethasone 3 mg/day for 4 days; on days 5 and 21, 6 out of 8 patients had significant improvement on mood rating measures. All six of the responders had elevated baseline cortisol levels.63

Herbal Treatments

There are no published data demonstrating the effectiveness of herbal augmentation of antidepressant medication. However, since there are no available pharmacokinetic data for these classes of compounds, any time ginseng, kava root, or St. John’s Wort is used in combination with centrally active medications, there is a risk of some type of untoward drug-drug reaction. One small study examined the use of melatonin SR in TRD. Nine patients with TRD received melatonin SR 5 mg/day up to 10 mg/day. Patients reported better sleep, but not improvement in core mood symptoms.64

Lamotrigine

Double-blind maintenance studies suggest that bipolar depression is responsive to lamotrigine therapy, but there are less data on its efficacy in unipolar depression. In one retrospective chart review of 37 patients, treated with a mean dose of 112 mg lamotrigine for 40 weeks, 21% mildly improved, 40% were much improved, and 37% did not change.65 Patients with shorter duration of depressive symptoms, fewer previous failed treatment trials, comorbid chronic pain, or comorbid anxiety tended to respond better. Two small studies looking at lamotrigine as an adjunctive agent to SSRI in the treatment of unipolar depression found that lamotrigine did not differ significantly from placebo on clinical
measures.66,67

Pindolol

Although there is a reasonable theoretical rationale to suggest that pindolol augmentation should enhance serotonergic neurotransmission, the double-blind trials do not support the initial open-label reports. One double-blind, randomized, controlled, 6-week trial of pindolol augmentation in patients resistant to SSRI monotherapy showed that there was no difference between groups assigned to pindolol 2.5–7.5 mg and those assigned to placebo.68 However, a study by Rabiner and colleagues,69 which examined 5-HT1A receptor occupancy using varied doses of pindolol, found that the 2.5 mg TID dose, a dose commonly used in clinical trials, had a suboptimal receptor occupancy as compared to the 5 mg TID dose, which had modest receptor occupancy. It is therefore possible that the pindolol dose used in the clinical trials was insufficient to demonstrate a response different from placebo.

Conclusion

MDD is a heterogeneous disorder that does not consistently respond to any single antidepressant therapy. Since depression is not a single disorder, it is likely that multiple neurotransmitter systems are involved in its pathogenesis. Response to treatment can be categorized as complete (remission), partial, or not at all. There are multiple modalities of treatment that range from somatic to psychotherapeutic to pharmacologic and combined treatment. Among the pharmacologic treatments, the antidepressants and augmentation agents have differing mechanisms of action so that in cases of partial response, or failure of response, the clinician has a variety of alternative approaches to employ. This article reviews some of the types of therapies available. Use of augmentation strategy improves the neurotransmitter transmission by either augmenting the antidepressant’s targeted neurotransmitter (ie, lithium augmentation of SSRI transmission) or by modulating additional neurotransmitter systems (ie, methylphenidate augmentation of SSRI). This increases neurotransmitter activity which, in turn, modulates second-messenger systems, which, in turn, affects transcription factors, RNA, and protein synthesis. These changes eventually regulate limbic and higher-cortical function, and impact mood, memory, humor, and emotional state. Even with aggressive therapy, a substantial proportion of patients with TRD achieve palliation rather than cure. Much remains to be understood about the final common pathway for the depressive disorders. PP

References

1. Thase M, Howland R, Friedman E. Treating antidepressant nonresponders with augmentation strategies: an overview. J Clin  Psychiatry. 1998;59(Suppl 5):5-12.

2. Nelson C. Managing treatment resistant major depression. J Clin Psychiatry. 2003;64(Suppl 1):5-12.

3. Ayd FJ. Patient compliance. Int Drug Ther Newsletter. 1972;7:33-40.

4. Charney DS, Nelson JC. Delusional and nondelusional uipolar depression. Am J Psychiatry. 1981;138:328-333.

5. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.Arch Gen Psychiatry. 2003;60(11):1079-88. Erratum in: Arch Gen Psychiatry. 2004;61(2):176.

6. Calabrese J, MacFadden W, McCoy R, Minkwitz M, Wilson E, Mullen J. Double-blind, placebo-controlled study for quetiapine in bipolar depression. Poster presented at: Annual Meeting of the American Psychiatric Association; May 1-6, 2004; New York, NY.

7. Thase M. New approaches to managing difficult to treat depressions. J Clin Psychiatry. 2003;64(Suppl 1):3-4.

8. Fava, M, Rosenbaum, JF, McGrath PJ, et al. Lithium and tricyclic     augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry.1994;151:1372-1374.

9. Schmidt ME, Fava M, Robinson JM, Judge R. The efficacy and safety of a new enteric-coated formulation of fluoxetine given once weekly during the continuation treatment of major depressive disorder. J Clin Psychiatry. 2000;61(Suppl 11):851-857.

10. Nemeroff CB. Augmentation strategies in patients with refractory depression. Depression Anxiety.1996-1997;4:169-81.

11. McGrath PJ, Stewart JW, Harrison W, et al. Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmocology Bull.1987;23:169-172.

12. Thase ME, Mallinger AG, McKnight D, et al. Treatment of imipramine- resistant recurrent depression, IV:A double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry.1992;149:195-198.

13. Thase ME, Rush JA. Treatment resistant depression. In: Bloom FE, Kypfer DJ, eds. Psychopharmacology. New York, NY: Raven Press; 1995:1081-1097.

14. Peselow ED, Filippi AM, Goodnick P, et al. The short-and long-term efficacy of paroxetine. HC: B data from a double-blind crossover study and from a year-long term trial vs imipramine and placebo. Psychopharmacology Bull.1989;25:272-276.

15. Thase ME, Rush AJ, Kornstein SG, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry. 2002;59:233-239.

16. Nelson JC. Treatment of antidepressant nonresponders: augmentation or switch? J Clin Psychiatry. 1998;59(Suppl 15):35-41.

17. Nelson JC. Managing treatment resistant major depression. J Clin Psychiatry. 2003;64(suppl 1):5-12.

18. Nelson JC, Mazure CM, Bowers MB, et al. A preliminary open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1998;48:303-307.

19. Rosenthal JS, Kasawan MJ, Hemlock C. et al. Fluoxetine enhancement of heterocyclic antidepressants. In: Amsterdam JD, ed. Refractory Depression. New York, NY: Raven Press;1991:105-108.

20. DeBattista C, Solvason HB, Poirer J, Kendrick E, Schatzberg AF. A prospective trial of bupropion SR augmentation of partial and nonresponders to serotonergic antidepressants. J Clin Psychopharmacol. 2003;23(Suppl 1):27-30.

21. Carpenter LL, Jocie Z, Hall JM, Rasmussen SA, Price LH. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry.1999;60(Suppl 1):45-49.

22. Folkerts HW, Michael N, Tolle R, et al. Electroconvulsive therapy vs paroxetine in treatment resistant-depression—a randomized study. Acta Psychiatr Scand.1997; 96(Suppl 5):334-342.

23. Gange, Furman, Carpenter, Price. Efficacy of continuation ECT and antidepressant drugs compared to long term antidepressants alone in depressed patients. Am J Psychiatry. 2000;157:1960-1965.

24. Sackheim, JA, Rush JA, Geroge MS, et al. Vagus nerve stimulation (VNS) for treatment resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. 2001;25(Suppl 5):713-728.

25. Carpenter LL, Friehs GM, Price LH. Cervical vagus nerve stimulation for treatment-resistant depression. Neurosurg Clin North Am. 2003;14(Suppl 2):275-282.

26. Boutros NN, Guerguieva R, Hoffman RE, Oren DA, Feingold A, Berman RM. Lack of a therapeutic effect of a 2-week subthreshold transcranial magnetic stimulation course for treatment-resisitant depression. Psychiatry Res. 2002;113(Suppl 3):245-254.

27. Levitt JA, Joffe RT, Kennedy SH. Bright-light augmentation in antidepressant nonresponders. J Clin Psychiatry. 1991;52(Suppl 8):336-337.

28. Thase M. New approaches to managing difficult-to-treat depressions. J Clin Psychiatry. 2003;64(Suppl 1):3-4.

29. Alexander B, Perry P. Treatment of refractory depression. Virtual Hospital Clinical Psychopharmacology Seminar; January 2003. Available at: www.vh.org.

30. Bouwer C, Claassen J, Dinan TG, Nemeroff CB. Prednisone augmentation in treatment-resistant depression with fatigue and hypocortisolaemia: a case series. Depress Anxiety. 2000;12(1):44-50.

31. De Montigny C. Lithium addition in treatment-resistant depression. Int Clin Psychopharmacol. 1994;9(Suppl 2):31-35.

32. Joffe RT, Levitt AJ, Sololov ST. Augmentation strategies. J Clin Psychiatry. 1996;57(Suppl 7):25-31.

33. Joffe RT, Singer W, Levitt ASJ, et al. A placebo-controlled comparison of lithium and triiodothyronine agumentation of tricyclic antidepressants in unipolar refractory depression. Arch  Gen Psychiatry. 1993;50:387-393.

34. Zhang W, Perry KW, Wong DT, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and DA in rat prefrontal cortex. Neuropsychopharmacology. 2000;23:250-262.

35. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for training resistant major depression. Am J Psychiatry. 2001;158(1):131-134.

36. Papakostas GI, Perersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry. 2004;65(2):217-221.

37. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999;60:256-259.

38. Hirose S, Ashby CR. An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy. J Clin Psychiatry. 2002;63:733-736.

39. Corya SA, Andersen SW, Detke HC, et al. Long-term antidepressant efficacy and safetly of olanzapine/fluoxetine combination: a 76-week open-label study. J Clin Psychiatry. 2003;64(Suppl 11):1349-1356.

40. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158:131-134.

41. Marangell LB, Johnson CR, Kertz B, et al. Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open label, flexible dose study. J Clin Psychiatry. 2002;63:391-395.

42. Levine J, Mishori A, Susnosky M, Martin M, Belmaker RH. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry. 1999;45(Suppl 3):270-273.

43. Gelber D, Levine J, Belmaker RH. Effect of inositol on bulimia nervosa and binge eating. Int J Eat Disord. 2001;29(Suppl 3):345-348.

44. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind controlled crossover trial of inositol vs fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21(Suppl 3):335-339.

45. Einat H, Belmaker RH. The effects of inositol treatment in animal models of psychiatric disorders. J Affect Disord. 2001;62(Suppl 1-2):113-121.

46. Bader G. Venlafaxine augmentation with methylphenidate for treatment refractory depression: a case report. J Clin Psychopharmacol. 1998;18(Suppl 3):255-256.

47. Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: a case series. Depress Anxiety. 1998;7(Suppl 2):89-91.

48. Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO. Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry. 1996;57(Suppl 2):72-76.

49. Lavretsky H, Kim MD, Kumar A, Reynolds CF. Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry. 2003;64(Suppl 12):1410-1414.

50. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neuroscience. 2001;24(Suppl 12):726-731.

51. Fava M, Thase M, DeBattista. Modafanil as antidepressant augmentation therapy in major depressive disorder. Presented at the 157th Annual Meeting of the American Psychiatric Association; May 1-6, 2004; New York, NY.

52. DeBattista C, Doghramji K, Menza MA, Rosenthao MH, Fieve RR; Modafinil in Depression Study Group. Adjunct modafinil for the short term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double blind, placebo controlled study. J Clin Psychiatry. 2003;64(9):1057-1064.

53. Westland T, Parry B. Does estrogen enhance the antidepressant effects of fluoxetine? J Affect Disord. 2003;77(Suppl 1):87-92.

54. Morrison MF, Kallan MJ, Ten Have, Katz I, Tweedy K, Battistini M. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55(Suppl 4):406-412.

55. Stoppe, G, Doren M. Critical appraisal of effects of estrogen-replacement therapy on symptoms of depressed mood. Arch Women’s Ment Health. 2002;5(Suppl 2):39-47.

56. Mischoulon D, Fava M. Docosahexaenoic acid and omega-3 fatty acids in depression. Psychiatr Clin North Am. 2000;23(Suppl 4): 785-794.

57. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder: a preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(Suppl 4):267-271.

58. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder: a preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(Suppl 4):267-271.

59. Marangell LB, Martinez JM, Zhoyan HA, Kertz H, Kim HF, Puryear LJ. A double-blind placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003;160(Suppl 5):996-998.

60. Strjer R, Strous RD, Shaked G, et al. Amantadine as augmentation therapy in the management of treatment-resistant depression. Int Clin Psychopharmacol. 2003;18(Suppl 2):93-96.

61. Sporn J, Ghaemi SN, Sambur MR, et al. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry. 2000;12(Suppl 3):137-140.

62. Bouwer C, Claassen J, Dinan TG, Nemeroff CB. Prednisone augmentation in treatment-resistant depression with fatigue and hypocortisolaemia: a case series. Depress Anxiety. 2000;12(1):44-50.

63. Dinan TG, Lavelle E, Cooney J, et al. Dexamethasone augmentation in treatment-resistant depression. Acta Psychiatr Scand. 1997;95(1):58-61.  

64. Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci. 2000;25(1):48-52.

65. Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry. 2002;63(Suppl 8):737-741.

66. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry. 2003;64(Suppl 4):403-407.

67. Normann C, Hummel B, Scharer LO, et al. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study. J Clin Psychiatry. 2002;63(Suppl 4):337-344.

68. Perry EB, Berman RM, Sanacora G, Anand A, Lynch-Colonese K, Charney DS. Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. J Clin Psychiatry. 2004;65(Suppl 2):238-243.

69. Rabiner LE, Bhagwager Z, Gunn RN, et al. Pindolol augmentation of selective serotonin reuptake inhibitors; PET evidence that the dose used in clinical trials is too low. Am J Psychiatry. 2001;158(12):2080-2082.