Targum_Art_Mar-Apr_2014by Steven D. Targum, MD
Dr. Targum is with Clintara, LLC, Boston, Massachusetts.

Innov Clin Neurosci. 2014;11(3–4):24–28

Funding: There was no funding for the development and writing of this article.

Financial disclosures: Dr. Targum has equity interests in Clintara LLC, Prana Biotechnology Ltd., and Methylation Sciences Inc. He has received funding and/or consultation fees from the following pharmaceutical sponsors: Acadia Pharmaceuticals, Alcobra, Alkermes Inc., AstraZeneca, BioMarin, BrainCells Inc., Civitas, Eli Lilly and Company, EnVivo Pharmaceuticals, Euthymics, Forest Research, Functional Neuromodulation inc, Johnson & Johnson PRD, Ironwood Pharmaceuticals, Methylation Sciences Inc., Mitsubishi Tanabe, NeoSync, Novartis Pharmaceuticals, Nupathe, Pfizer Inc., ReViva, Roche Labs, Sophiris, Sunovion, Takeda, Targacept, Theravance, and Transcept.

Key words: Antidepressant, antidepressant tolerance, antidepressant tachyphylaxis, drug tolerance, major depressive disorder, breakthrough depression

Abstract: Antidepressant tachyphylaxis describes a condition in which a depressed patient loses a previously effective antidepressant treatment response despite staying on the same drug and dosage for maintenance treatment. It has been suggested that antidepressant tachyphylaxis is a form of relapse related to evolving drug tolerance, but it is also clear that there are other possible reasons for the loss of treatment response unrelated to tolerance, such as medication nonadherence. It has been reported that depressed patients with “true” antidepressant tachyphylaxis may be less responsive to new treatment interventions. Therefore, it is important to identify these patients as part of a comprehensive treatment planning process.


Many patients with major depressive disorder (MDD) will experience a recurrent depressive episode despite receiving an adequate maintenance dose of an antidepressant medication.[1–3] The condition of losing a previously effective response while still on adequate treatment is known as antidepressant treatment (ADT) tachyphylaxis.[1,3–6] ADT tachyphylaxis (also known as antidepressant tolerance, antidepressant “poop-out,” or “breakthrough” depression) describes a recurrent depressive episode that is a form of relapse. As a loss of response, ADT tachyphylaxis is distinct from a non-response to treatment (resistance) or a partial (inadequate) ADT response. Previous exposure to long-term ADT may be a factor in the development of antidepressant drug tolerance.[4]

The Incidence of ADT Tachyphylaxis

ADT tachyphylaxis (or “poop-out”) was initially recognized in patients receiving monoamine oxidase inhibitors (MAOIs) before the advent of selective serotonin reuptake inhibitors (SSRIs) in the early 1980s.[1,4,5,7] Patients who lost their initial response to a MAOI responded poorly to subsequent treatment and revealed greater depressive severity after relapse than before the new treatment was initiated.[7,8] SSRIs were introduced in the United States in 1988 and ADT tachyphylaxis was subsequently identified with these drugs as well.[3,9,10] Fava et al found that 26 of 77 depressed patients (33.7%) who had achieved full remission of symptoms on fluoxetine 20mg daily experienced a recurrence of symptoms (ADT tachyphylaxis) between 14 and 54 weeks despite maintenance treatment.[10] In another small study, 15 patients who had lost their response to antidepressants failed multiple treatment strategies including augmentation with mood stabilizers and, in some cases, electroconvulsive therapy.[11] Therefore, it appears that patients who experience ADT tachyphylaxis may be less responsive to subsequent treatment interventions.

The incidence of true ADT tachyphylaxis in contrast to other explanations for an apparent loss of antidepressant response (pseudo-tachyphylaxis) is not known.[9,12] Frank and colleagues reported that 18 percent of patients initially responding to imipramine in a three-year treatment maintenance study relapsed during that time period.[2] From a meta-analysis of studies published prior to 1993, Byrne and Rothschild[3] calculated the rate of ADT tachyphylaxis to be between 9 and 33 percent of treated, depressed patients.[3] Recently, the National Institute of Mental Health Collaborative Depressive Study reported that the rate of ADT tachyphylaxis was 25 percent.[9] In this 20-year follow-up study of 103 MDD patients, ADT tachyphylaxis occurred in 43 of the 171 subsequent recurrent depressive episodes (25%) experienced by these patients.[9]

The Identification and Differential Assessment of ADT Tachyphylaxis

The recognition of true ADT tachyphylaxis requires a differentiation from several other potential reasons that a patient might lose a previously efficacious treatment response. For instance, it is important to confirm that the patient actually has a recurrent MDD as opposed to other psychiatric conditions (a cycling bipolar disorder or comorbid substance use problem) that may compromise a sustained antidepressant treatment response. Some other possible reasons for a loss of antidepressant response include 1) medication nonadherence; 2) increased worsening (severity) of the emerging depressive episode; or 3) the loss of an associated placebo response due to co-existing non-specific factors.[3]

Medication nonadherence. One obvious explanation for apparent antidepressant tachyphylaxis may be that the patient has simply stopped taking the prescribed medication. Clearly, it is important to assess the possibility of nonadherence with the patient prior to initiating any new treatment regimen. A review of pharmacy records can easily document adherence and identify patients who have not been taking medications. Although this is a plausible explanation for some patients, it is clear that many patients do adhere to medication regimens and still experience recurrent depression despite maintenance treatment.

Increased worsening of the underling depressive episode. An evolving increase of the severity of depressive symptoms during the course of illness may explain the loss of an apparent initial treatment response in some depressed patients.3 In these cases, mild to moderate depressive symptoms may become more severe despite the initial dose of antidepressant treatment. Consequently, these patients are not really drug tolerant but have, instead, an inadequate (partial) response to their prescribed medication. Patients who have increasing severity of depressive symptoms despite an initial treatment response may improve by simply increasing the dose of the same medication (dose optimization).

Nonspecific factors contributing to early antidepressant response. It is well documented that the true “drug” effect achieved by antidepressants is only part of the overall treatment response that follows the initiation of antidepressant treatment.[13,14] In fact, Lambert suggested that only 15 percent of the putative “drug” effect following antidepressant treatment is actually due to the drug itself.[13] Similarly, in a meta-analysis of 19 randomized, clinical trials for MDD, Kirsch and Sapirstein calculated that the placebo response and other nonspecific factors accounted for nearly 75 percent of the observed symptomatic improvement observed in drug-treated groups.[14] Consequently, nonspecific factors such as the positive effects of the therapeutic relationship or expectation biases about recovery may contribute to an early improvement of symptoms regardless of the treatment regimen. Over time, these nonspecific (nondrug) treatment response components may dissipate such that the severity of residual depressive symptoms increases and yields pseudo-tolerance that is not true ADT tachyphylaxis.

The loss of the nonspecific placebo response cannot fully account for the loss of antidepressant response in many depressed patients. Chronic exposure to antidepressants may have a deleterious effect on the course of the disease.[4] In fact, many MDD patients with ADT tachyphylaxis have a poor response to subsequent treatment interventions and are often described as treatment resistant.[12,15] Fava suggested that depressed patients who receive chronic treatment might develop an antidepressant-induced recurrent depression that is not always reversible.[16,17] If these treatment-resistant (TRD) patients respond at all to any subsequent antidepressants, the extent of improvement is usually less robust than their initial response.[5] In support of these findings, Amsterdam and colleagues found that the number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio=0.81, p=0.0035) and noted that this odds ratio conveyed a 19.9-percent reduced likelihood of response in the current episode with each prior antidepressant treatment trial.[18]

The specific recurrent depressive symptoms seen in many patients with ADT tachyphylaxis may aid in the differentiation of these patients from the other possible reasons for a loss of treatment response. Rothschild and colleagues suggested a conceptualization of ADT tachyphylaxis characterized by symptoms of apathy (or lassitude or decreased motivation), fatigue, dullness in cognitive function, sleep disturbance, weight gain, and sexual dysfunction.[12,19] Rothschild developed the RSAT (Rothschild Scale for Antidepressant Tachyphylaxis) that contains six self-report items (energy level, motivation and interest, cognitive functioning, weight gain, sleep, and sexual functioning) and one clinician-rated item for affect.[19] Each item of the RSAT is rated on a 5-point scale and has anchor points to assist scoring. The RSAT does not correlate with the severity of depression as rated by the Hamilton rating scale for depression (HAM-D) or the HAM-D mood item supporting the discriminant validity of the RSAT for tachyphylaxis.

The Etiology of ADT Tachyphylaxis

There are numerous possible explanations for the development of ADT tachyphylaxis. Several reports and reviews have suggested that ADT tachyphylaxis may result from an evolving drug sensitization that causes a pharmacokinetic and/or pharmacodynamic tolerance to the previously effective concentration or actions of the drug.[3,16] In this regard, prolonged antidepressant treatment may induce sensitization changes not unlike the tolerance/dependence issues induced by chronic benzodiazepine exposure.

Pharmacokinetic tolerance is defined as changes that occur in drug concentration at the target site resulting from absorption, distribution, biotransformation, or elimination of the drug. In this case, patients who lost response to one dose of the drug might respond to a higher dose. For instance, Fava and colleagues reported that some depressed patients with apparent tachyphylaxis while taking maintenance fluoxetine 20mg responded to an increased dose of 40mg.[10]

Pharmacodynamic tolerance involves adaptations at a cellular or subcellular level that comprise changes in the sensitivity and/or number of receptors, second-messenger systems, or ion channels. For instance, down regulation of five HT1a receptors might be responsible for the loss of antidepressant effects in some patients.[4,7] Fava has proposed an oppositional model of drug tolerance suggesting that prolonged drug treatment actually recruits oppositional neurobiological processes that may actually increase vulnerability to relapse and/or refractoriness to treatment.[16] This model suggests that prolonged antidepressant treatment can induce permanent neurobiological changes in the underlying pathophysiology of the depressive disorder. Consistent with this idea, it is possible that chronic exposure may alter the process of hippocampal neurogenesis that has been implicated in the antidepressant effect.[20] El-Mallakh et al proposed that neuroplastic processes related to dendritic arborization following chronic antidepressant use might foster the emerging tachyphylaxis.[21] Since the prodepressant effect is seen after prolonged antidepressant use, these authors suggested the term tardive dysphoria to describe the condition.[21] These putative models would explain why patients experiencing ADT tachyphylaxis are often less responsive to subsequent treatment interventions.

Treatment Strategies for ADT Tachyphylaxis

The obvious first step in treating ADT tachyphylaxis in depressed patients is to identify the condition and to clearly differentiate true ADT tachyphylaxis from other conditions (“pseudo” tachyphylaxis), such as medication non-adherence or inadequate dose or duration of treatment.

A comprehensive assessment for ADT tachyphylaxis requires re-visiting the psychiatric diagnosis (Is it really MDD?) as well as a review of the psychopharmacological history, comorbid medical history, current treatment response pattern, and documentation of medication adherence.

In addition, it is important to consider possible confounding factors that might obscure the identification of true ADT tachyphylaxis. For instance, patients with bipolar disorder may appear to lose their ADT response but could actually be cycling through different stages of illness severity. Similarly, comorbid personality disorders may influence the way some patients perceive their depressive symptoms, and these patients may be profoundly affected by environmental situations. Alternatively, a loss of ADT response may be related to comorbid medical conditions, like a gastrointestinal absorption problem that adversely affects the potential efficacy of the antidepressants.

In some patients, the psychopharmacologic history may reveal a record of inadequate dose or duration of treatments or a pattern of response (abrupt improvement followed by gradual recurrence of symptoms) that suggest a propensity toward placebo response.

As noted above, it is well documented that many patients simply stop taking their prescribed medications. Therefore, a review of medication adherence with the patient (perhaps a review of pharmacy records as well) to affirm that a previously effective dose response has in fact been lost may be a meaningful first step prior to initiating a new treatment.

There is limited research about specific treatment strategies for ADT tachyphylaxis, but the treatment options are essentially those employed for any patient who has experienced a relapse or for treatment-resistant patients. These strategies need to be customized for each patient and his or her specific clinical circumstances. Although it is not the intent of this paper to fully explore the treatment options for ADT tachyphylaxis, we will briefly explore several options including adjustment of the current antidepressant dose, drug holidays, changing to a different drug, and augmentation strategies.

Increasing the current antidepressant dose. It is clear that patients respond to a range of different antidepressant doses and may need more than six weeks to respond to the treatment. The history of psychopharmacology reveals that many patients have simply taken too little medication for too short a duration to achieve an adequate treatment response. Non-psychiatric clinicians, in particular, may underdose a patient to avoid potential adverse event liability. Increasing the dosage of the current antidepressant is probably the first, most logical treatment strategy for patients with apparent ADT tachyphylaxis.[3]

However, it is noteworthy that increasing the dose does not always work or sustain clinical response. Schmidt and colleagues examined the effectiveness of dosage increases in depressed patients who had lost their treatment response (tachyphylaxis) during maintenance therapy with fluoxetine 20mg or with an enteric-coated 90mg weekly dose.[22] Doubling the dose of fluoxetine from 20 to 40mg daily was effective in 57 percent of these patients, and doubling the enteric-coated 90mg from once weekly to twice weekly was effective in 72 percent of these patients. The latter response rate of 72 percent is high and suggests that nonspecific factors (e.g., high expectation bias) may have enhanced the positive response to the dosage increase beyond the mere drug effect. In fact, 20 percent of these responsive patients relapsed again during the 25 weeks of this trial suggesting that the dosage increase alone was not sufficient to sustain remission. Hence, an increase in medication dosage does not always sustain clinical response in true ADT tachyphylaxis.

Drug holidays or decreasing the current antidepressant dose. It is well known that psychotropic medications and drug combinations, in particular, can cause adverse events that accentuate clinical symptoms and may impede the potential clinical benefit of the drug. It is also known that classic drug tolerance or dependence, such as that induced by opioid drugs is treated by a gradual withdrawal of the drug to facilitate a restoration of the normal state. Similarly, the institution of a drug holiday for patients afflicted by ADT tachyphylaxis is a reasonable strategy if it can be accomplished safely.

The requisite length of a drug holiday for patients with ADT tachyphylaxis is not known, although the minimum interval may need to be at least 3 to 4 weeks to restore receptor sensitivity. It may not be clinically feasible to completely discontinue pharmacologic treatment via drug holidays in some patients.

Although it may seem somewhat counter-intuitive, depressive symptoms may improve in some patients when the dosage is simply reduced. In their paper discussing antidepressant tachyphylaxis, Byrne and Rothschild cite several case reports describing a symptomatic recovery of the initial antidepressant efficacy when the dosage of an SSRI was actually lowered.[3]

Changing antidepressant drugs (to the same mechanism or a different mechanism of action). A proposed etiology of ADT tachyphylaxis suggests that there is an evolving combination of pharmacodynamic and pharmacokinetic tolerance to the current antidepressant medication. Although switching to a drug with a similar mechanism of action may work, it may be more prudent to introduce a drug that has an entirely different mechanism of action in order to regain the previously effective treatment response blunted by drug tolerance. Obviously, switching medications in acutely ill patients can be challenging and must be conducted carefully because it generates new concerns related to possible discontinuation side effects or the exacerbation of depressive severity. Generally, patients are weaned (transitioned) from one agent while another medication is introduced. These challenging transitional issues may warrant the use of augmentation strategies in lieu of simply switching antidepressant medications.

Augmentation strategies for ADT tachyphylaxis. It is not surprising that many patients with MDD receive more than one medication in order to treat residual symptoms and sustain the antidepressant response.[23,24] Clinicians have explored several different augmentation/combination strategies including the addition of dopaminergic agonists (e.g., bupropion), tricyclic antidepressants, buspirone, mood stabilizers (e.g., lithium, valproic acid, lamotrigine), antipsychotic medications (e.g., quetiapine, aripiprazole), S-adenosylmethionine (SAMe) or methylfolate, thyroid supplementation, stimulants (e.g., amphetamine, methylphenidate, pemoline), and blocking 5-HT1 receptor sensitization with pindolol.[23–26]
The subject of augmentation and combination treatment strategies is beyond the scope of this paper and warrants separate consideration.

Summary and Conclusion

It is well known that MDD is a recurrent illness and that many patients experience numerous depressive episodes during their lifetime. Some depressed patients have an efficacious response to antidepressant medication but subsequently lose the clinical efficacy and experience a recurrence of their depressive symptoms despite ongoing maintenance treatment. This condition of losing a previously effective antidepressant response while on adequate treatment is called antidepressant tachyphylaxis and is a form of relapse that may auger an increased vulnerability to recurrent depressive episodes and refractoriness to future treatment efforts. The rate of ADT tachyphylaxis is estimated to be approximately 25 percent of treated, depressed patients, although other causes for relapse while on maintenance treatment (such as medication nonadherence) may be embedded in this estimate. It has been suggested that the etiology of ADT tachyphylaxis is due to evolving pharmacokinetic and/or pharmacodynamic tolerance resulting from chronic exposure to antidepressants. Available treatment strategies to address ADT tachyphylaxis are similar to those employed for any depressed patient who has relapsed or is treatment resistant, and should be customized for the specific clinical circumstances of the patient. Future research is needed to ascertain whether the risk for ADT tachyphylaxis is generic among all patients receiving antidepressant medications or whether there are specific risk factors that might predispose some depressed patients to this condition.

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