Journal of Affective Disorders 245 (2019) 488–497

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Tachyphylaxis in major depressive disorder: A review of the current state of T

research
Gustavo Kinrysa,b, , Alexandra K. Goldc, Vincent D. Pisanoa, Marlene P. Freemana,b,
⁎

George I. Papakostasa,b, David Mischoulona,b, Andrew A. Nierenberga,d, Maurizio Favaa,b

a
Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, MA, USA
b
Harvard Medical School, Boston, MA, USA
c
Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA
d
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

ARTICLE INFO ABSTRACT

Keywords: Background: Patients with major depressive disorder (MDD) often experience a re-emergence or worsening of
Tachyphylaxis symptoms despite ongoing treatment with previously effective antidepressant pharmacotherapy. This lost or
Major depressive disorder reduced antidepressant response during maintenance, referred to as tachyphylaxis, negatively impacts treatment
outcomes and quality of life for patients with MDD. This review assesses the prevalence of antidepressant ta-
chyphylaxis as well as the evidence for interventions to manage it.
Methods: We searched PubMed/Medline for the relevant clinical trials and meta-analyses on antidepressant
tachyphylaxis up to January 2017. Search terms included “depression” paired with “treatment” (n = 186,674),
“tachyphylaxis” paired with “depression” (n = 112), “tachyphylaxis” paired with “major depressive disorder”
(n = 21), and “antidepressant” paired with “tachyphylaxis” (n = 68). Studies were included if they reported on a
clinical trial or meta-analysis exploring tachyphylaxis in MDD and were excluded if the sample population did
not have a primary DSM diagnosis of MDD.
Results: Rates of tachyphylaxis varied from 9% to 57% depending on the patient population and duration of
follow-up. Limited evidence suggests potentially beneficial strategies for managing tachyphylaxis, including
change in antidepressant dosing, switch of class of antidepressant medication, augmentation or combination
pharmacotherapy, and psychotherapy.
Limitations: Studies of antidepressant tachyphylaxis are largely heterogeneous in nature and employ strict in-
clusion/exclusion criteria; thus, these findings may not be generalizable to all depressed populations.
Conclusion: Few established treatment strategies exist to manage antidepressant tachyphylaxis. Further inter-
ventional research is needed to provide symptomatic relief for patients with tachyphylaxis in MDD.

1. Introduction patients who initially respond to antidepressant medication (Emslie et al.,

2005; Keller et al., 2007), a subset of patients experience a return or
Major depressive disorder (MDD) is a chronic and recurring disorder, worsening of depressive symptoms despite continued treatment with a
with a greater number of prior depressive episodes associated with a previously effective antidepressant. Antidepressant tachyphylaxis is best
greater likelihood of relapse (e.g., return of depressive symptomatology; defined as “the loss of efficacy of an antidepressant that had a prior es-
refer to Keller et al. (1983) and recurrence (e.g., new episode of MDD tablished response (Lieb and Balter, 1984).” This loss of response can
during the maintenance phase that follows the continuation phase; refer to occur as a relapse or as a recurrence. Tachyphylaxis can occur within the
Solomon et al. (2000) , Keller et al., (1983, 2007); Solomon et al., (2000); continuation phase and beyond into the maintenance phase
Thase and Sullivan, (1995). Though continuation antidepressant therapy, (Nierenberg et al., 2003). The term has since evolved to incorporate var-
or continued antidepressant use following an acute episode, decreases the iations such as antidepressant tolerance and antidepressant “poop out”
likelihood of relapse, and maintenance therapy, or long-term anti- (Solomon et al., 2005). A timeline of where these terms fit into a classic
depressant treatment, has been found to reduce recurrence rates in MDD treatment course is presented in Fig. 1.

⁎
Corresponding author at: Massachusetts General Hospital, Clinical Trials Network and Institute, 1 Bowdoin Square, 9th Floor, Boston, MA 02114, USA.
E-mail address: gkinrys@mgh.harvard.edu (G. Kinrys).

https://doi.org/10.1016/j.jad.2018.10.357
Received 5 August 2018; Received in revised form 8 October 2018; Accepted 27 October 2018
Available online 28 October 2018
0165-0327/ © 2018 Elsevier B.V. All rights reserved.

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G. Kinrys et al. Journal of Affective Disorders 245 (2019) 488–497

Fig. 1. Tachyphylaxis within MDD course.

1.1. Risk factors for tachyphylaxis trials of adequate dose and duration that are unsuccessful due to lack of
efficacy are used to measure a patient's degree of treatment resistance
Certain factors appear to increase an individual's risk for developing (Fava, 2003; Sackeim et al., 2001; Thase and Rush, 1997). Tachyphy-
antidepressant tachyphylaxis. Some early studies found that a later laxis may lead to TRD, perhaps through a form of neuro-receptor tol-
lifetime onset of depression, three or more prior depressive episodes, erance or down-regulation. Potential treatment approaches for tachy-
and increased residual symptoms were all independent risk factors for phylaxis and TRD are similar: dose increases, medication switching, and
relapse or recurrence (Georgotas and McCue, 1989). Of note, however, combination or augmentation strategies may all be effective, although
many studies do not make a clear distinction between relapse and re- little research has been done to support one method over the others.
currence (Georgotas and McCue, 1989) and these terms are sometimes
used interchangeably. Risk of tachyphylaxis may also vary according to
1.3. Prevalence of tachyphylaxis in MDD
MDD subtype; for instance, tachyphylaxis prior to the maintenance
phase is twice as likely to occur in patients with melancholic depression
Over the past few decades, several clinical trials have explored the
compared to patients without melancholic depression(Solomon et al.,
recurrence of major depressive episodes among patients receiving
2005). Risk of recurrence also grows after successive depressive epi-
continuation/maintenance therapy. In a series of randomized, con-
sodes; that is, a patient with at least one prior episode of depression has
trolled clinical trials of maintenance therapy lasting up to three years,
a 10-fold greater risk for recurrence than a patient who has not ex-
between 9% and 57% of participants experienced a recurrent major
perienced a prior episode(Thase and Sullivan, 1995). Finally, repeated
depressive episode while receiving active treatment (Byrne and
courses of antidepressant drug therapy may also put an individual at
Rothschild, 1998; Solomon et al., 2005). Studies have also found that
risk(Amsterdam et al., 2009). Amsterdam and Shults (2008) proposed
between 50 and 80% of patients experience ongoing, recurring unipolar
that tachyphylaxis may result from physiological adaptation following
depression (Byrne and Rothschild, 1998; Coryell et al., 1990;
repeated antidepressant exposures as well as a genetic predisposition
Hirschfeld, 1994; Kupfer, 1993; Thase and Sullivan, 1995). Though
for non-response (Amsterdam and Shults, 2008).
prior studies have critically enhanced our understanding of tachyphy-
laxis within depressed populations, their applicability to the wider
population may be somewhat limited. Randomized, controlled clinical
1.2. Tachyphylaxis vs placebo response vs TRD
trials often necessitate strict inclusion criteria and certain symptom
categories are frequently excluded (e.g., psychotic traits, suicidal
There is an important distinction between antidepressant tachy-
ideation, and mild depression). Many potential subjects fall within
phylaxis and a placebo response. Tachyphylaxis is the loss of a true drug
these excluded categories; accordingly, findings from these studies may
response confirmed over an acute period. Placebo response may occur
not be generalizable to the tachyphylaxis-experiencing patient popu-
in patients taking both placebo and active medications. However, 80%
lation as a whole. For the same reason, it is difficult to definitively
of placebo response has been shown to occur in the first half of clinical
measure the frequency at which tachyphylaxis occurs in the general
trials,(Yang et al., 2005) and a significant drug–placebo difference is
population (Solomon et al., 2005).
nearly always noticeable after four weeks of treatment in positive trials
Recent data suggest that tachyphylaxis during long-term anti-
(Walsh et al., 2002). These findings highlight the importance of using
depressant pharmacotherapy affects 25–50% of patients(Amsterdam and
the acute treatment phase to confirm true drug response and to limit the
Shults, 2008). Antidepressant tachyphylaxis thus remains a relevant pro-
diagnosis of tachyphylaxis to the post-acute (e.g., maintenance) phase.
blem for countless patients suffering from depression; accordingly, more
Thus, by definition, an individual can only be experiencing anti-
effective and sustainable treatment approaches for antidepressant tachy-
depressant tachyphylaxis if they have had continuous pharmacotherapy
phylaxis are essential. Despite potential limitations, recent randomized,
treatment. The same is not true for relapse and recurrence: an in-
controlled clinical trials are our best source for understanding current and
dividual can have a depressive relapse or recurrence without having
potential tachyphylaxis treatment options. The objective of the current
received consistent treatment(Katz, 2011). In addition, there is also an
review was to assess the present state of the science regarding anti-
important difference between a failed antidepressant trial and tachy-
depressant tachyphylaxis and clinical management strategies.
phylaxis. A failed antidepressant trial is characterized by initial failure
of an antidepressant to yield improvements in depressive symptoms
(< 50% improvement per patient report). By contrast, tachyphylaxis is 2. Methods
characterized by initial effectiveness of an antidepressant in improving
depressive symptoms (≥ 50% improvement per patient report), with 2.1. Data sources
the antidepressant subsequently losing its effectiveness (Desseilles
et al., 2013; Desseilles et al., 2011). We searched PubMed/MEDLINE for clinical trials and meta-analyses
Tachyphylaxis may play a role in the development of some forms of on antidepressant tachyphylaxis up to January 2017. There was no
treatment-resistant depression (TRD). In the treatment of major de- restriction on the initial date of article publication. We also searched for
pression, multiple steps are often needed before a patient achieves articles discussing the etymology, phenomenology, and assessment of
symptom remission (Crismon et al., 1999). The number of sequential antidepressant tachyphylaxis. Search terms included “tachyphylaxis”

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G. Kinrys et al. Journal of Affective Disorders 245 (2019) 488–497

paired with “depression” (n = 112), “tachyphylaxis” paired with RSAT. The items are all scored within a five-point ordinal scale, with
“major depressive disorder” (n = 21), “antidepressant” paired with anchor points developed to illustrate each rating (Rothschild, 2008).
“tachyphylaxis” (n = 68), and “depression” paired with “treatment” Rothschild (2008) applied the RSAT in a study of 50 patients who had
(n = 186,674). been effectively treated for major depression in the past 4–12 months
yet reported to their psychiatrist that the antidepressant was no longer
2.2. Study selection effective. These patients did not meet criteria for a relapse or recurrence
of MDD as defined by the Hamilton Depression Rating Scale (HDRS
Clinical studies were included if they were an open trial, a rando- score < 12). Rothschild et al. found that both total RSAT score as well
mized clinical trial, a case study, or a meta-analysis that addressed ta- as individual items failed to correlate with either total HDRS score or
chyphylaxis in the context of MDD. Articles discussing the historical individual items. Accordingly, they concluded that the RSAT measured
context or assessment of tachyphylaxis did not necessarily meet these a distinct phenomenon from either relapse or recurrence of MDD (Katz,
criteria. In this review, we did not include any trials of tachyphylaxis in 2011; Rothschild, 2008). The Treatment Response to Antidepressant
bipolar disorder. We also excluded trials in which the primary diagnosis Questionnaire (TRAQ(Posternak et al., 2004)) developed by
was not MDD. We also evaluated the reference lists from selected ar- Posternak et al., (2004) is another useful assessment for collecting
ticles to find papers that could be missing. standardized information regarding antidepressant treatment history,
including the occurrence of tachyphylaxis. The TRAQ is a semi-struc-
2.3. Data extraction tured interview for the documentation of information regarding the
adequacy of trials, nature of response, and previous antidepressant
All selected clinical studies (n = 45) were examined for relevant treatment. With strong reliability and validity, the information supplied
data including tachyphylaxis rates, relapse rates, remission rates, and by the TRAQ can be applied to generate a systematic measure of ta-
treatment outcomes for patients with persistent MDD receiving various chyphylaxis (Posternak et al., 2004). The Massachusetts General Hos-
antidepressant pharmacotherapies. Manuscripts (n = 3) exploring ta- pital Antidepressant Treatment Response Questionnaire (ATRQ,
chyphylaxis-relevant clinical assessments were evaluated for specifics Chandler et al., 2010) is another systematic tool for the assessment of
surrounding content, administration, and clinical utility. treatment history in MDD. The ATRQ defines an adequate duration of
treatment as at least six weeks of an antidepressant trial at an appro-
3. Results priate dosage. The ATRQ also outlines specific parameters for adequate
dosage for a range of commonly used antidepressants (Chandler et al.,
3.1. Tachyphylaxis: a phenomenology 2010; Desseilles et al., 2011). Of note, the exact timeframe of anti-
depressant treatment and antidepressant type/dose are adaptable for
Tachyphylaxis, which has a literal meaning of “rapid protection,” is different studies. Chandler et al., (2010) found the ATRQ to be con-
presently best defined across medical disciplines as increased tolerance cordant in 76.3% of subjects (n = 142) in a study of antidepressant
to a drug that develops following continuous or repeated exposure to medication augmented with low-dose aripiprazole. The ATRQ re-
that drug(Lieb and Balter, 1984; Solomon, 2005). The current usage of presents a user-friendly tool for providers to easily assess prior treat-
the term evolved through a series of papers by Cohen et al., (1968), ment and provides crucial insight regarding treatment history for ta-
Bromage et al., (1969), and Spoerel et al., (1970) that explored the chyphylaxis patients (Chandler et al., 2010). Of note, scales such as the
development of resistance to the effects of local and epidural anes- ATRQ do not themselves determine tachyphylaxis; rather, information
thetics (Bromage et al., 1969; Cohen et al., 1968; Spoerel et al., 1970). from the scale can help guide providers towards additional questions
Cohen et al., (1968) suggested that such tachyphylaxis may be asso- that can distinguish tachyphylaxis from failed antidepressant trials
ciated with changes in pH and alterations in ionized and non-ionized (Desseilles et al., 2013; Desseilles et al., 2011). Overall, studies that
forms of local anesthetics (Cohen et al., 1968), while Bromage et al., have investigated assessments for tachyphylaxis reveal that the clinical
(1969) noted that this acute tolerance emerged with repeated doses of presentation of tachyphylaxis may be distinct from that of a common
local anesthetics (Bromage et al., 1969). Mann (1983) and Zetin et al. depressive episode. As such, it may be useful to create a prototypical
(1983) published the first case studies of tachyphylaxis as it pertained “tachyphylaxis” presentation to help clinicians arrive at proper diag-
to antidepressant medications(Mann, 1983; Zetin et al., 1982). noses. However, though the creation of such a prototype may be the
Mann (1983) noted that long-term monoamine oxidase inhibitor best path forward, it could add additional complexity to diagnostic
treatment sometimes resulted in loss of antidepressant efficacy, while assessment and will require effective dissemination in order to be
Zetin, Aden, and Moldawsky (1983) reported that many patients widely applied and understood.
treated with the antidepressant amoxapine initially responded well, but
soon experienced a relapse that responded poorly to dose adjustment 3.3. Longitudinal studies
(Mann, 1983; Zetin et al., 1982). It was Lieb and Balter (1984) who first
proposed the term “antidepressant tachyphylaxis” and, in doing so, for- Solomon et al., (2005) conducted a longitudinal observational study
mally introduced the application of tachyphylaxis to the area of anti- of tachyphylaxis using subjects from the NIMH Collaborative Depres-
depressant medications. sion Study, a multicenter longitudinal study of mood disorders that
enrolled subjects between 1978 and 1981 and followed them for 20
3.2. Tachyphylaxis assessments years (Solomon et al., 2005). Study participants (n = 103) had diag-
noses of unipolar MDD and were selected for the study if, at some point
The introduction of standardized rating scales for antidepressant during follow-up treatment, they received antidepressant medication
tachyphylaxis have allowed for more systematic measurements of this for the treatment of a depressive episode, recovered, and then received
phenomenon. The Rothschild Scale for Antidepressant Tachyphylaxis maintenance pharmacotherapy. Within the sample, there were 171
(RSAT, Rothschild, 2008) consists of five self-rated items over the past maintenance treatment intervals in which a subject received main-
two week period (energy level, motivation/interest, cognitive function, tenance pharmacotherapy after recovering from a major depressive
sleep disturbances, and sexual functioning), affect rated by the clin- episode. The median duration of maintenance treatment was found to
ician, and weight gain self-reported over the past four weeks. Such be 20 weeks and tachyphylaxis occurred during 43 out of the 171
items were selected to best reflect how a patient may present with maintenance intervals, or approximately 25% of the time.
antidepressant tachyphylaxis, which is typically not with a depressed Solomon et al., (2005) is one of the few studies that explore tachy-
mood but with the array of symptoms captured by the items of the phylaxis by following individuals over time and has helped supply

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crucial evidence for tachyphylaxis as a relevant and prevalent clinical venlafaxine, 2.9% for TCA treatment, and 14.1% for those receiving
problem(Solomon et al., 2005). SSRI treatment (Posternak and Zimmerman, 2005). These data raise the
question as to whether broader mechanisms of action could prevent
3.4. Dose increase tachyphylaxis.
Despite Posternak and Zimmerman's (2005) findings, as well as
Byrne and Rothschild (1997) surveyed 145 psychiatrists’ interven- clinical lore of SSRIs being less effective than other antidepressant
tion strategies when presented with hypothetical cases of patients ex- classes during the maintenance phase, a large multiphase, double-blind,
periencing breakthrough depression despite continued fluoxetine, ser- placebo-controlled trial did not find a significant difference.
traline, or nortriptyline treatment at adequate dose and duration Rothschild et al., (2009) analyzed rates of tachyphylaxis in the Pre-
(Byrne and Rothschild, 1997). In all cases, the most common response vention of Recurrent Episodes of Depression with Venlafaxine ER for
was to first try a dose increase with the next two common responses Two Years (PREVENT) study (Rothschild et al., 2009). The efficacy of
being lithium augmentation or medication change. The efficacy of in- venlafaxine ER and fluoxetine versus placebo was explored during two
creasing dosage as a tachyphylaxis treatment was first supported by sequential, one-year maintenance phases (maintenance phase A,
Fava et al. who examined relapsed patients’ response to dose increase n = 337 and maintenance phase B, n = 128) in patients with recurrent
during long-term maintenance treatment (Fava et al., 1995). Patients MDD. The primary outcome was the cumulative probability of tachy-
who experienced tachyphylaxis on 20 mg fluoxetine had their dose in- phylaxis defined as receiving a score of 7 or greater on the RSAT in
creased to 40 mg. Of these patients, 83% (n = 18) responded to the patients with prior adequate therapeutic response. No significant dif-
dose increase and 61% maintained the response through a follow-up ference was found between venlafaxine and fluoxetine tachyphylaxis
period of at least one month (with a maximum follow-up of approxi- rates in phase 1 (61% vs. 66%) or phase 2 (63% vs. 53%), respectively.
mately 12 months). Schmidt et al., (2002) found similar results in their However, at the completion of maintenance phase A, a significantly
double-blind study of 125 tachyphylaxis patients who relapsed on greater number of patients who were treated with placebo did meet
20 mg fluoxetine or 45 mg weekly enteric fluoxetine. 57% percent of tachyphylaxis criteria compared with patients receiving venlafaxine ER.
patients whose daily dose was doubled and 72% of patients whose Further, a significant relationship between tachyphylaxis and recur-
weekly enteric dose was doubled responded and maintained response rence was observed.
for at least six months (Schmidt et al., 2002). Very similar results were In their review of SSRI and new-generation tachyphylaxis studies,
obtained in a double-blind study of duloxetine, where the percentage of Zimmerman et al. (2007) calculated an overall tachyphylaxis rate of
patients who responded to treatment after relapse was 62% of those 7.9% for SSRIs compared with a 24% rate of tachyphylaxis in the pla-
whose duloxetine dose was increased from 60 mg QD to 60 mg BID cebo population (Zimmerman and Thongy, 2007). However,
(Fava et al., 2006). Zimmerman et al. (2007) further analyzed these studies utilizing a
formula developed by Quitkin et al., (1993) to determine what portion
3.5. Dose decrease of response loss was due to placebo effect (Quitkin et al., 1993;
Zimmerman and Thongy, 2007). Using this formula, they concluded
There is also evidence that antidepressants may have a therapeutic that the majority of patients who lost their medication response were
window; specifically, a subset of patients may be responsive to anti- not true drug responders. Of note, this method required studies to re-
depressant dosages that are below a normal dose. In a seminal study, port the placebo population tachyphylaxis rate and limited their ana-
Cain et al. (1992) presented a series of four cases in which patients who lysis to four studies (n = 754, including both active and placebo po-
had failed to respond to 20 mg daily fluoxetine were withdrawn from pulations, Zimmerman and Thongy, 2007).
their medication and then responded to 20 mg fluoxetine every other
day(Cain, 1992). Fichtner et al., (1994) responded to Cain and collea- 3.7. Treatment considerations
gues with two additional case studies of patients with major depression
who responded to treatment after their antidepressant dose was re- Prior to proceeding with a treatment approach, the patient's return
duced. Fichtner et al. suggested that future studies should explore of depressive symptoms needs to be assessed to determine a true loss of
whether certain sedative antidepressant side effects are indicative of drug effect. Providers should proceed with a complete patient evalua-
patients that would benefit from a dose decrease (Fichtner et al., 1994). tion, first confirming the diagnosis of MDD. Of particular importance, a
However, as these studies are both case reports, evidence from larger- misdiagnosed bipolar patient might appear to have initially responded
scale clinical trials is needed to inform whether certain patients may to a medication, but the improvement may actually be a result of cy-
benefit from antidepressant treatment at a lower dose. cling through different stages. Clinically, bipolar patients are more
likely to have higher mood reactivity, reverse vegetative symptoms
3.6. Changing antidepressant medication class (e.g., increased appetite, weight gain, or hypersomnia) and signs of
mania/hypomania (e.g., rapid speech, increased motor activity,
Given the theory that receptor tolerance to drug action contributes Goodwin and Jamison, 2007). Some of these symptoms could be mis-
to antidepressant tachyphylaxis, many clinicians change a patient's interpreted as depressive improvement in a patient erroneously diag-
antidepressant medication class as a treatment strategy. Considerable nosed with unipolar depression.
evidence suggests that the rate of tachyphylaxis varies with anti- It is also important to confirm proper dose and duration of anti-
depressant class. Posternak and Zimmerman (2005) retrospectively depressant treatment. Tachyphylaxis scales have minimum dose re-
assessed rates of tachyphylaxis among patients receiving venlafaxine, quirements for an adequate trial that have been determined by expert
tricyclic antidepressants (TCAs), or selective-serotonin reuptake in- consensus (Fava, 2003). These scales also measure the duration of each
hibitors (SSRIs). Patients (n = 237) seeking treatment at an outpatient prior medication trial and are flexible enough to accommodate variable
psychiatric practice who had a diagnosis of MDD completed the semi- definitions of adequate dose and duration. Adequate antidepressant
structured Treatment Response to Antidepressant Questionnaire trial length is vital to determining a true drug response has occurred as
(TRAQ) interview(Posternak et al., 2004; Posternak and Zimmerman, opposed to a placebo response, and also to determine if a ‘failed’ drug
2005). Tachyphylaxis rates for this cohort's 487 total medication trials was given a fair chance to work. In their review of placebo response
were compared as a function of antidepressant class. The rates of ta- rates in antidepressant trials of MDD, Yang et al., (2005) analyzed four
chyphylaxis were significantly lower with the dual reuptake inhibitor meta-analyses of more than 150 randomized clinical trials that included
venlafaxine and TCAs relative to tachyphylaxis rates with SSRIs. Pos- over 6,500 subjects and found response rates to placebo medication
ternak and Zimmerman reported rates of 4.3% for those receiving between 25% and 35% (Mulrow, 2000; Stolk et al., 2003; Storosum

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Table 1
includes studies that reported decrease in patient response rates with prior antidepressant exposure. Rush et al. reported the rate of response for several steps and the
rate of reduced response was calculated by averaging the differences of each step.
Study Antidepressant class % reduced chance of response w prior exposure n

Amsterdam et al. 2005 MAOIs 30% 59

Amsterdam et al., 2009 SSRI, SSRI+ atomoxetine 19.9% 267
Rush et al., 2006 SSRI, SNRI, TCA, others 10.8% 3,671

et al., 2004; Walsh et al., 2002; Yang et al., 2005), which likely reflects prior antidepressant exposures were associated with a poor paroxetine
a lower than actual range due to the selective reporting of positive trials therapy outcome. Findings from this study indicate that cognitive
(publication bias). Walsh et al., (2002) also found that significant therapy may be a superior treatment approach with TRD patients
drug–placebo difference is generally noticeable after 2.4 weeks and (Leykin et al., 2007).
nearly always noticeable by 4 weeks (Walsh et al., 2002). This ob- In the Sequenced Treatment Alternatives to Relieve Depression
servation was supported in Yang et al. (2005)’s meta-analysis that (STAR*D) trial, Rush et al., (2006) followed a large outpatient popu-
found 79.5% of placebo improvement occurred in the first half of their lation with depression through four treatment steps. Remission was
trial (Yang et al., 2005). This is consistent with Posternak and defined as a score of 15 or less on the QIDS-SR, at which point the
Zimmerman's (2005) report that in 76 randomized clinical trials, >80% patient entered a 12-month follow-up phase (Rush et al., 2006).
of placebo improvement occurred in the first half of the trial Treatments included bupropion, sertraline, venlafaxine, citalopram,
(Posternak and Zimmerman, 2005). These placebo improvement rates nortriptyline, mirtazapine, lithium augmentation, and T3 augmenta-
support the notion that in clinical trials and for individual patient tion. Cognitive therapy was only present in the two second-phase
treatment, an acute treatment phase of at least 4–6 weeks is necessary groups (e.g., citalopram with cognitive therapy versus cognitive
to confirm a true drug (as opposed to a placebo) response monotherapy). QIDS-SR remission rates were 36.8% (first phase),
(Posternak and Zimmerman, 2005). 30.6% (second phase), 13.7% (third phase), and 13.0% (fourth phase),
or fell an average of 10.8% after each phase (Rush et al., 2006). Across
the phases, the cumulative remission rate was 67%.
3.8. “Stepwise” tachyphylaxis Table 1 summarizes findings across studies that have reported de-
creased patient response rates with prior antidepressant exposure.
In 1994, Giovanni Fava proposed that prolonged antidepressant
drug use increases depressive symptoms, decreases the period of ‘well’
time between depressive episodes, and contributes to a poorer depres- 3.9. Augmentation and combination
sion prognosis (Fava, 1994). Even prior to his hypothesis, double-blind
placebo-controlled trials were published showing imipramine to in- Augmentation of antidepressant medication is a treatment strategy
crease depression among patients who scored two standard deviations often used in refractory or treatment-resistant depression. Common
below the mean on the Depression scale of the Minnesota Multiphasic augmentation psychotropics include lithium and atypical anti-
Personality Inventory and another found an association between psychotics such as risperidone or aripiprazole. Positive response to
chronic tricyclic antidepressant treatment and depression recurrence(Di augmentation is associated with an earlier age of depression onset;
Mascio et al., 1968; Van Scheyen, 1973). however, different augmentation strategies have not historically pre-
In a series of treatment-resistant depression studies, Amsterdam dicted response (Perlis et al., 2003). A meta-analytic review of atypical
et al. developed the concept of “stepwise” tachyphylaxis, which pro- antipsychotic augmentation in TRD patients reported response and re-
posed that repeated administration of antidepressants decreases a pa- mission rates for 10 studies but only for the acute treatment phase,
tient's likelihood of responding during subsequent antidepressant trials giving little insight to tachyphylaxis rates (Papakostas et al., 2007). Of
(leading to a “stepwise” reduction in response, Amsterdam and Shults, note, this review found an average remission rate of 57% across a
2005; Amsterdam et al., 2009). In 2005, they published a retrospective subject pool of 1,500 outpatients with TRD that was significantly dif-
study of 59 early-stage treatment-resistant patients who had been pre- ferent from patients receiving placebo (Papakostas et al., 2007).
viously treated with MAOIs (Amsterdam and Shults, 2005). The results Alexopoulos et al., (2008) conducted a 24-week augmentation relapse
showed that the odds of achieving a CGI score of 1 (“very much better”) prevention study in elderly citalopram-resistant depressed patients.
decreased by 30% with each prior trial. In a subsequent study, 56% percent of initial responders to citalopram + risperidone during a
Amsterdam et al., (2009) directly explored SSRI stepwise tachyphy- 4–6 week acute phase subsequently experienced tachyphylaxis and met
laxis. Patients with MDD (n = 276) were treated with sertraline relapse criteria (Alexopoulos et al., 2008). In another study,
(150–200 mg daily) for an eight week period (Amsterdam et al., 2009). Rapaport et al., (2006) also explored citalopram-resistant patients who
Those patients with ongoing MDD after that period were randomized to were given risperidone augmentation and found that 53.3% of acute
receive either continuation therapy with sertraline plus atomoxetine phase responders experienced relapse during the 24-week follow-up
(n = 72) or sertraline plus placebo (n = 74) for another eight weeks. phase (Rapaport et al., 2006). A study of aripiprazole augmentation for
The number of prior antidepressant exposures was negatively asso- patients resistant to SSRIs and the tricyclic clomipramine found a re-
ciated with response to initial sertraline therapy (odds ratio = 0.81), sponse rate of 54.2% after eight weeks that increased to 91% at the end
which corresponded with a 19.9% reduced likelihood of response with of the 24-week study (Fabrazzo et al., 2012). However, since relapse
each prior antidepressant trial. In addition, the number of prior anti- rates were not reported, it is impossible to calculate tachyphylaxis rates.
depressant treatment trials was not linked to response to continuation Table 2 compares response and tachyphylaxis rates for citalopram
therapy of sertraline plus atomoxetine or sertraline plus placebo +risperidone augmentation studies.
(Amsterdam et al., 2009). Lithium augmentation is also a popular treatment for patients who
Leykin et al., (2007) further explored stepwise tachyphylaxis in a fail to respond to antidepressant medications. A meta-analysis found
sample of patients (n = 240) with MDD who were randomly assigned to that 41.2% of antidepressant non-responders had a positive response to
receive paroxetine or cognitive therapy treatment for 16 weeks. Cog- lithium augmentation compared with 14.4% of placebo patients.
nitive therapy outcomes were not significantly associated with the However, none of the unipolar depression studies included a long-term
number of prior antidepressant exposures; however, a higher number of patient follow-up; thus, these studies are inadequate for calculating

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G. Kinrys et al. Journal of Affective Disorders 245 (2019) 488–497

provides a comparison of response and tachyphylaxis rates for citalopram+risperidone augmentation studies. In order to minimize the impact of placebo response, only trials that included an acute phase were included.
Tachyphylaxis rates were calculated by comparing acute antidepressant response with relapse/recurrence rates after long-term treatment. A limitation of drawing conclusions from this table is that studies did not tachyphylaxis rates (Crossley and Bauer, 2007). Upon discontinuation

CGI = 6 or 7 or HAMD > = 16 or discont efficacy or

of lithium augmentation, Reynolds et al., (1996) found over half of the

CGI = 6 or 7, HAMD > = 16, discont efficacy, SI/B

initial responders relapsed, suggesting that, if effective, lithium aug-
mentation should not be discontinued in the continuation or main-
tenance phases. Only one antidepressant combination study of both
adequate acute and continuation length was found(Reynolds et al.,
1996). Rush et al., (2011) found that the overall response rate for bu-
propion+escitalopram increased from about 39% to 53% between
week 12 and month 7. The response rate for venlafaxine+mirtazapine
also increased, from about 38% to 42% over the same time course.
However, having only reported response and remission rates (as op-
posed to also including relapse rates), calculating the occurrence of
tachyphylaxis is impossible(Rush et al., 2011).
criteria

3.10. Treatment recommendations

SI/B

The importance of an effective second treatment step is highlighted

56.0%
53.3%

by the likelihood of tachyphylaxis to signal the degeneration of a single

%

depressive episode into treatment resistance. A decision between in-

n lost response

creasing/decreasing dosage, changing class, pharmacologic augmenta-

tion/combination, or augmenting/switching the patient to non-psy-
chopharmacological interventions (e.g., cognitive behavioral therapy)
18
65

needs to be made. Trivedi et al., (2008) discussed the possibility that

depressive symptoms that show up over time during SSRI treatment
n pts

123
32

may be reflective of the delayed onset of SSRI side effects. Thus, an

intervention approach rooted in the treatment of possible side effects
HAMD < = 7 or CGI = 1 or 2

may be warranted (Trivedi et al., 2008).

Previous research is conflicted as to whether some antidepressant
classes are more susceptible to tachyphylaxis, which may be due to
differences in sample sizes across studies. Posternak and
HAMD < = 7

Zimmerman (2005) found that tachyphylaxis is several times more

common in patients treated with SSRIs as opposed to SNRIs or tri-
criteria

cyclics. However, Rothschild et al., (2009) found much higher tachy-

phylaxis rates and no significant difference between SSRIs and SNRIs in
68%
63%

a large two-year study (Posternak and Zimmerman, 2005; Rothschild

%

et al., 2009). Zimmerman et al. (2007) and Zimmerman and

n responders

Thongy (2007) found SSRI tachyphylaxis rates of 8%, much closer to

specifically measure tachyphylaxis and therefore rates are based on relapse/recurrence criteria.

the 14% reported by Posternak and Zimmerman (2005). On further

analysis, Zimmerman et al. attributed all tachyphylaxis incidences to be
243
63

equivalent to placebo response (Zimmerman and Thongy, 2007).

n acute pts

4. Discussion
386
93

This review of antidepressant tachyphylaxis in MDD has several

cont length

methodological limitations. Primarily, it relies on heterogeneous clin-

ical trials to draw treatment conclusions. Due to strict inclusion/ex-
24wk
24wk

clusion criteria, clinical trials often restrict the enrollment of diverse

patient populations, such as psychotic depression, psychiatric co-
acute length

morbidities, or concomitant medications; therefore, these findings are

4–6wk
4–6wk

not generalizable to all depressed populations. Additionally, clinical

trials often require patients to leave their current providers and receive
care from unfamiliar clinicians, subjecting them to additional physical
citalopram + risperidone
citalopram + risperidone

and emotional stress, which may in turn contribute to tachyphylaxis.

Further, we only evaluated articles that were published in the English
language.
One important question that naturally stems from this review per-
Augment

tains to semantics: specifically, what is the best clinical definition for

“tachyphylaxis”? Ultimately, a clear answer to this question remains
unknown. This review synthesizes the various studies that provide a
Alexopoulos et al., 2008

perspective on tachyphylaxis and, in doing so, highlights the extent to

Rapaport et al., 2006

which tachyphylaxis remains a minimally evaluated and understood

concept. A challenge for upcoming research will be to systematically
evaluate the appropriate onset and window for tachyphylaxis. Until we
arrive at a universal clinical understanding of tachyphylaxis, it may be
Table 2

Study

best to view tachyphylaxis as a lost or reduced antidepressant response

that occurs 6 weeks or later following the start of the acute phase

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G. Kinrys et al. Journal of Affective Disorders 245 (2019) 488–497

(Fig. 1). Identification and exploration of loss of antidepressant re- depression found that this method of administration was not effectively
sponse is an important and emerging area of research in MDD that tolerated and yielded varied absorption patterns across participants
underscores our lack of effective, long-term intervention strategies. (Galvez et al., 2018).
Additional direct comparison trials are needed to differentiate between Kappa opioid receptor antagonists have been recently evaluated as
antidepressant classes and rates of tachyphylaxis as well as the asso- treatments for major depressive disorder as the dysphoria associated
ciation between medication class and the progression of stepwise ta- with ongoing stress is thought to stem from dynorphin action on kappa-
chyphylaxis. There is also a lack of tachyphylaxis data on the efficacy of opioid receptors(Ionescu and Papakostas, 2016; Land et al., 2008).
lithium augmentation and medication combinations for maintaining a Some kappa opioid receptor antagonists that have shown effectiveness
sustained response. Rapid depression relief strategies, such as tran- across studies of patients with treatment-resistant depression include
scranial magnetic stimulation, low field magnetic stimulation, low dose low-dose buprenorphine (Karp et al., 2014) and combined buprenor-
naltrexone, ketamine, or a kappa-opioid antagonist immediately after phine and samidorphan (Peckham et al., 2018).
tachyphylaxis, may prove effective and may be an important primary In addition to the ongoing evaluation of rapid depression relief
focus for subsequent research efforts on interventions for major de- strategies, a critical path forward for research investigations in treat-
pression that yield sustained responses. Transcranial magnetic stimu- ment-resistant depression should incorporate both loss of response
lation (TMS) is a non-invasive neuromodulation approach that involves (antidepressant tachyphylaxis) and lack of response as study outcomes.
the delivery of magnetic pulses via a coil to hyper- and hypo-active Indeed, to date, many clinical trials in major depression fail to distin-
regions of the dorsolateral prefrontal cortex, thereby modifying pat- guish between these two categories in reporting outcomes, making it
terns of brain connectivity (Brunelin et al., 2014; Garnaat et al., 2018). difficult to adequately identify those patients who are experiencing
Many studies in this domain have focused on repetitive transcranial antidepressant tachyphylaxis.
magnetic stimulation (rTMS), which involves repeated pulses to a pre-
determined cortical area (Mishra et al., 2011). Overall, outcomes from Author contributions
rTMS in major depression have been associated with small to moderate
effect sizes (McGirr and Berlim, 2018) though, across studies, results GK, AKG, VDP, MPF, GIP, DM, AAN, and MF contributed to the
are somewhat inconsistent with some rTMS protocols receiving more writing and editing of this paper. AKG and VDP were responsible for
consistent evaluation than others and some protocols being potentially searching databases for the relevant papers. GK was responsible for the
more effective than others (Brunoni et al., 2017). Of note, one meta- initial conception and design of this article. All authors approved the
analytic review of rTMS in patients with treatment-resistant depression final version of this article.
found that electroconvulsive therapy was superior to rTMS
(Ontario, 2016). Moreover, there are mixed opinions as to whether the Role of the funding source
benefits of rTMS can be sustained over time and, indeed, few studies
have evaluated maintenance rTMS over an extended period (Ontario, This research was not funding, supported, or sponsored by any
2016; Rachid, 2018). Future research directions may wish to further funding body.
evaluate maintenance rTMS and to systematically compare the effec-
tiveness of various rTMS protocols. Acknowledgments
Low-field magnetic stimulation (LFMS) is another neuromodulation
technique that can modify brain activity via a device that produces Not applicable
electromagnetic fields (Ionescu and Papakostas, 2016). One open trial
found that LFMS adjunctive to antidepressant medication yielded rapid Study Limitations
mood improvements in patients with unipolar or bipolar depression
(Rohan et al., 2014). However, a subsequent randomized, controlled Studies of antidepressant tachyphylaxis are largely heterogeneous in
study of patients with treatment-resistant depression found no sig- nature and employ strict inclusion/exclusion criteria; thus, these find-
nificant differences between LFMS and a sham intervention in treat- ings may not be generalizable to all depressed populations.
ment response (Fava et al., 2018). Nonetheless, as LFMS has still been
the focus of limited research in major depression to date, it may be Conflicts of interest
useful to evaluate varied LFMS protocols, particularly as both the open
and randomized studies employed LFMS treatments of different lengths. Dr. Kinrys has received research support from Astra-Zeneca,
Recently, Mischoulon and colleagues explored low-dose naltrexone Bristol-Myers Squibb Company, Cephalon, Elan Pharmaceuticals, Eli
augmentation versus placebo augmentation for patients who experi- Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline,
enced a depressive episode relapse while taking dopaminergic agents Sanofi/Synthelabo, Sepracor Inc., Pfizer Inc, UCB Pharma, and Wyeth-
(Mischoulon et al., 2017). Low-dose naltrexone is thought to resemble Ayerst Laboratories, Agency for Healthcare Research and Quality
antidepressant activity by increasing dopamine signaling. Relative to (AHRQ) Grant R01 HS019371-01, and Takeda Pharmaceuticals. He has
patients receiving the placebo augmentation, those receiving the low- been an advisor or consultant for Astra-Zeneca, Cephalon, Eli Lilly &
dose naltrexone augmentation demonstrated greater improvements in Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Janssen
depressive symptoms and greater overall clinical response with large Pharmaceutica, Pfizer Inc, Sepracor Inc., UCB Pharma, and Wyeth-
effect sizes favoring the low-dose naltrexone group (Mischoulon et al., Ayerst Laboratories. Dr. Kinrys has been a speaker for Astra-Zeneca,
2017), suggesting that low-dose naltrexone may be a promising direc- Forest Pharmaceuticals Inc., GlaxoSmithkline, Sepracor Inc., and
tion for upcoming investigations in major depressive disorder. Wyeth-Ayerst Laboratories.
Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist most Ms. Gold has no competing interests to report.
commonly administered via an intravenous route, has shown effec- Mr. Pisano has no competing interests to report.
tiveness as a rapid depression relief strategy(Ionescu and Dr. Freeman reports the following disclosures: research support - MGH
Papakostas, 2016). Relative to placebo, ketamine has demonstrated National Pregnancy Registry for Atypical Antipsychotics (Alkermes
significant effectiveness in relieving depressive symptoms(Abdallah Biopharmaceuticals, AstraZeneca Pharmaceuticals, Otsuka Pharmaceuticals,
et al., 2015; Lee et al., 2015) and an open trial suggests that it may be a Forest/ActavisPharmaceuticals, Ortho-McNeil Janssen, Sunovion Pharma-
good maintenance treatment for patients with treatment-resistant de- ceuticals, Inc.); Other Research Support—Takeda Pharma-
pression (Archer et al., 2018). Of note, a recent study evaluating re- ceuticals, JayMac Pharmaceuticals; Advisory/Consulting—Janssen, Sage,
peated intranasal ketamine for patients with treatment-resistant JDS Therapeutics, Sunovion; Independent Data Safety and Monitoring

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G. Kinrys et al. Journal of Affective Disorders 245 (2019) 488–497

Committee—Janssen (Johnson & Johnson); Medical Editing—GOED Lichtwer Pharma, Marriott Foundation, Mylan, NIMH, PamLabs,
newsletter; As an employee of MGH, Dr. Freeman works with the MGH Patient Centered Outcomes Research Institute (PCORI), Pfizer
CTNI, which has had research funding from multiple pharmaceutical Pharmaceuticals, Shire, Stanley Foundation, Takeda/Lundbeck, and
companies and NIMH. Wyeth-Ayerst. Honoraria - Belvoir Publishing, University of Texas
Dr. Papakostas has served as a consultant for Abbott Laboratories, Southwestern Dallas, Brandeis University, Bristol-Myers Squibb,
Acadia Pharmaceuticals, Inc*, AstraZeneca PLC, Avanir Hillside Hospital, American Drug Utilization Review, American Society
Pharmaceuticals, Axsome Therapeutics*, Brainsway Ltd, Bristol-Myers for Clinical Psychopharmacology, Baystate Medical Center, Columbia
Squibb Company, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., University, CRICO, Dartmouth Medical School, Health New England,
Genentech, Inc*, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Harold Grinspoon Charitable Foundation, IMEDEX, International
Inflabloc Pharmaceuticals, Janssen Global Services LLC*, Jazz Society for Bipolar Disorder, Israel Society for Biological Psychiatry,
Pharmaceuticals, Johnson & Johnson Companies*, Methylation Johns Hopkins University, MJ Consulting, New York State, Medscape,
Sciences Inc, Mylan Inc*, Novartis Pharma AG, One Carbon MBL Publishing, MGH Psychiatry Academy, National Association of
Therapeutics, Inc*, Osmotica Pharmaceutical Corp.*, Otsuka Continuing Education, Physicians Postgraduate Press, SUNY Buffalo,
Pharmaceuticals, PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, University of Wisconsin, University of Pisa, University of Michigan,
Ridge Diagnostics (formerly known as Precision Human University of Miami, University of Wisconsin at Madison, APSARD,
Biolaboratories), Shire Pharmaceuticals, Sunovion Pharmaceuticals, ISBD, SciMed, Slack Publishing and Wolters Klower Publishing, ASCP,
Taisho Pharmaceutical Co, Ltd, Takeda Pharmaceutical Company LTD, NCDEU, Rush Medical College, Yale University School of Medicine,
Theracos, Inc., and Wyeth, Inc. Dr. Papakostas has received honoraria NNDC, Nova Southeastern University, NAMI, Institute of Medicine,
(for lectures or consultancy) from Abbott Laboratories, Acadia CME Institute, ISCTM, World Congress on Brain Behavior and Emotion,
Pharmaceuticals, Inc, Asopharma America Cntral Y Caribe, Astra Congress of the Hellenic Society for Basic and Clinical Pharmacology,
Zeneca PLC, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, ADAA. Stock - Appliance Computing, Inc. (MindSite); Brain Cells, Inc.,
Brainsway Ltd, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Evotec Medavante. Copyrights - Clinical Positive Affect Scale and the MGH
AG, Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc Structured Clinical Interview for the Montgomery Asberg Depression
Pharmaceuticals, Grunbiotics Pty LTD, Jazz Pharmaceuticals, H. Scale exclusively licensed to the MGH Clinical Trials Network and
Lundbeck A/S, Medichem Pharmaceuticals, Inc, Meiji Seika Pharma Co. Institute (CTNI). Speaker Bureaus - none since 2003.
Ltd, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Dr. Fava reports the following disclosures: Research Support - Abbott
Pfizer, Pharma Trade SAS, Pierre Fabre Laboratories, Ridge Diagnostics, Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American
Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir
Pharmaceutical Company LTD, Theracos, Inc., Titan Pharmaceuticals, Pharmaceuticals; AXSOME Therapeutics; Biohaven; BioResearch;
and Wyeth Inc. Dr. Papakostas has received research support (paid to BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon;
hospital) from AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Cerecor; Clintara, LLC; Covance; Covidien; Eli Lilly and
Pharmaceuticals, the National Institute of Mental Health, Neuralstem, Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.;
Inc*, PAMLAB LLC, Pfizer Inc., Ridge Diagnostics (formerly known as Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden
Precision Human Biolaboratories), Sunovion Pharmaceuticals, Tal Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute;
Medical, and Theracos, Inc. Dr. Papakostas has served (not currently) Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen
on the speaker's bureau for BristolMyersSquibb Co and Pfizer, Inc. R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical
* Asterisk denotes activity undertaken on behalf of Massachusetts Research & Development; Lichtwer Pharma GmbH; Lorex
General Hospital. Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante;
Dr. Mischoulon has received research support from Nordic Methylation Sciences Inc; National Alliance for Research on
Naturals. He has provided unpaid consulting for Pharmavite LLC and Schizophrenia & Depression (NARSAD); National Center for
Gnosis USA, Inc. He has received honoraria for speaking from the Complementary and Alternative Medicine (NCCAM);National
Massachusetts General Hospital Psychiatry Academy. He has received Coordinating Center for Integrated Medicine (NiiCM); National
royalties from Lippincott Williams & Wilkins for published book Institute of Drug Abuse (NIDA); National Institute of Mental Health
“Natural Medications for Psychiatric Disorders: Considering the (NIMH); Neuralstem, Inc.; NeuroRx; Novartis AG; Organon
Alternatives.” Pharmaceuticals; Otsuka Pharmaceutical Development, Inc.; PamLab,
Dr. Nierenberg reports the following disclosures: Consultant - LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research
Abbott Laboratories, Alkermes, American Psychiatric Association, Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics;
Appliance Computing Inc. (Mindsite), Basliea, Brain Cells, Inc., Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC
Brandeis University, Bristol Myers Squibb, Clintara, Corcept, Dey (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire;
Pharmaceuticals, Dainippon Sumitomo (now Sunovion), Eli Lilly and Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute
Company, EpiQ, L.P./Mylan Inc., Forest, Genaissance, Genentech, (SMRI); Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceuticals;
GlaxoSmithKline, Healthcare Global Village, Hoffman LaRoche, Tal Medical; VistaGen; Wyeth-Ayerst Laboratories.
Infomedic, Intra-Cellular Therapies, Lundbeck, Janssen Pharmaceutica, Advisory Board/ Consultant - Abbott Laboratories; Acadia; Affectis
Jazz Pharmaceuticals, Medavante, Merck, Methylation Sciences, Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect
NeuroRx, Naurex, Novartis, PamLabs, Parexel, Pfizer, PGx Health, Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir
Otsuka, Ridge Diagnostics Shire, Schering-Plough, Somerset, Sunovion, Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice
Takeda Pharmaceuticals, Targacept, and Teva; consulted through the Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.;
MGH Clinical Trials Network and Institute (CTNI) for Astra Zeneca, Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx
Brain Cells, Inc, Dianippon Sumitomo/Sepracor, Johnson and Johnson, BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis
Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life
Schering-Plough, Targacept and Takeda/Lundbeck Pharmaceuticals, Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov
NeuroRx Pharma, Pfizer, Physician's Postgraduate Press, Inc. Grants/ Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli
Research support - American Foundation for Suicide Prevention, AHRQ, Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions;
Brain and Behavior Research Foundation, Bristol-Myers Squibb, EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer
Cederroth, Cephalon, Cyberonics, Elan, Eli Lilly & Company, Forest, Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum
GlaxoSmithKline, Intra-Cellular Therapies, Janssen Pharmaceuticals, Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal

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