A Comparison of Two Antidepressant Tapering Regimens
Phase: NA
Conditions: Major Depressive Disorder, Anxiety Disorder, Obsessive Compulsive Disorder, Post-Traumatic Stress Disorder
Sponsor: Emory University

 
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A Comparison of Two Antidepressant Tapering Regimens   
 
29 January 2016 
 
NCT02661828 
 

 
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Full Title: A Comparison of Two Antidepressant Tapering Regimens 
 
Short Title: Tapering off Antidepressants  
 
Principal Investigator: Boadie Dunlop, MD 
 
Co-Investigator: Jeffrey Rakofsky, MD 
 
Draft Date:  January 29, 2016 
 
Precis/Abstract: 
 
One hundred adults currently taking an antidepressant for at least four weeks for 
the treatment of major depressive disorder, an anxiety disorder, obsessive compulsive 
disorder (OCD) or posttraumatic stress disorder (PTSD) will be randomly assigned to 
receive one of two different medication tapering regimens.  The study will aim to 
characterize: 1) the clinical characteristics predictive of antidepressant discontinuation 
symptoms; and 2) which of two tapering regimens is more effective at minimizing 
antidepressant discontinuation symptoms.  Participants will be enrolled in this study 
ONLY if they no longer wish to take the antidepressant medication they are currently 
prescribed, due to one of the following reasons: 1) ineffective for symptoms; 2) 
intolerable side effect; 3) improvement of their illness for sufficient duration that it is 
clinically appropriate to consider tapering the medication.  The study will consist of 4 
study visits. At the first visit, all participants will complete a psychiatric interview and 
questionnaires. The subsequent visits will involve assessment of discontinuation 
symptoms and mental health symptoms. Upon completion of the antidepressant taper, 
patients will be assisted in pursuing options for additional treatment if required.   
 
Introduction and Background: 
 
It is widely recognized that abrupt cessation of antidepressant medication (ADM) 
causes distressing symptoms (known as antidepressant discontinuation symptoms).  
Discontinuation symptoms can occur regardless of the diagnosis under treatment, 
whether major depressive disorder (MDD), an anxiety disorder, obsessive compulsive 
disorder (OCD) or posttraumatic stress disorder (PTSD). These symptoms vary 
substantially in character, intensity and duration, and there are currently no reliable 
means of predicting which patients will experience discontinuation symptoms.  In most 
cases these symptoms last less than one week, but occasionally can persist for weeks 
to months (Fava et al, 2015). 
 
The rates of ADM discontinuation symptoms are not consistent across studies, but the 
most frequent are as follows: 
 
Symptom 
 
% Patients Experiencing 
Worsened mood:  
 
22-45 
Irritability/Agitation: 
 
17-35 
Anxiety: 
 
 
12-42  
Dizziness: 
 
 
  3-50 
Confusion: 
 
 
10-42 
Headache: 
 
 
13-42 
 

 
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Other less frequent symptoms include vivid dreams, insomnia, nausea, sweating, and 
electric shock  feelings (“zaps”).  In rare cases (<1%), suicidal thoughts have occurred 
(Fava et al, 2015).  
 
An “antidepressant discontinuation syndrome” has been defined in the research 
literature as the occurrence of 4 or more new or worsened psychic or physical symptoms 
that arise after stopping an antidepressant (Rosenbaum et al, 1998).  Rates of ADM 
discontinuation syndrome have ranged from 14 – 60% (Baldwin et al, 2006; Khan et al, 
2014; Rosenbaum et al, 1998; Sir et al, 2005; Tint et al, 2008). 
 
Most of the research on discontinuation symptoms conducted to date has focused on 
symptoms arising after cessation of drugs that block the serotonin transporter (selective 
serotonin reuptake inhibitors, SSRIs, or serotonin norepinephrine reuptake inhibitors, 
SNRIs).  However, before the SSRIs were developed, discontinuation symptoms had 
been noted to occur with the older tricyclic antidepressants, and case reports have been 
published for other newer antidepressants that do not affect the serotonin transporter 
(DIlsaver, et al, 1987).  The standard in clinical practice is now to taper off SSRIs and 
SNRIs, though there is no widely accepted taper rate or protocol to follow when tapering 
(Ogle et al, 2012).  Tapering is often not performed with other classes of 
antidepressants, though data that could inform clinicians about discontinuation 
symptoms from those medications is sparse.  
 
Previous controlled studies of antidepressant discontinuation have been conducted on 
patients who have benefitted from the medication and were willing to be tapered off.  
The prior randomized discontinuation studies limited to patients who have not responded 
to their antidepressant had small sample sizes (Tint et al, 2008). Some data suggests 
that antidepressant side effects at drug initiation may predict eventual treatment 
response if patients adhere to the medication.  It is theorized that certain side effects 
may reflect the responsivity of biological systems (such as monoamine signaling 
systems) to the antidepressant (Renoir, 2013).  Extending this model to discontinuation 
suggests that non-responders to medication may have fewer side effects when 
discontinuing the antidepressant.  
 
Clinical practice would be enhanced if predictors of difficulty tapering ADM could be 
identified.  Currently, very little is known about which patients are likely to develop 
discontinuation symptoms.  The most consistently replicated finding is that the long half-
life antidepressant fluoxetine is associated with fewer discontinuation symptoms than the 
short half-life agent paroxetine.  However, discontinuation symptoms are known to arise 
with fluoxetine cessation, and both these drugs are SSRIs. Identification of patients who 
will or will not develop difficulty coming off antidepressants is of significant clinical 
importance because tapers that are longer or shorter than necessary can negatively 
impact patient care.   
 
This study will aim to assess the frequency of discontinuation symptoms across all 
classes of antidepressants among patients who have not responded to medication.  Only 
patients who wish to be tapered off their medication will be eligible to participate.   
 
Objectives: 
There are two primary objectives to this study:  
 
 

 
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AIM 1: Compare the tolerability of two antidepressant tapering regimens.  
 
Hypothesis 1. Tapering antidepressant dose over two weeks will be associated a 
lower incidence of antidepressant discontinuation symptoms than tapering over one 
week.  
 
Hypothesis 2. Discontinuing medications that inhibit the serotonin transporter (SSRIs 
and SNRIs) will show greater difference in the frequency of discontinuation 
symptoms between the two week and one-week tapering regimens than medications 
that do not inhibit the serotonin transporter.   
 
AIM 2: Identify demographic and clinical features that predict the emergence of 
antidepressant discontinuation symptoms.  
 
Hypothesis 2. SSRIs and SNRIs will be associated with greater numbers of 
discontinuation symptoms compared to non-SSRI/SNRI medications. 
 
Hypothesis 1. Duration of treatment will positively associated with the number of 
discontinuation symptoms. 
 
Study Design and Methods: 
 
Sample 
The sample will include 125 subjects currently taking an FDA-approved antidepressant.  
We anticipate an approximate screen fail rate of 20%, allowing for 100 subjects to enter 
randomization. 
 
Inclusion Criteria:  
1. Male or female, age 18-75 
2. Currently taking an FDA-approved antidepressant for at least four weeks. 
3. Primary psychiatric diagnosis of major depressive disorder, an anxiety 
disorder, OCD, or PTSD. 
4. Ability to read and understand English language 
Exclusion Criteria for all Subjects; 
1. Has met criteria at any time during their life for a primary psychotic disorder 
(e.g. schizophrenia), or dementia. 
2. Meets criteria for DSM-5-defined substance use disorder within three months 
of the screening visit. 
3. Currently taking two or more antidepressants. 
4. Presents with a clinically significant suicide risk, as assessed by a study 
physician.  
5. Presence of any unstable or central nervous system-related medical illness 
that would interfere with cognition or participation.    
 
6. Women who are currently pregnant or lactating, or plan to become pregnant 
during the study.   
 
 

 
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Setting 
The setting of the study will occur in the Mood and Anxiety Disorders Program 
research clinic at the Emory University Executive Park campus.   
 
Recruitment 
 
Patients will be recruited through advertisements and clinician referral.   
 
Procedures 
 
The study consists of four visits.   
 
Visit 1. 
Visit 1 commences with the informed consent discussion and signing the 
informed consent form for the study. Subsequently, the following procedures will 
be performed: 
1. Demographic information 
2. Psychiatric interview and MINI.  
3. Clinician ratings of symptoms:  MADRS, HAMA 
4. Clinician rating of suicidality: CSSRS 
5. Clinician assessment of discontinuation symptoms present at baseline: DESS 
6. Vital signs (temperature, height, weight, blood pressure, pulse) 
7. Urine pregnancy test for women of child-bearing potential. 
8. Medical History 
9. Past psychiatric treatment history 
10. Review of concomitant medications and supplements 
11. Review of recall of side effects experienced when starting the antidepressant. 
12. Patient questionnaires:  DEBS, Q-LES-Q, BIS 
 
Participants with internet access, either by cell phone or computer, will be asked 
to record their mood symptoms daily on the self-report Scale for Anxiety and 
Depression (SAD).  This is a free internet app available at sad.ecu.edu.  
Participants will use their de-identified study ID code as their login name to 
preserve confidentiality.  After completing the scale in the office at Visit 1, 
participants will complete the SAD daily until Visit 4. Participants who lack 
internet access will be given paper versions of the form to fill out each day. 
 
Upon completion of these components, the patient will be randomized to either 
Taper A or Taper B (see below).  The physician will discuss the tapering process 
with the patient.  
 
Visit 2 
Visit 2 occurs 1 week after initiating the antidepressant taper.  The following 
procedures will be performed:  
1. Clinician ratings of symptoms:  MADRS, HAMA 
2. Clinician rating of suicidality: CSSRS 
3. Clinician assessment of discontinuation symptoms: DESS, PWC-20 
4. Vital signs (temperature, height, weight, blood pressure, pulse) 
5. Review of concomitant medications and supplements 
6. Review of adverse events 

 
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7. Patient questionnaires:  DEBS, BIS, PGI-C 
 
Visit 3:  
Visit 3 occurs 2 weeks after initiating the antidepressant taper.  The following 
procedures will be performed:  
1. Clinician ratings of symptoms:  MADRS, HAMA 
2. Clinician rating of suicidality: CSSRS 
3. Clinician assessment of discontinuation symptoms: DESS, PWC-20 
4. Vital signs (temperature, height, weight, blood pressure, pulse) 
5. Review of concomitant medications and supplements 
6. Review of adverse events 
7. Patient questionnaires:  DEBS, BIS, PGI-C 
 
Visit 4: 
 
Visit 4 occurs 3 weeks after initiating the antidepressant taper.  The following 
procedures will be performed:  
1. Clinician ratings of symptoms:  MADRS, HAMA 
2. Clinician rating of suicidality: CSSRS 
3. Clinician assessment of discontinuation symptoms: DESS, PWC-20 
4. Vital signs (temperature, height, weight, blood pressure, pulse) 
5. Review of concomitant medications and supplements 
6. Review of adverse events 
7. Patient questionnaires:  DEBS, BIS, PGI-C, Q-LES-Q 
8. Planning of transition of care. 
9. Download of SAD daily scale data from website sad.ecu.edu. 
 
Multiple potential referral options will be discussed, depending on the patient’s 
improvement and insurance status. Final referral selected will be based on the 
patient’s preference. Options include referral to a primary care physician, 
psychiatrist, therapist, community mental health center, or other research 
studies. If necessary, patients may be seen for 1 or 2 post-study follow-up visits 
until their care transfer is completed.  
 
 

 
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Schedule of Events: 
 
BIS: Barratt Impulsiveness Scale; CSSRS: Columbia Suicide Severity Rating Scale; 
DEBS: Dunlop Emotional Blunting Scale; DESS: Discontinuation Emergent Signs and 
Symptoms; HAM-A: Hamilton Anxiety Rating Scale; MADRS: Montgomery Asberg 
Depression Rating Scale; MINI: Mini-International Neuropsychiatric Interview; PGI-C: 
Patient Global Impression, Change; PWC-20: Physician Withdrawal Checklist; Q-LES-Q: 
Quality of Life Satisfaction Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
Visit Number 
V1 
V2 
V3 
V4 
Day 
0 
7 
14 
21 
   Informed consent 
X 
 
 
 
   Demographics 
X 
 
 
 
   Vital signs 
X 
X 
X 
X 
   Weight 
X 
 
 
X 
   Psych/Medical History  
X 
 
 
 
   MINI v.7.0 
X 
 
 
 
Clinician Ratings 
 
 
 
 
  MADRS 
X 
X 
X 
X 
  HAMA 
X 
X 
X 
X 
  DESS 
X 
X 
X 
X 
  PWC-20 
 
X 
X 
X 
Patient Ratings 
 
 
 
 
  DEBS 
X 
X 
X 
X 
  BIS 
X 
X 
X 
X 
  Q-LES-Q 
X 
 
 
X 
  PGI-C 
 
X 
X 
X 
  SAD (Daily) 
X 
X 
X 
X 
Safety Measures 
 
 
 
 
  Concomitant Meds 
X 
X 
X 
X 
  Adverse Events 
 
X 
X 
X 
  CSSRS 
X 
X 
X 
X 
 
 
 
 
 

 
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Taper Regimens: 
 
Taper A:  
Days 1-7:  
Take 50% of baseline dose 
Days 8-14:  
Take 25% of baseline dose 
Day 15:  
Stop antidepressant 
 
Taper B: 
Days 1-3:  
Take 50% of baseline dose 
Days 4-7:  
Take 25% of baseline dose 
Day 8:   
Stop antidepressant 
 
 
Monitoring for Suicidality 
The emergence of suicidal thoughts or behaviors are not considered part of 
antidepressant discontinuation symptoms, but rather are thought to reflect the 
breakthrough of a new depressive episode. Patients who do not believe their 
antidepressant is helping them may nevertheless experience worsening depression with 
discontinuation of the medication. Therefore, we will conduct a standardized assessment 
for suicidal ideation or behavior, the CSSRS, at every study visit.  Any patient who 
exhibits and increase in suicidal ideation, any form of suicidal behavior, or about whom 
the study physician has concern for their safety will be immediately withdrawn from the 
study and treated as clinically appropriate.   
 
Operationalized Discontinuation Criteria for Suicidality: 
Research participants are exited from the study should any of the following occur: 
 
Any emergent CSSRS defined suicidal behavior  
 
A suicidal ideation score of 5 (indicating active suicidal ideation with specific plan and 
some level of intent) on the CSSRS 
 
In the absence of a CSSRS suicidal ideation score of 5 or CSSRS-defined suicidal 
behavior, the investigator determines the patient to have a significant short-term risk 
for a suicide attempt.   
 
Randomization: 
Patients will be randomized in a 1:1 manner to Taper A or Taper B.   Randomization will 
be stratified based on mechanism of action of drug (serotonin reuptake inhibitor or not).  
The two randomization schedules will be created prior to study commencement by a 
staff member not involved in the clinical components or data analytic components of the 
study.  Randomization assignments will be placed in numbered and sealed envelopes, 
and opened sequentially for each subject who qualifies for randomization at Visit 1.  
 
Included Medications: 
The patient will be responsible for the cost of the antidepressant prescription (if 
necessary) and going to a pharmacy to get the prescription filled. Antidepressant 
medications eligible for discontinuation in this protocol include the SSRIs (citalopram, 
escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vilazodone or vortioxetine), 
SNRIs (desvenlafaxine, duloxetine, levomilnacipran, venlafaxine) and other classes 
(amitriptyline, bupropion, desipramine, doxepin, mirtazapine, nefazodone, nortriptyline, 
phenelzine, selegiline, or tranylcypromine).  Clomipramine, a tricyclic antidepressant 
approved for the treatment of OCD, will also be included, but will be classed as an SSRI 

 
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for this study because inhibition of the serotonin transporter is its primary therapeutic 
mechanism.  
 
Measures 
Clinician-Rated: 
1. The Mini International Neuropsychiatric Interview (MINI, Sheehan et al, 1998), 
will be used to assess psychiatric diagnoses, which will be confirmed by an 
interview with a study psychiatrist.  
2. The Montgomery Asberg Depression Rating Scale (MADRS, Montgomery & 
Åsberg, 1979) will assess clinical depressive symptoms. 
3. The Hamilton Anxiety Rating Scale (HAMA, Hamilton, 1959) will assess 
clinical anxiety symptoms. 
4. The Discontinuation Emergent Signs and Symptoms (DESS, Rosenthal et al, 
1998) questionnaire will assess the frequency of discontinuation symptoms.  
5. The Physician Withdrawal Checklist (PWC-20, Rickels et al, 2008) will assess 
the intensity of discontinuation symptoms. 
6. The Columbia Suicide Severity Rating Scale (CSSRS, Posner et al, 2007) will 
assess for the emergence of any suicidal ideation or behaviors during 
antidepressant tapering.  
 
Patient-Rated:  
1. The Barratt Impulsiveness Scale (BIS, Patton et al, 1995) will assess 
impulsivity.  
2. The Dunlop Emotional Blunting Scale (DEBS) will assess for changes in 
emotional reactivity. 
3. The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q, 
Endicott et al, 1993) 
4. The Patient Global Impressions- Change (PGI-C) will assess the patient’s 
overall perceived level of mental health compared to baseline.  
5. Scale for Anxiety and Depression (SAD).  This 17-item scale is a self-report 
questionnaire asking about 17 common symptoms of depression over the past 
24 hours and anxiety rated on a 1-10 visual analogue scale.  The SAD is 
completed daily, providing a more fine-grained analysis of symptom change 
over short periods, such as tapering of antidepressants. The scale is accessed 
through a free internet app and takes approximately 3 minutes to complete.   
   
Payment: 
Patients will receive no compensation for participating in this study.  
 
Outcomes: 
  
Primary outcome:  
The primary outcome is the change in the DESS, defined as the number of 
symptoms that are either new or worsened compared to baseline at Visit 4.   
 
 
Secondary outcomes include: 
1. Change in the PWC-20 from baseline to Visit 4 
2. Number of patients who meet criteria for antidepressant discontinuation 
syndrome, defined as ≥4 new or worsened DESS symptoms, at visit during 
the study. 

 
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3. 3. Change in SAD daily score from baseline to peak SAD score during the 
taper period.  
Statistical Analysis: 
 
The primary analyses will be carried out on a modified intent to treat (ITT) sample, which 
will include all randomized patients who returned for at least one post-randomization 
study visit. The primary outcome variable is change in DESS score, defined as the 
number of symptoms that are either new or worsened at Visit 4 compared to baseline 
(Visit 1).  For patients who terminate early the principle of last observation carried 
forward will be used.  If amount of change for the total sample is non-normally 
distributed, raw change will be log-transformed to approximate a normal distribution 
before parametric tests are conducted. The primary analysis analyzing the taper groups 
will be an overall, 2-way ANCOVA, with appropriate covariates, on change in DESS 
score. Treatment groups will be compared on baseline variables that have a potential 
relationship to amount of change with the DESS.  These include duration in months on 
ADM, dose equivalents of ADM at Visit 1, gender, age, Visit 1 HAMA score, Visit 1 
MADRS score, and comorbid anxiety disorder.  Only those Baseline variables that differ 
among randomized treatment groups at P<0.10 and are significantly associated with the 
primary outcome variable for the entire sample will be entered into the analysis as 
covariates.   
 
Secondary analyses will include a similar 2-way ANCOVA assessing change from 
baseline in PWC-20 and SAD peak daily scores between the two taper groups following 
the same analytic plan as for the DESS.  The proportion of patients experiencing the 
ADM discontinuation syndrome in each taper arm will be compared by Chi-Square test. 
The frequency of individual discontinuation symptoms between the two taper arms will 
be assessed using Fisher’s Exact Test.   
 
Power Calculation: 
An sample size of 48 patients per taper group provides 80% power to detect a clinically 
meaningful difference of 1.0 points on the DESS, with a standard deviation of 1.75 (at 
two-sided α=.05). With 49 subjects per taper group, we will have 70% power to detect a 
difference of 20% (10% vs 30%) incidence in ADM discontinuation syndrome.  
 
 
Adverse event reporting: 
 
Risks to participation 
 
Risks to participation include experiencing side effects from the taking or 
discontinuing antidepressant medications. All study antidepressants share some risks, 
including headache, nausea, anxiety, sleep and appetite disturbance.  In patients under 
age 25, antidepressant initiation and dose increase has been associated with a small 
increased risk of developing thoughts of self-harm or suicidal ideas.    
 
Benefits to subject or future benefits 
 
Patients who participate will receive an expert psychiatric assessment and 
treatment.  With treatment, patients may be able to come off ineffective or no longer 
desired antidepressant medication. Patients will have the benefit of participating in a 
clinical trial that could inform future treatment of patients with antidepressants.  
 
Training: 

 
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No training will be necessary for the rating scales used in this study because all 
research personnel involved in this project as they are currently trained and involved in 
ongoing clinical trials with mentally ill patients.  
 
Confidentiality: 
 
Patient’s confidentiality will be maintained throughout the duration of their study 
participation.  Patient files will be kept in locked offices, and the computerized data is 
kept on password-protected computers in the locked Mood and Anxiety Disorders 
Program offices. 
 
Informed consent: 
 
At the screening visit, patients will be provided with an informed consent form 
that will outline the risks and benefits of participating in this study.  It will also outline 
which assessments occur at the various study visits.    
 
Plans to inform participants of new findings or research results that might affect health: 
 
If new findings emerge regarding risks or benefits of the study medications used 
in our study, patients will be informed of this information as soon as possible and 
reminded of their ability to continue participation in the study at their own will.  
 
Data and safety monitoring plan (DSMP): 
 
The tapering regimens provided in this protocol are consistent with standard-of-
care for MDD, OCD, PTSD and anxiety disorders.  It is expected that some patients will 
experience the known antidepressant discontinuation symptoms – these will not be 
classified as adverse events.  Any unanticipated mental or physical symptoms that are 
not anticipated as adverse events (i.e., not listed on the DESS scale), or any breaches of 
confidentiality or other social harms will be coded as adverse events.  We will review the 
adverse event data twice-yearly to evaluate whether unexpected frequencies of adverse 
events are occurring.  
 
Plans for data management and monitoring: 
  
Data will be stored on an Excel spreadsheet on a password-protected computer, 
stored in our research clinic.   
 
Pharmaceutical, biologic, and device information: 
Package inserts for the antidepressants that could be used in the study are available 
at  http://dailymed.nlm.nih.gov/dailymed/about.cfm 
 
 
APPENDICIES 
Questionnaires and scales attached include:  
 
Hamilton Anxiety Rating Scale (HAM-A) 
Montgomery Asberg Depression Rating Scale (MADRS) 
Dunlop Emotional Blunting Scale (DEBS) 
Barratt Impulsiveness Scale (BIS) 
Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) 
Mini Neuropsychiatry Interview, Version 7.0 (MINI) 
Discontinuation Emergent Signs and Symptoms (DESS)  
Physician Withdrawal Checklist (PWC-20)  
Columbia Suicide Severity Rating Scale (CSSRS) 
Scale for Anxiety and Depression (paper version) 

 
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