Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications - Karger Publishers
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Standard Review Article
Psychother Psychosom 2020;89:283–306 Received: October 24, 2019
Accepted after revision: February 27, 2020
DOI: 10.1159/000506868 Published online: April 7, 2020
Acute and Persistent Withdrawal
Syndromes Following Discontinuation of
Psychotropic Medications
Fiammetta Cosci a, b Guy Chouinard c
a Department of Health Sciences, University of Florence, Florence, Italy; b Department of Psychiatry and
Neuropsychology, Maastricht University, Maastricht, The Netherlands; c Clinical Pharmacology and Toxicology
Program, McGill University and Mental Health Institute of Montreal Fernand Seguin Research Centre, University of
Montreal, Montreal, QC, Canada
Keywords alterations of clinical course, whereas the distress associated
Withdrawal · Discontinuation · Selective serotonin reuptake with benzodiazepines discontinuation appears to be short-
inhibitor · Serotonin noradrenaline reuptake inhibitor · lived. As a result, the common belief that benzodiazepines
Benzodiazepine · Antipsychotic · Lithium · Mood stabilizers · should be substituted by medications that cause less depen-
Antidepressant · Tolerance dence such as antidepressants and antipsychotics runs coun-
ter the available literature. Ketamine, and probably its deriva-
tives, may be classified as at high risk for dependence and
Abstract addiction. Because of the lag phase that has taken place be-
Studies on psychotropic medications decrease, discontinua- tween the introduction of a drug into the market and the de-
tion, or switch have uncovered withdrawal syndromes. The scription of withdrawal symptoms, caution is needed with
present overview aimed at analyzing the literature to illus- the use of newer antidepressants and antipsychotics. Within
trate withdrawal after decrease, discontinuation, or switch of medication classes, alprazolam, lorazepam, triazolam, parox-
psychotropic medications based on the drug class (i.e., ben- etine, venlafaxine, fluphenazine, perphenazine, clozapine,
zodiazepines, nonbenzodiazepine benzodiazepine receptor and quetiapine are more likely to induce withdrawal. The
agonists, antidepressants, ketamine, antipsychotics, lithi- likelihood of withdrawal manifestations that may be severe
um, mood stabilizers) according to the diagnostic criteria of and persistent should thus be taken into account in clinical
Chouinard and Chouinard [Psychother Psychosom. 2015;84 practice and also in children and adolescents.
(2):63–71], which encompass new withdrawal symptoms, re- © 2020 S. Karger AG, Basel
bound symptoms, and persistent post-withdrawal disorders.
All these drugs may induce withdrawal syndromes and re-
bound upon discontinuation, even with slow tapering. How- Introduction
ever, only selective serotonin reuptake inhibitors, serotonin
noradrenaline reuptake inhibitors, and antipsychotics were Psychotropic drugs may cause withdrawal reactions
consistently also associated with persistent post-withdrawal which can occur after abrupt discontinuation or gradual
disorders and potential high severity of symptoms, including tapering [1] with a prevalence of 54% among adults with
karger@karger.com © 2020 S. Karger AG, Basel Fiammetta Cosci
www.karger.com/pps Department of Health Sciences, University of Florence
Via di San Salvi, 12
IT–50135 Florence (Italy)
fiammetta.cosci @ unifi.itTable 1. New withdrawal symptoms following decrease, discontinuation, or switch of psychotropic medications
Type New withdrawal symptoms
Peak of onset 36–96 h (or later depending on drug duration of action)
Course Transient
Duration Up to 6 weeks (depending on drug elimination half-life)
Outcome Reversible, with complete recovery
Clinical manifestations Appearance of new symptoms, that is symptoms which were not experienced before the beginning of the
treatment
Diagnostic criteria (A) Dose decrease, discontinuation, or switch of a psychotropic medications
(B) Rapid appearance of at least 2 new symptoms which might be unspecific or specific for the psychotro-
pic medication class
(C) Symptoms in criteria B are characterized by a peak of onset within 36–96 h after decrease, discontinu-
ation, or switch of a psychotropic medication (depending on drug duration of action) and last for up to 6
weeks (depending on drug elimination half-life)
(D) Symptoms in criteria B cause clinically significant distress
(E) Symptoms in criteria B are not due to a general medical condition and are not better accounted for by
another mental disorder or substance use
a diagnosis of serious mental illness [2]. A recent review ible symptoms which represent a rapid return of the pri-
of the literature suggested that benzodiazepines, Z-drugs, mary symptoms usually at a greater intensity than before
ketamine, selective serotonin reuptake inhibitors (SSRIs), treatment [13, 14]. Third, persistent post-withdrawal dis-
serotonin-norepinephrine reuptake inhibitors (SNRIs), orders (Table 3) are a set of long-lasting, severe, poten-
tricyclic antidepressants (TCAs), antipsychotics, mono- tially irreversible symptoms [10] which entitle rebound
amine oxidase inhibitors (MAOIs), and gabapentin are primary symptoms or primary disorder at greater inten-
associated with withdrawal symptoms [3]. Thus, it con- sity and/or new withdrawal symptoms and/or new symp-
firmed what was previously reported in reviews focus- toms or disorders that were not present before treatment.
ing on specific drug classes [4–9]. Regarding SSRIs and They persist >6 weeks.
SNRIs, the term “discontinuation syndrome” had been Withdrawal from psychotropic medications can pro-
used for several years. However, this definition is no lon- duce psychiatric symptoms often confounded with re-
ger accepted; the term “withdrawal syndrome” is more lapse (i.e., a return of the same episode) or recurrence
appropriate and there are no reasons to believe that there (i.e., a new episode) of the original illness [10]. However,
are differences from other classes of psychotropic drugs both relapse and recurrence have 2 clinical features dif-
[3–5, 7, 10]. ferent from withdrawal syndromes: (1) the gradual onset
Based on the literature, Chouinard and Chouinard of the original symptoms and illness, while drug with-
proposed in 2015 [10] 3 types of withdrawal syndromes drawal produces acute, abrupt return; (2) symptom se-
for psychotropic medications: new withdrawal symptoms verity as before drug treatment, while drug withdrawal
[5, 11–16], rebound symptoms [1, 13, 14, 17–20], and produces greater severity [10]. On the other hand, Fava et
persistent post-withdrawal disorders [21, 22] (Tables al. [24] suggested that withdrawal from psychotropic
1–3). First, new withdrawal symptoms (Table 1) are usu- medications can be associated with modifications of the
ally short-lasting, transient, reversible symptoms, which illness course such as switching to mania as well as other
are new to the patient. New symptoms are usually the forms of tolerance [24] such as loss of antidepressant clin-
same, common to all psychotropic medications during ical effects [25], resistance when the same medication is
withdrawal [12, 15, 23] (e.g., nausea, headaches, sleep dis- administered again [26], and general refractoriness to
turbances) [10], but also specific and unique for a drug treatment [25, 27, 28].
class (e.g., specific serotonin-related symptoms: flu-like The aim of the present overview of the literature was
symptoms, diarrhea, confusion) [10]. Second, rebound to apply the use of the diagnostic criteria proposed by
symptoms (Table 2) are short-lasting, transient, revers- Chouinard and Chouinard [10] to illustrate withdrawal
284 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868Table 2. Rebound symptoms following decrease, discontinuation, or switch of psychotropic medications
Type Rebound symptoms
Peak of onset 36–96 h (or later depending on drug duration of action)
Course Transient
Duration Up to 6 weeks (depending on drug elimination half-life)
Outcome Reversible, with complete recovery
Clinical manifestations Return of the original symptoms at a greater intensity than before treatment
Diagnostic criteria (A) Dose decrease, discontinuation, or switch of a psychotropic medication
(B) Rapid return of original symptoms at a greater intensity than before treatment
(C) Symptoms in criteria B are characterized by a peak of onset within 36–96 h after decrease, discon-
tinuation, or switch of a psychotropic medication (depending on drug duration of action) and last for
up to 6 weeks (depending on drug elimination half-life)
(D) Symptoms in criteria B cause clinically significant distress
(E) Symptoms in criteria B are not due to a general medical condition and are not better accounted for
by another mental disorder or substance use
Table 3. Persistent post-withdrawal disorder following decrease, discontinuation, or switch of psychotropic medications
Type Persistent post-withdrawal disorder
Peak of onset 24 h to 6 week (or later depending on drug duration of action)
Course Persistent
Duration More than 6 weeks (depending on drug elimination half-life)
Outcome Potentially irreversible
Clinical manifestations Return of original symptoms at greater intensity and/or new withdrawal symptoms that persist over 6
weeks and/or appearance of new symptoms that were not present before
Diagnostic criteria (A) Dose decrease, discontinuation, or switch of a psychotropic medication
(B) Rapid return of original symptoms at a greater intensity than before treatment and/or rapid appear-
ance of new withdrawal symptoms which can be unspecific or specific for the psychotropic medication
class
(C) Symptoms in criteria B are characterized by a peak of onset within 24 h and 6 weeks after decrease,
discontinuation, or switch of a psychotropic medication (depending on drug duration of action), and last
more than 6 weeks (depending on drug elimination half-life)
(D) Symptoms in criteria B cause clinically significant distress
(E) Symptoms in criteria B are not due to a general medical condition and are not better accounted for by
another mental disorder or substance use
after decrease, discontinuation, or switch of psychotro- Methods
pic medications based on the drug class (i.e., benzodiaz-
epines, nonbenzodiazepine benzodiazepine receptor ag- Eligible articles included papers in English published
onists, antidepressants, ketamine, antipsychotics, lithi- in peer-review journals reporting data on adult subjects
um, mood stabilizers) and different molecules. The who decreased, discontinued, or switched psychotropic
ultimate purpose is to organize the data in a clinically medications.
useful way. MEDLINE was comprehensively searched from in-
ception to January 2020. In addition, a manual search of
reference lists from all articles selected, for full-text re-
Withdrawal Syndromes Psychother Psychosom 2020;89:283–306 285
DOI: 10.1159/000506868views, and relevant reviews were done. Search terms were reports of abrupt discontinuation of zolpidem were asso-
“discontinuation/withdrawal,” combined using the Bool- ciated with rebound insomnia [32, 33]; (3) three reports
ean “AND” operator with “benzodiazepine/nonbenzodi- of 2 cases of zolpidem withdrawal seizure were described
azepine benzodiazepine receptor agonist/Z-drug/antide- [34, 35]; (4) zopiclone, the S-isomer of eszopiclone, was
pressant/ketamine/esketamine/antipsychotic/neurolep- found to induce daytime inter-dose rebound anxiety [36].
tic/lithium/mood stabilizer.” There is no reason to believe that Z-drugs are any differ-
Titles and abstracts were screened by 1 reviewer (F.C.). ent than benzodiazepines. Short-acting and short elimi-
Articles appearing potentially relevant were retrieved and nation half-life Z-drugs with high potency are predicted
2 reviewers (F.C. and G.C.) independently assessed each to be similar to their benzodiazepine counterpart to pro-
of the full reports, arriving at consensus regarding eligi- duce withdrawal symptoms. Up to now, no data on per-
bility. sistent post-withdrawal disorders are published for Z-
When information about the methods or results was drugs. Apparently, little is still known on these recently
omitted, the writers of the report were contacted to obtain marketed molecules, and no studies evaluated how to
the missing information. In case of the suspect of dupli- manage withdrawal syndromes after their decrease or
cate publications, the authors of the reports were con- discontinuation. Published data so far have been linked
tacted to receive further details. directly or indirectly with pharmaceutical companies.
Since new withdrawal symptoms have been described
in the literature in several ways and using different words, New Withdrawal Symptoms after Benzodiazepine
a categorization used previously for antidepressant dis- Discontinuation
continuation symptoms [5, 6, 10] was adopted. It includes Benzodiazepine discontinuation is known to produce
general symptoms; cardiovascular symptoms; gastroin- minor as well as major new withdrawal symptoms. Table
testinal symptoms; genitourinary symptoms; sensory-re- 4 reports most frequent minor new withdrawal symp-
lated symptoms; neuro-muscular symptoms; sexual toms [37–41], among them sweating, tachycardia, nau-
symptoms; central nervous system symptoms (which sea, visual changes, tremor, confusion, restlessness. Ma-
were articulated as: neurological, cognitive, affective, psy- jor withdrawal symptoms, such as seizure [42, 43] and
chotic, behavioral, sleep-related symptoms). psychosis [43], are rare. Seizure usually occurs in predis-
posed subjects (i.e., history of brain damage, alcohol ad-
diction, abnormal electroencephalograms) [44] or in
Benzodiazepines and Nonbenzodiazepine those treated with drugs which lower the seizure thresh-
Benzodiazepine Receptor Agonists old (i.e., TCAs, bupropion, antipsychotics) [45].
New withdrawal symptoms are generally mild, tran-
The first systematic review on withdrawal symptoms sient, and subside within 2–4 weeks [46, 47]. They appear
associated with benzodiazepine discontinuation was more frequently [37, 44, 48] and are more severe [49] with
published in 1980 by the Committee on the Review of high-potency benzodiazepines with short to medium
Medicines [29]. Interestingly, they concluded that the elimination half-life. More new withdrawal symptoms
true addiction potential of benzodiazepines was low, were found upon discontinuation of lorazepam (high po-
since a dependence rate of 5–10 cases per million patient tency and short-acting) than with diazepam [38]. Elimi-
months was estimated [30]. Such cases of addiction were nation rates of benzodiazepines also predict the time of
more frequent in drug misusers. Few reports described onset [15] of new withdrawal symptoms: after discontin-
dependence during medically supervised treatment uation of rapidly eliminated benzodiazepines (i.e., loraz-
which occurred when high doses were used for extended epam, oxazepam) [50], new withdrawal symptoms oc-
periods [29]. curred within 48 h; with slowly eliminated benzodiaze-
As for nonbenzodiazepine benzodiazepine receptor pine (i.e., diazepam) new withdrawal symptoms occurred
agonists (i.e., eszopiclone, zaleplon, zolpidem, zopiclone), after 5 days with peak severity after 9.6 days. However,
or Z-drugs, when they are discontinued, patients also re- 75% of patients who withdrawn after long-term use of
port new withdrawal and rebound symptoms. Based on benzodiazepines developed new withdrawal symptoms
our review of what has been published in the literature, regardless of rapidly eliminated or slowly eliminated
we found: (1) one report of eszopiclone cessation pro- compounds [51].
duced new withdrawal symptoms (i.e., abnormal dreams, In the 12-year Luxemburg study (n = 214,170 sub-
nausea, upset stomach) and rebound anxiety [31]; (2) two jects), all available hypnotics (including triazolam) and
286 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868Table 4. New withdrawal symptoms after decrease or discontinuation of psychotropic medications
System involved Benzodiazepines Nonbenzodiazepine SSRI/SNRI Tricyclics, MAOIs, other Antipsychotics Lithium Mood stabilizers
benzodiazepine antidepressants
receptor agonists
General Sweating Sweating Sweating Sweating Sweating
Flu-like symptoms Flu-like symptoms Flu-like symptoms Flu-like symptoms Flu-like
symptoms
Headache Headache Headache Headache Headache
Flushing Flushing
Chills Chills Chills
Fatigue Fatigue Fatigue
Weakness Weakness Weakness
Pain Pain Pain
Malaise Malaise
Perceptual ataxia
Itching, skin rash
Tiredness
Lethargy
Infection
Hypothermia
Dizziness Dizziness
Lacrimation
Cardiovascular Tachycardia Tachycardia Tachycardia Tachycardia Tachycardia
Dizziness Dizziness Dizziness
Lightheadedness, vertigo Lightheadedness Lightheadedness
Chest pain Chest pain Chest pain
Hypertension Hypertension Hypertension
Postural hypotension Postural hypotension Hypotension
Vertigo
Syncope Pre-syncope
Dyspnea
Angina pectoris
Risk of myocardial infarction
Arrhythmia
Gastrointestinal Nausea Nausea Nausea Nausea Nausea Nausea
Vomiting Vomiting Vomiting Vomiting Vomiting
Anorexia, weight loss Anorexia, appetite Low appetite Anorexia Anorexia
problems
Diarrhea Diarrhea Diarrhea Diarrhea
Abdominal pain/cramp Abdominal pain/cramp/ Abdominal pain/cramp
distention
Loose stools Loose stools
Salivation
Esophagitis
Increased bowel
movements
Constipation
Dry mouth
Gastrointestinal Gastric problems Gastrointestinal problems Gastrointestinal
problems problems
Withdrawal Syndromes Psychother Psychosom 2020;89:283–306 287
DOI: 10.1159/000506868Table 4 (continued)
System involved Benzodiazepines Nonbenzodiazepine SSRI/SNRI Tricyclics, MAOIs, other Antipsychotics Lithium Mood stabilizers
benzodiazepine antidepressants
receptor agonists
Genitourinary Increased urinary
frequency
Sensory Electric shock sensations Electric shock sensations Electric shock sensations
Tinnitus Tinnitus
Blurred vision, visual Blurred vision, visual Photophobia
changes changes
Brain zaps Zaps Zaps
Hypersensitivity to touch/ Hyperesthesia
sound/smell
Taste/smell Altered taste
disturbances, metallic
taste in mouth
Perceptual distortions
(e.g., sensation of the floor
undulating)
Pruritus
Crowling/pricking
sensations
Buzzing noise within
the head
Neuromuscular Paresthesia Paresthesia Paresthesia Paresthesia
Myoclonus Myoclonus Inducible clonus
Tremor Tremor Tremor Tremor Tremor
Coordination problems Coordination problems Coordination problems Coordination
problems
Numbness Numbness
Stiffness Stiffness Stiffness
Myalgia Myalgia Myalgia Myalgia
Ataxia Ataxia Ataxia Ataxia
Muscular spasm Muscular spasm
Fasciculation
Twitches cramps Twitches cramps
Neuralgias
Jerkiness
Arthralgias
Cramp
Hemiplegia
Myosis
Hyperreflexia Hyperreflexia
Dystonia
Sexual Premature ejaculation Premature ejaculation
Genital hypersensitivity Genital hypersensitivity
Central nervous system
Neurological Seizures Seizures Seizures Seizures Tonic clonic seizures
Stroke-like symptoms
Coma
Akathisia Akathisia
Parkinsonism Parkinsonism
288 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868Table 4 (continued)
System involved Benzodiazepines Nonbenzodiazepine SSRI/SNRI Tricyclics, MAOIs, other Antipsychotics Lithium Mood stabilizers
benzodiazepine antidepressants
receptor agonists
Cognitive Confusion Confusion Confusion Confusion
Amnesia Amnesia Amnesia Ipomnesia
Decreased concentration Decreased concentration Decreased
concentration
Disorientation Disorientation
Lethargy Lethargy, drowsiness Lethargy
Attention difficulties Attention difficulties
Indecision
Slurred speech
Affective Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety
Agitation Agitation Agitation Agitation Agitation
Depression Depression Depression Depression Depression
Irritability Irritability Irritability Irritability Irritability Irritability
Panic Panic Panic
Derealization Derealization
Depersonalization Depersonalization Depersonalization Depersonalization
Dysphoria Dysphoria Dysphoria Dysphoria Dysphoria
Mood swings
Suicidal ideation
Hypomania, Hypomania, mania
euphoria
Anhedonia
Fear
Nervousness Nervousness
Tension Tension
Anger
Feeling of imminent death
Terror
Agoraphobia
Psychotic Hallucinations Visual/auditory Hallucinations Hallucinations
hallucinations
Delirium Delirium
Catatonia Catatonia
Paranoia Paranoia Paranoia
Distortion of body image
Psychosis
Delusions
Behavioral Restlessness Restlessness Restlessness Restlessness
Aggressive behavior Aggressive behavior Aggressive behavior
Impulsivity
Bouts of crying/outbursts
of anger
Withdrawal Syndromes Psychother Psychosom 2020;89:283–306 289
DOI: 10.1159/000506868Table 4 (continued)
System involved Benzodiazepines Nonbenzodiazepine SSRI/SNRI Tricyclics, MAOIs, other Antipsychotics Lithium Mood stabilizers
benzodiazepine antidepressants
receptor agonists
Sleep Insomnia Insomnia Insomnia Insomnia Insomnia
Nightmares Nightmares Nightmares
Sleep problems Sleep problems Restless sleep Sleep
problems
Abnormal dreams Vivid dreams Vivid frightening dreams
Hypersomnia
SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin noradrenaline reuptake inhibitor; MAOIs, monoamine oxidase inhibitors.
triazolo benzodiazepine, alprazolam, were found to be at following a bedtime dose of triazolam [71], daytime inter-
higher risk of continuous and high-dose use. In contrast, dose rebound anxiety in triazolam- and zopiclone-treated
anxiolytic benzodiazepines, in particular, clobazam and patients for insomnia in generalized anxiety disorder
clonazepam, were found to be significantly less problem- [36], clock-watching rebound anxiety 3–4 h after the last
atic having lower risk of high-dose use [52]. dose in lorazepam- and alprazolam-treated panic disor-
der patients [72].
Rebound Symptoms after Benzodiazepine Clonazepam [73–76] has a long elimination half-life,
Discontinuation induced less frequently rebound anxiety than alprazolam
Kales et al. [17] first reported rebound insomnia upon [77].
abrupt cessation of a nightly single dose of benzodiaze-
pines after short-term use. This was confirmed by other Persistent Post-Withdrawal Disorders after
studies [53–59]. Rebound anxiety was also observed [1, Benzodiazepine Discontinuation
38, 50]. It is an acute return of pretreatment anxiety above The literature on persistent post-withdrawal disorders
baseline following benzodiazepine withdrawal, even after after long-term benzodiazepine use and discontinuation
short-term use. The symptoms are transient but may last is hardly existent. Notwithstanding this, anxiety, depres-
3 weeks after drug cessation [20]. sion, psychosis, cognitive impairment, insomnia, sensory
The prevalence of rebound insomnia was found to be phenomena (i.e., tinnitus, tingling, numbness, paresthe-
significantly lower in all benzodiazepines compared to sia, deep or burning pain in limbs, feeling of inner trem-
triazolam [52, 60–69] and was lower than that with tri- bling or vibration, strange skin sensations), motor phe-
azolam. Thus, similarly to rebound anxiety, the risk seems nomena (i.e., muscle pain, weakness, painful cramps,
related to benzodiazepine elimination half-life and po- tremor, jerks, spasms, shaking attacks), and gastrointes-
tency [20, 23] and independent form the length of treat- tinal disturbances (patients complain of food intolerance
ment [1]. and gaseous abdominal distension) have been described
Short and intermediate elimination half-life benzodi- [41]. Length of treatment and high potency with short to
azepines are at a greater risk of rebound anxiety com- intermediate elimination half-life seem important to fa-
pared to long elimination half-life agents [20, 44, 70]. In vor the occurrence of persistent post-withdrawal disor-
a placebo-controlled double-blind study [1], abrupt with- ders [41]. It has been observed that withdrawal symptoms
drawal resulted in 7 cases of rebound anxiety: 5 of 7 after discontinuation of low-dose benzodiazepine may
(71.4%) treated with bromazepam and 2 of 7 (28.6%) take 6–12 months to subside completely [47] and in some
treated with diazepam, bromazepam is a high potency cases they persist for years [41].
benzodiazepine with intermediate elimination half-life,
whereas diazepam is a medium potency benzodiazepine Associated Clinical Manifestations
with long elimination half-life [14]. Rebound anxiety can We found no evidence in the literature for clinical
also occur during ongoing treatment with rapidly elimi- symptoms or disorders associated to withdrawal due to
nated benzodiazepines when their pharmacological ef- benzodiazepine decrease or discontinuation.
fects decrease. For example, increased daytime anxiety
290 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868Management of Benzodiazepine Discontinuation Antidepressants
Slow tapering, often extending over a year or more, has
been suggested to manage new withdrawal symptoms The literature indicates that antidepressant withdraw-
[78]. However, even a more flexible tapering at a rate that al reactions are frequent, with incidence rates ranging
the patient can tolerate, typically in about 3–6 months, from 27 to 86% (weighted average of 56%) [7]. Even
has shown to be appropriate [37]. Some authors suggest- though discontinuation symptoms were mostly reported
ed tapering from other BZDs such as lorazepam after sub- after abrupt discontinuation, they were found to occur
stituting diazepam [79], according to Murphy and Tyrer after gradual tapering [5, 6] and differ in prevalence ac-
[80] such substitution has shown little evidence to sup- cording to the pharmacological profile of the antidepres-
port its efficacy. sant [89].
The adjunct of cognitive behavioral therapy to a care- New withdrawal symptoms from TCAs were first re-
ful tapering schedule was found of limited value by ported with imipramine in 1959, described in 1961 [90],
Voshaar et al. [81], although 2 trials showed that cognitive and later confirmed [91]. In 1980 and 1990s, Dilsaver
behavioral therapy facilitated tapering among chronic documented general somatic and gastrointestinal dis-
benzodiazepine users [82, 83]. In addition, it has been tress; sleep disturbances characterized by initial and mid-
suggested that gradual discontinuation can reduce both dle insomnia or excessively vivid and frightening dreams;
rebound insomnia [84, 85] and rebound anxiety [1]. In akathisia or parkinsonism; hypomania or mania as man-
contrast, in a randomized controlled trial evaluating the ifestations of new withdrawal symptoms due to TCA dis-
relative efficacy of 3 interventions for benzodiazepine dis- continuation [92–95]. Cardiac arrhythmia rebound after
continuation among panic disorder patients (i.e., taper discontinuation of imipramine was described [96] and
alone, taper plus relaxation, and taper plus exposure- persistent insomnia following discontinuation or de-
based cognitive-behavioral therapy), the rate of success- crease of amitriptyline documented [13, 14].
ful discontinuation of benzodiazepine treatment was sig- Following abrupt discontinuation of MAOIs, severe
nificantly higher for those receiving the cognitive-behav- rebound panic was described [73] and subsequent studies
ioral program (13 of 17; 76%) than for those receiving the reported that new withdrawal symptoms may occur [97].
slow taper program alone (4 of 16; 25%); the results were Overall, TCAs and MAOIs aroused little interest [97],
confirmed at a 3-month follow-up [86]. These findings since withdrawal was seen in those days as part of a drug
suggest that cognitive behavioral therapy may help ben- treatment necessary for the patient illness and a progress
zodiazepine discontinuation. They were confirmed by compared to previous treatments.
Fava et al. [87] who observed an improvement in anxiety Case reports of new withdrawal symptoms (i.e., hypo-
and anxiety sensitivity after stopping long-term benzodi- mania, anxiety, restless sleep, nightmares, depersonaliza-
azepines in patients who had recovered from panic disor- tion, formication, headache) after discontinuation of tra-
der and agoraphobia after a successful behavioral treat- zodone were published [98–101].
ment. However, when Otto et al. [86] attempted to repli- Among noradrenergic and specific serotonergic anti-
cate their own results published in 1993, the effect size depressants (i.e., mirtazapine, mianserin, setiptiline),
was used instead of p values, since significance levels did clinical case reports described new withdrawal symptoms
not allow to identify differences between groups, only the (i.e., panic, anxiety, restlessness, irritability, hypomania,
number of years of benzodiazepine use emerged as a sig- insomnia, dizziness, paresthesia, nausea, vomiting) and
nificant predictor of benzodiazepine discontinuation in rebound mania after decrease or discontinuation of mir-
the regression models, only in the context of this single tazapine [102]. One case of seizure [103] and one case of
covariate the cognitive-behavioral therapy demonstrated panic attacks [104] were described after the abrupt dis-
significantly better outcome for benzodiazepine-free sta- continuation of mianserin, while no data were reported
tus than both relaxation and taper alone at 6-month fol- for setiptiline.
low-up [88]. One study found acute dystonia as new withdrawal
On the other hand, we did not find studies which in- symptom resulting from abrupt discontinuation of bu-
vestigate strategies to manage benzodiazepine persistent propion [105].
post-withdrawal disorders. The literature on the withdrawal of the more recently
introduced antidepressants other than SSRI/SNRI is lim-
ited. The discontinuation of agomelatine was investigated
in a 24-week randomized double-blind placebo-con-
Withdrawal Syndromes Psychother Psychosom 2020;89:283–306 291
DOI: 10.1159/000506868trolled study, after a brief 8- to 10-week open treatment being the least likely to be associated with severe depres-
[106]. The authors looked at adverse events “suggestive of sive and somatic symptoms [5, 111].
withdrawal symptoms” within the first month after ran- A systematic review of the literature [6] indicated that
domization in placebo-treated patients withdrawn from new withdrawal symptoms may occur also after discon-
agomelatine. They found 3 emergent potentially with- tinuation of SNRIs (i.e., venlafaxine, desvenlafaxine,
drawal symptoms (i.e., depression, irritability, palpita- duloxetine, milnacipran, levomilnacipran). Once again,
tions). However, they did not study withdrawal at the end new withdrawal symptoms include a wide range of clini-
of the 24-week randomized placebo-controlled study. In cal manifestations which are described in detail in Table
Stein et al. [107] and in Montgomery et al. [108], discon- 4. They occur irrespective of whether gradual or abrupt
tinuation symptoms in patients switched to placebo were discontinuation is implemented and are similar to those
similar to those of patients maintained on agomelatine. observed after discontinuation of SSRIs [5]. They typi-
No case reports after vilazodone or vortioxetine de- cally appear within a few days from drug discontinuation
crease or discontinuation are available. However, we and last a few weeks. The prevalence of new withdrawal
should keep in mind that new antidepressants have a symptoms vary among the different drugs but was highest
mechanism of action similar to that of first- and second- after the discontinuation of venlafaxine (rates of with-
generation antidepressants. The difference is that they drawal from controlled trials and open trials rage from 23
have new, or different, receptor targets, but the approach to 78%) and lowest after the discontinuation of levomil-
of looking for antidepressants which inhibit neurotrans- nacipran (rates of withdrawal from controlled trials and
mitters reuptake is repeated [109]. Thus, future reviews open trials rage from 9 to 10%) [6].
of the literature might report more evidence on with-
drawal syndromes after decrease or discontinuation of Rebound Symptoms after SSRIs/SNRIs
new antidepressants; this is likely because of their rela- Discontinuation
tively recent release: the delay between the placing on the Controlled discontinuation studies [111, 113, 114]
market of a drug and the publication of the first reports showed that rebound may occur following SSRI discon-
on adverse events is widely known for every new mole- tinuation. Rebound depression has been observed at a
cule. greater frequency with paroxetine or short-acting SSRIs
SSRIs are the leading cause of withdrawal, followed by [10, 13]. In 2 double-blind placebo studies, patients with
SNRIs [7]. The first systematic review of SSRIs withdraw- major depression had their maintenance medications
al reactions was published in 2015 [5] and a few years (paroxetine, sertraline or fluoxetine) discontinued after
later, Fava et al. [6] published the first systematic review 4–24 months and replaced with placebo and then reinsti-
on SNRIs. tuted [111, 113]. In one of the studies [111], patients tak-
ing paroxetine or sertraline had a sudden worsening of
New Withdrawal Symptoms after SSRIs/SNRIs depressive symptoms upon drug discontinuation with a
Discontinuation return to pre-placebo measurements following re-institu-
New withdrawal symptoms following decrease or dis- tion of the drug. In both studies [111, 113], patients treat-
continuation of SSRIs have been widely documented and ed with paroxetine had acute return of pre-treatment
include a wide range of symptoms [5] which are listed in symptoms [10, 111, 113], while patients taking fluoxetine
detail in Table 4. did not.
Peaks of onset occur 36 h to 10 days after dose decrease Few studies also reported on rebound anxiety after
or discontinuation, they are usually reversible and last venlafaxine discontinuation [115, 116].
from a few hours to 6 weeks [5, 16, 97]. Their frequency
and duration depend on the drug discontinued [5, 16, 97]. Persistent Post-Withdrawal Disorders after SSRIs/
A bulk of literature, derived from controlled trials [18, SNRIs Discontinuation
110, 111], case reports [19], and patients’ online reports After SSRIs long-term use, persistent post-withdrawal
[112], showed that new withdrawal symptoms may occur disorders have been described [10, 13, 18, 19, 112, 117,
with any type of SSRI, but paroxetine is the most likely to 118]. Following discontinuation of a long-term treatment
be associated with new symptoms, while fluoxetine being with paroxetine, Shoenberger [117] first reported the
the least associated. Severity varies according to the SSRI, emergence of persistent post-withdrawal panic disorder,
paroxetine being the most likely to be associated with se- which was some years later also documented by Bhanji et
vere depressive and somatic symptoms, and fluoxetine al. [18]. Fava et al. [19] conducted a study of gradual SSRI
292 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868discontinuation in panic disorder and found that 3 out of it has been described the case of a patient in which PSSD
the 9 patients treated with paroxetine had persistent post- symptoms were part of a broader syndrome which was
withdrawal disorders after 1-year post-withdrawal. Be- diagnosed as persistent post-withdrawal disorder [129].
laise et al. [112] analyzed online reports from individuals This case rises the suspicion that PSSD might be a with-
who described persistent post-withdrawal disorders after drawal syndrome occurring after decrease/discontinua-
SSRI discontinuation; the most frequent disorders were: tion of SSRIs or SNRIs and that withdrawal symptoms
disturbed mood, depression, emotional liability, mood might include a wider variety of sexual manifestations
swings, irritability, anxiety, insomnia, impaired concen- which are under-reported, probably due to a poor atten-
tration, impaired memory. In another study, following tion of clinicians toward sexual symptoms and a lack of
paroxetine cessation, Belaise et al. [118] reported the investigations by clinicians as well as researchers [129].
emergence of persistent post-withdrawal disorders such
as pathological gambling and generalized anxiety. Stock- Associated Clinical Manifestations
mann et al. [119] analyzed the content of a sample of posts Withdrawal syndromes after decrease or discontinua-
on an antidepressant withdrawal website and found that tion of antidepressants may be associated with additional
patients assessing antidepressant withdrawal websites re- clinical manifestations. They include modifications of the
port experienced persistent post-withdrawal disorders illness course, such as switching to mania or other forms
more frequently with SSRIs than SNRIs, with neurolog of excessive behavioral activations [24], but also loss of
ical symptoms more common among SNRI users and clinical effects and refractoriness to treatment; they have
psychosexual/genitourinary symptoms more common been reported with SSRI and SNRI [5, 6, 27]. When mania
among SSRI users. Finally, Chouinard and Chouinard or other forms of excessive behavioral activations occur,
[10] illustrated 3 cases of persistent post-withdrawal dis- it may be self-limiting or may require specific anti-manic
orders: one had generalized anxiety disorder, one cyclo- treatment [130]. Loss of clinical effects involves the return
thymic disorder, and one had major depressive episode of symptoms during maintenance treatment that only
with melancholic features. Overall, based on the literature temporarily respond to dose increase [25]. Refractoriness
here described, which is still limited, paroxetine seems at to treatment is the lack of response to a previously effec-
higher risk to induce persistent post-withdrawal disor- tive pharmacological treatment when it is started again
ders than other SSRIs. after a drug-free period [25], as was reported in the case
Episodes of long duration of withdrawal symptoms illustrated by Jha et al. [89].
(i.e., depression, anxiety, mania, tinnitus, nausea, unex-
plained fear, and dizziness) were described after SNRIs Management of SSRIs/SNRIs Discontinuation
discontinuation, suggesting the occurrence of persistent An initially hypothesized strategy to manage antide-
post-withdrawal disorders [120–123]. To be noted that 3 pressant withdrawal was restarting the antidepressant
out of the 4 studies reporting SNRI persistent post-with- [97]; of course this meant for the patients never being able
drawal disorders were on venlafaxine [120–122] and 1 to decrease or discontinue the drug which was responsi-
was on duloxetine [123]. ble for the withdrawal manifestation. Thereafter, it was
Finally, since 2006, persistent sexual side effects after proposed to switch to a longer half-life SSRI (i.e., fluox-
SSRIs and SNRIs discontinuation have been described etine) [111], since it is less likely to induce withdrawal
[124]. These sexual manifestations have been rapidly problems; however, this switch may favor subsequent ep-
identified as a syndrome called post-SSRI sexual dysfunc- isodes of illness deterioration [27]. Another suggested op-
tion (PSSD) [125], that is a sexual dysfunction, caused by tion was slow tapering; however, it was shown that with-
both SSRIs and SNRIs, characterized by a decrease or ab- drawal symptoms and syndromes may occur during and
sence of libido, genital anesthesia, numbness in nipples, despite slow tapering [5, 6]. A hyperbolically decreasing
orgasmic disorders (i.e., anorgasmia or anhedonic or- pattern of SSRI dose decrease has been recently proposed
gasm), erectile dysfunction, delayed or premature ejacu- to produce a linear reduction of pharmacological effect
lation, testicular pain or atrophy (in males), lack of lubri- [131], but its validity needs to be tested in randomized
cation (in females) and by psychological symptoms such controlled trials. A multistep dose reduction paradigm
as anhedonia, difficulty in concentrating, memory prob- was suggested by Ruhe et al. [132]. In this paradigm, the
lems, inability to experience sexual attraction to the sight, initial step is to reduce the dose to half of the minimally
touch, or idea of a sexual partner [125–127]. The symp- effective dose in 1 week and then reduce very gradually.
toms may last months or even years [127, 128]. Recently, However, even this approach has not been tested yet.
Withdrawal Syndromes Psychother Psychosom 2020;89:283–306 293
DOI: 10.1159/000506868Regarding non-pharmacological interventions, when regarding the safety of esketamine […]. The risks of abuse
a group cognitive-behavioral therapy aimed at relapse and associated harms are important considerations in de-
prevention was proposed to patients who were tapering termining appropriate risk mitigation strategies and post
antidepressants within 4 months according to a fixed marketing surveillance for esketamine” [143]. Addition-
schedule, only 37% (n = 26) of the subjects succeeded in ally, the FDA reported that the safety concerns for esket-
discontinuing the drug and only 28% (n = 20) succeeded amine are misuse, abuse, dissociation, and sedation, for
in discontinuing without recurrence. This finding sug- which a Risk Evaluation and Mitigation Strategy was
gests that cognitive behavioral therapy does not help with planned [143, 144].
antidepressants withdrawal. However, the results might New acute withdrawal symptoms after ketamine dis-
be partly due to the timing of administration of the cog- continuation have been described. They are craving, dys-
nitive-behavioral therapy, which was simultaneous with phoria, shaking, sweating, palpitations, tiredness, low ap-
the discontinuation period, although it is known that the petite, low mood, chills, autonomic arousal, lacrimation,
right timing of cognitive-behavioral therapy is crucial restlessness, anxiety, nightmares, paranoia, delusions,
[118], as well as to the vulnerability of the sample under and hallucinations [145–147]. Addiction websites (i.e.,
study, the majority had unsuccessfully tried to discon- American Addiction Centers and Addiction Center) also
tinue before [133]. mentioned agitation, confusion, loss of motor skills, rage,
Fava and Belaise [27] proposed pharmacological (i.e., nausea, decreased respiratory and cardiac functions, in-
lessen withdrawal symptomatology by the use of psycho- somnia, cognitive impairment, tremors [3]. New with-
tropic drugs that are not antidepressants, for instance drawal symptoms typically begin within 24 h of discon-
clonazepam) and non-pharmacological (i.e., a 3-module tinuation and last approximately 3 days, although in some
intervention which includes explanatory therapy, cogni- cases, they may persist for 2 weeks and thereafter stabilize
tive behavioral treatment, and well-being therapy) strate- [3].
gies to manage SSRI withdrawal which are, however, In view of the inevitable decay of the response to ket-
based on their extensive clinical experience and in need amine due to pharmacological tolerance [148] and its
of being tested in randomized clinical trials. possible benefit as maintenance therapy in treatment-re-
sistant depression [142], and considering that some clini-
cians use ketamine formulations for chronic use despite
Ketamine and Esketamine the alarm regarding “the rapid proliferation of off-label
ketamine administration in the absence of evidence of
Esketamine, the enantiomer of ketamine and an lasting therapeutic benefit or safety with long-term ad-
NMDA receptor antagonist, has been marketed as nasal ministration” [p. 686 in 142], the use of ketamine in psy-
spray approved by the Food and Drug Administration chiatry is at risk of replicating the 2016 opioid US epi-
(FDA) in 2019 for intranasal treatment of treatment-re- demic abuse [149] with the risk to induce neurotoxicity,
sistant depression in conjunction with an oral antidepres- which might be associated with persistent post-with-
sant [134, 135]. drawal disorders.
Ketamine (intravenous anesthetic) and esketamine
(nasal spray) potentially produce psychological depen-
dence and rapidly induce pharmacological tolerance Antipsychotics
[136–139]. Ketamine is used for recreational purposes
because it produces mental and behavioral changes, such Chouinard et al. [9] described withdrawal reactions
as euphoria, perceptual changes, dissociation, and hallu- due to antipsychotics dose decrease, discontinuation, or
cinations [140]. These effects, together with a risk of switch and concluded that acute withdrawal symptoms,
abuse and misuse, made ketamine a popular street drug, rebound, and persistent post-withdrawal disorders may
also known as “Special K” [141]. In addition, a prolonged occur and that 2 persistent post-withdrawal disorders,
exposure to ketamine may predispose to neurotoxicity tardive dyskinesia and supersensitivity psychosis, were
[142]. specifically induced by antipsychotics [21, 22, 150, 151].
Studies showing that esketamine has less risks of abuse Studies on withdrawal reactions associated with antipsy-
than ketamine are lacking. Before approval, the FDA chotics switch were extensively reviewed also by Cerovecki
committee wrote in its documentation that “data on safe- et al. [8] and similar conclusions were reached.
ty of ketamine may be considered relevant to discussions
294 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868In the era of first-generation antipsychotics (FGAs) risperidone, ziprasidone). They evaluated 61 studies and
both supersensitivity psychosis and tardive dyskinesia 7 case reports. Among the 61 studies, 32 (52%) did not
were widely studied [9]. Second-generation antipsychot- report withdrawal or rebound symptoms, while 14 re-
ics (SGAs) decreased the prevalence of drug-induced ported new withdrawal symptoms. Among the case re-
movement disorders, including tardive dyskinesia [13], ports, 5 did not report new withdrawal or rebound symp-
but concerns [13] have remained about supersensitivity toms. In 1 case, the switching from clozapine triggered
psychosis [9]. Since both FGAs and SGAs have shown to new withdrawal symptoms.
trigger withdrawal at decrease, switch, or discontinua- Overall, SGAs are associated as frequently with new
tion, we will here describe the literature on antipsychotics withdrawal symptoms as FGAs, when we take into con-
withdrawal using Chouinard and Chouinard [10] diag- sideration the early 1960–1970 studies of FGAs.
nostic criteria and highlighting the different impact,
when present and available, of FGAs and SGAs. Rebound Symptoms after Antipsychotic
Discontinuation
New Withdrawal Symptoms after Antipsychotic Rebound symptoms have been described during dis-
Discontinuation continuation and switch [9]. Rebound psychosis is a rap-
New withdrawal symptoms following dose decrease, id return above pretreatment levels of original symptoms
discontinuation, or switch may occur with any type of (i.e., illusion, hallucination, catatonia, passivity experi-
antipsychotic and include a wide range of symptoms [8, ence, delusion) [152, 153]. It is generally short lasting (i.e.,
9] which are reported in Table 4.al symptoms and/or emerging new psychotic symptoms higher total scores for drug-induced movement disorders
of another type, such as disorganized behavior, persist on the Extrapyramidal Symptom Rating Scale and higher
longer than 6 weeks, have been described after discon- scores on the negative symptoms sub-scale of the Brief
tinuation of antipsychotics. In addition to the several Psychiatric Rating Scale. The SP group showed signifi-
clinical manifestations of persistent post-withdrawal dis- cantly greater improvement on the Brief Psychiatric Rat-
orders which have been observed also for other psycho- ing Scale total score than non-SP group. Kimura et al.
tropic medication classes, 2 specific persistent post-with- [167] did a second-year follow-up, similar results were
drawal disorders, named persistent post-withdrawal tar- found. Patients with SP showed greater improvement on
dive dyskinesia and persistent post-withdrawal positive and negative symptoms and significantly less re-
supersensitivity psychosis, have been well described [21, lapses during the first- and second-year follow-up, com-
22, 150, 151]. Thus, when dyskinesia or psychosis last 6 weeks after peak
onset [22]. Kimura et al. [158] studied long-acting inject- Associated Clinical Manifestations
able risperidone as adjunctive therapy to treatment-resis- Persistent post-withdrawal tardive diskinesia and per-
tant schizophrenia in a 1-year multicenter prospective sistent post-withdrawal supersensitivity psychosis may
follow-up study, the mean dose was equivalent to 1,000 be associated with additional clinical manifestations.
mg/day chlorpromazine. They found a prevalence of SP They include loss of clinical effects, modifications of the
of 65%. At baseline, schizophrenia patients with SP had illness course, and refractoriness to treatment [169, 170].
296 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
DOI: 10.1159/000506868Loss of clinical effects implies the occurrence of relapse in Other Mood Stabilizers
treatment adherent schizophrenic patients who did not
discontinue or decrease or switch the drug [169, 170]. Re- Food and Drug Administration approved anticonvul-
lapse is also characterized by modifications of the illness sants for the treatment of bipolar disorder in adults; they
course: positive psychotic symptoms are more severe are carbamazepine, valproate, lamotrigine [176].
[169], the duration of the episode is longer [169], and The literature on withdrawal after decrease or discon-
more residual negative symptoms occur [170]. Refracto- tinuation of carbamazepine in psychiatric patients is lim-
riness to treatment is another possible manifestation ited. However, a preliminary study on carbamazepine-
since relapse occurs when the patients are treated with associated withdrawal reaction after microvascular de-
higher doses of antipsychotics [169]. compression to treat trigeminal neuralgia showed the
occurrence of new withdrawal symptoms (i.e., insomnia,
Management of Antipsychotic Discontinuation dysphoria, hand fremitus, hallucination, severe head-
A gradual decrease over a long period of time, over ache), which were found dependent on the pre-operative
several months when clinically appropriate, was suggest- dosage of carbamazepine and the changing rate of pre-
ed to reduce the severity of new withdrawal and rebound and post-operative drug blood concentrations [177]. In
symptoms [1], however this strategy does not reduce the addition, in patients with active epilepsy, the following
risk of occurrence of new withdrawal and rebound symp- new withdrawal symptoms were observed at decrease of
toms and has not shown effects on persistent post-with- carbamazepine (which was part of a programmed ratio-
drawal disorders [9]. The use of adjunctive long half-life nalization of therapy for each patient): anxiety, tension,
drugs, such as long-acting injectable SGAs, and antisei- agitation, irritability, lack of energy, impaired memory/
zure drugs has been proposed for the treatment of with- concentration, depression, depersonalization, insomnia,
drawal syndromes [9]. Lamotrigine and antiseizure drugs anorexia, headache, muscle aches, twitching, tremor,
(in particular valproic acid, carbamazepine, phenytoin) shaking, dizziness, incoordination, paranoia, hyper-re-
have been suggested as useful for supersensitivity psycho- flexia, gait ataxia, hypotension, tachycardia, faintness
sis [171], while clozapine and risperidone were consid- [178].
ered palliative treatment [158–160]. Limited data are Also, the literature on withdrawal due to decrease or
presently available for other potential pharmacological discontinuation of valproate or lamotrigine in psychiatric
intervention of supersensitivity psychosis (e.g., clozapine, patients seems limited although some studies on epileptic
asenapine, blonanserin) [9]. patients are available. Duncan et al. [178] found the fol-
Given the evidence for the risk of rebound withdrawal lowing new withdrawal symptoms at decrease of sodium
with quetiapine, doses ≤150 mg/day of quetiapine as ad- valproate in patients with active epilepsy: anxiety, agita-
junctive therapy instead of monotherapy was recom- tion, irritability, lack of energy, impaired memory/con-
mended [157, 172]. When giving quetiapine as adjunctive centration, depression, depersonalization, insomnia, an-
or monotherapy for 2 months and more, attempts to de- orexia, tension, headache, muscle ache, twitching, nau-
crease the dose with alternate dosing interval or with sea/vomiting, tremor, shaking, hyperreflexia, sweating,
gradual decrease of quetiapine daily dose were recom- dizziness, photophobia, incoordination, faintness, tachy-
mended [9]. cardia. However, in Duncan et al. [178] study, which was
also mentioned for carbamazepine, new withdrawal
symptoms occurred also in those who remained on stable
Lithium therapy (the entire study was double-blind, with match-
ing placebos replacing active drug in a stepwise fashion).
The evidence for withdrawal after lithium decrease or Gelisse et al. [179] observed a case who presented anhe-
discontinuation is weak and ambiguous. Early manic and donia, tremor, slight tachycardia, and severe hands hy-
depressive recurrences after lithium discontinuation may perhidrosis, which were considered new withdrawal reac-
suggest rebound symptoms, but studies carried out with tions to lamotrigine discontinuation. In addition, 6 epi-
appropriate methodology failed to confirm it [173]. Anx- leptic patients on stable-dose lamotrigine monotherapy
iety, sleep problems, and irritability following lithium presented end-of-dose new withdrawal symptoms (i.e.,
discontinuation were suggested as new withdrawal symp- anxiety, emotional lability, irritability) [180].
toms in one review [174] and in one study [175]. No data No data are available on rebound symptoms and per-
on persistent post-withdrawal disorders are available. sistent post-withdrawal disorders.
Withdrawal Syndromes Psychother Psychosom 2020;89:283–306 297
DOI: 10.1159/000506868Table 5. Withdrawal at decrease, discontinuation, or switch of psychotropic medications
Type of withdrawal according to Drug classes Molecules
Chouinard and Chouinard [10]
(2015) diagnostic criteria
New withdrawal symptoms MAOIs
TCAs
Trazodone
Noradrenergic and specific serotonergic antidepressants Mirtazapine
Bupropion
Lithium
Food and Drug Administration-approved mood stabilizers for
the treatment of bipolar disorder in adults
New withdrawal symptoms Benzodiazepines Alprazolam, triazolam
rebound symptoms
Z-drugs Eszopiclone
New withdrawal symptoms SSRIs, SNRIs Paroxetine, venlafaxine
rebound symptoms persistent
postwithdrawal disorders First-generation antipsychotics, second-generation Quetiapine, clozapine
antipsychotics
New withdrawal symptoms Ketamine Ketamine
TCAs, tricyclic antidepressants; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin noradrenaline reuptake inhibitors;
MAOIs, monoamine oxidase inhibitors.
Considering that the phenomenon of withdrawal after illness symptoms, including alterations of clinical course.
discontinuation of anticonvulsants seems documented in Regarding specific molecules, alprazolam, lorazepam, tri-
the neurologic literature only, attention on this topic azolam, paroxetine, venlafaxine, clozapine, and quetiap-
should be turned on by psychiatrists who use anticonvul- ine are more likely to induce withdrawal than other com-
sants as mood stabilizers. pounds of the same class.
Table 5 content should be evaluated under the light of
the timing of release on the market of the different class-
Discussion es of drugs. Additional research reports may come for Z-
drugs, the more recent zaleplon was approved only in
Psychotropic Medications in the Debate on Substance 1999. The literature on SNRIs may increase since they
Use Disorders were released 13 years later SSRIs. Additional evidence is
Like all other pharmacological agents used in medi- also expected for new antidepressants. Interestingly, al-
cine, psychotropic medications discontinuation can in- though esketamine was approved only on March 05, 2019
duce withdrawal syndromes but not all psychotropic by the FDA as medication for treatment-resistant depres-
medications are the same between classes and within a sion, the literature on ketamine already shows new with-
class [13, 181]. A summary of the types of withdrawal at drawal symptoms and neurotoxicity, which may indicate
decrease, discontinuation, or switch of psychotropic future evidence of persistent post-withdrawal disorders.
medications is proposed in Table 5. Ketamine has a ca- Finally, knowledge on FDA-approved mood stabilizers
pacity to induce drug use disorders including psycholog- for the treatment of bipolar disorder in adults is limited
ical problems and tolerance. In addition, SSRIs, SNRIs, to the neurologic field.
antipsychotics were consistently associated with persis- In this framework, it seems important to clarify wheth-
tent post-withdrawal disorders and increased severity of er the clinical phenomenon of withdrawal can equate psy-
298 Psychother Psychosom 2020;89:283–306 Cosci/Chouinard
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