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Tapering of SSRI treatment to mitigate withdrawal symptoms

Mark Abie Horowitz, David Taylor

All classes of drug that are prescribed to treat depression are associated with withdrawal syndromes. SSRI withdrawal Lancet Psychiatry 2019
syndrome occurs often and can be severe, and might compel patients to recommence their medication. Although the Published Online
withdrawal syndrome can be differentiated from recurrence of the underlying disorder, it might also be mistaken for March 5, 2019
http://dx.doi.org/10.1016/
recurrence, leading to long-term unnecessary medication. Guidelines recommend short tapers, of between 2 weeks S2215-0366(19)30032-X
and 4 weeks, down to therapeutic minimum doses, or half-minimum doses, before complete cessation. Studies have
Prince of Wales Hospital,
shown that these tapers show minimal benefits over abrupt discontinuation, and are often not tolerated by patients. Sydney, NSW, Australia
Tapers over a period of months and down to doses much lower than minimum therapeutic doses have shown greater (M A Horowitz PhD); Health and
success in reducing withdrawal symptoms. Other types of medication associated with withdrawal, such as Environment Action Lab,
London, UK (M A Horowitz);
benzodiazepenes, are tapered to reduce their biological effect at receptors by fixed amounts to minimise withdrawal
and Institute of Pharmaceutical
symptoms. These dose reductions are done with exponential tapering programmes that reach very small doses. This Science, King’s College London,
method could have relevance for tapering of SSRIs. We examined the PET imaging data of serotonin transporter London, UK (Prof D Taylor PhD)
occupancy by SSRIs and found that hyperbolically reducing doses of SSRIs reduces their effect on serotonin Correspondence to:
transporter inhibition in a linear manner. We therefore suggest that SSRIs should be tapered hyperbolically and Dr Mark Abie Horowitz, Prince of
Wales Hospital, Sydney,
slowly to doses much lower than those of therapeutic minimums, in line with tapering regimens for other medications
NSW 2031, Australia
associated with withdrawal symptoms. Withdrawal symptoms will then be minimised. [email protected]

Introduction withdrawal effects and reported that nearly half of par­

Many medications are associated with withdrawal ticipants who had experienced withdrawal effects chose
syndromes, most commonly those that act on the the most extreme option in the scale offered to them to
cardiovascular system and CNS.1 All major classes of describe the severity of those effects.13 The discontinuation
antidepressants—monoamine oxidase inhibitors, tri­cyclic period (14 days after cessation) is also associated with a
antidepressants, SSRIs, and SNRIs—are associated with 60% increase in suicide attempts compared with previous
withdrawal symptoms on cessation.2,3 The term discon­ users of antidepressants (the increased risk therefore
tinuation syndrome was coined to refer to the withdrawal attributed to the process of withdrawal and not to being
syn­ drome related to antidepressants.4 SSRI discontin­ untreated).20
uation syndrome, as outlined in DSM-5,5 and captured in SSRI withdrawal syndrome can last substantially longer
the Discontinuation-Emergent Signs and Symptoms than the period of 1–2 weeks13 that has been previously
checklist,6 comprises a wide variety of somatic and suggested.4 In one study, withdrawal symptoms generally
psychological symptoms (figure 1). lasted for up to 6 weeks, with a quarter of patients
SSRI withdrawal symptoms can, in part, resemble the reporting symptoms that lasted more than 12 weeks.18
symptoms of anxiety or depression for which the Another study reported that for 86·7% of respondents the
medication was originally given.5 However, the with­ syndrome had lasted at least 2 months, for 58·6% it had
drawal syndrome can be distinguished from a relapse or lasted at least 1 year, and for 16·2% it had lasted for more
recurrence of the underlying disorder by its quickness of than 3 years.21 Case reports identify symptoms lasting for
onset (days rather than weeks),3,7,8 rapid response to a year or longer.22,23
reintroduction of the SSRI (generally within hours, The increasingly long-term use of SSRIs (with nearly
certainly within days),3,7,9 and the presence of somatic and half of the patients in the UK who take antidepressants
psychological symptoms quite distinct from the original [usually SSRIs] doing so for more than 2 years)19,24 has
illness (including dizziness, nausea, and shock-like arisen in part because patients are unwilling to stop due
sensations).7,10 The withdrawal syndrome can be mis­ to the aversive nature of the withdrawal syndrome,19,25
diagnosed as depressive recurrence, leading to prolonged and a scarcity of information on how to mitigate the
treatment for patients who might not require it,11–13 but it syndrome.19,25 Doctors feel that there is not enough
is not clear how often this occurs.14 guidance on how to proceed with discontinuation.19
SSRI withdrawal symptoms occur in many patients,
with reported incidence varying from 42% to 100% for Tapering SSRIs
paroxetine,6,15–18 and from 9% to 77% for fluoxetine,6,15,17,18 Guidelines recommend short tapers of SSRIs, rather than
with a mean rate of 53·6% for SSRIs across 14 studies abrupt discon­tinuation, to avoid withdrawal symptoms.
that examined antidepressant withdrawal.13 The incidence The National Institute for Health and Care Excellence,26
and severity appear to be influenced by half-life and the British Association for Psychopharmacology,12 the
receptor affinities, treatment duration and dose, method Monthly Index of Medical Specialities,27 and UpToDate28
of tapering, and individual patient characteristics, poten­ suggest tapering periods of between 2 weeks and 4 weeks,
tially including anticipation effects.3,9,19 A systematic with linear reductions of dose down to the minimum
review identified five studies that evaluated the severity of therapeutic dose, or half of the minimum therapeutic

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 Personal View

required to avoid withdrawal symptoms in one man,

Affective symptoms Sleep disruption whose withdrawal-induced orthostatic hypotension
Irritability Insomnia
Anxiety or agitation Nightmares allowed objective measurement.36
Low mood or depression Excessive dreaming Two studies from 2018 confirm that shorter tapering
Sensory symptoms Tearfulness
Dread
regimens, as advised by guidelines, are not effective. One
Paraesthesia
Numbness Gastrointestinal symptoms
study found that tapering over 4 weeks was not feasible,
Shock-like sensations Nausea with 60% of patients (51 of 85) tapering their medications
Rushing noises Vomiting
Palinopsia (visual trails)
over 4 months.39 Another study that used largely linear
SSRI withdrawal Diarrhoea
Anorexia reductions, with final doses equal to minimum thera­
(discontinuation)
syndrome peutic doses (or half that value) found that only 37% of
General somatic symptoms patients (26 of 71) were able to discontinue their
Flu-like symptoms Sexual symptoms
Lethargy or fatigue Genital hypersensitivity medication.40 A large study involving 400 patients showed
Headache Premature ejaculation a significantly lower risk of relapse if antidepressants
Tremor Disequilibrium
Sweating Dizziness (most common)
were tapered gradually (>14 days) rather than rapidly
Anorexia Light-headedness Cognitive symptoms (1–7 days).41
Weakness Vertigo Confusion
Tachycardia Ataxia
Gait instability
Decreased concentration
Amnesia
Neurobiology of withdrawal and its
management
The strategy of tapering SSRIs is based on the rationale
Figure 1: Symptoms of SSRI withdrawal (discontinuation) syndrome
that biological systems will have more time to adapt
to reductions in available ligand, thus reducing the
dose, before complete cessation. These guidelines suggest intensity of withdrawal symptoms.3,12,32,42 Receptors that
that fluoxetine does not require tapering,28 or that, at are activated by a medication are often downregulated, or
high doses, it could be reduced over 2 weeks.27 Drug exhibit reduced sensitivity, to maintain homoeostasis.43
manufacturer advice was found to be similarly “vague Abrupt removal of medication disturbs the homoeostatic
and non-specific” according to a systematic review.29 equilibrium, resulting in reduced stimulation, which is
In randomised studies, tapering for up to 14 days experienced as withdrawal symptoms that are often
showed either no16 or minimal30 reduction in withdrawal opposite in nature to the original effect of the drug.43
symptom severity compared with abrupt discontinuation.31 For example, the withdrawal syndrome from tricyclic
It has generally been concluded from these studies that antidepressants, which have strong anti­ cholinergic
longer tapering regimens are required.3,32 Indeed, studies actions, is typified by cholinergic effects.44 Adaptation to
using tapering periods of months in duration33–35 have medication is more likely in the case of long-term and
shown better outcomes (table 1). In one study, reduction high-dose use.45,46 Medications with shorter half-lives
of paroxetine by 10 mg every 2 weeks lowered withdrawal produce withdrawal symptoms with greater incidence,
incidence from 33·8% to 4·6%.33 When the patients greater severity, and quicker onset than medications with
who had withdrawal symptoms in this study were longer half-lives, probably because their withdrawal is
recommenced on medication and then tapered at 5 mg associated with more rapid decreases in the amount of
every 2–4 weeks, withdrawal symptoms were successfully available ligand.45,47,48 Withdrawal symptoms can usually
avoided.33 In another study, patients who tapered their be eliminated by reintroduction of the discontinued
SSRI dose over up to 4 months had 5·1 Discontinuation- agent, returning the system to homoeostatic equilibrium.43
Emergent Signs and Symptoms events, compared with The principal approach to mitigate withdrawal symp­
11·7 events for patients who discontinued abruptly.34 toms is to reduce the rate at which this equilibrium is
In another study with paroxetine, patients who tapered disrupted, allowing time for adaptation of the system
their dose over an average duration of 38·6 weeks (range, to lowered levels of ligand, thus limiting withdrawal
2–197 weeks), titrated to the individual, had a 6·1% symptoms to tolerable severity.45 This process is achieved
incidence of withdrawal syndrome, compared with either by substitution of a longer-acting medication before
78·2% for abrupt discontinuation (table 1).35 Tapering tapering, or slow tapering of a drug with a short half-life.45,48
strips for anti­depressants, which reduce the medication Notably, decreasing medication by constant amounts
to small fractions of the minimum therapeutic dose (linear tapering) tends to cause increasingly severe side-
(eg, 0·5 mg for paroxetine and citalopram), have shown effects over time.45,48,49 This effect is probably a con­
favourable outcomes; 71% of 895 patients, 97% of whom sequence of the hyperbolic dose-response relationship
had experienced withdrawal previously, were able to between a drug and receptor, following the law of mass
discontinue their medication over a median of action,50 as typified by the effect of diazepam on its target
56 days (IQR 28–84 days).14 Several case studies also receptor, γ-aminobutyric-acid A (GABA-A, figure 2A).
support the improved efficacy of slower tapering.36–38 In Consequently, tapering recommendations for benzo­
one instructive case, several months of tapering down to diazepines advise increasingly small decreases in dosage
an average dose of 6·25 mg of sertraline per day was as it approaches zero,45,48,49 or “stop slow as you go low”.1

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Number of patients Medication Tapering period Lowest dose before Outcome (% with Odds ratio AD Comment
zero discontinuation versus taper
syndrome or DESS score)
Groot and van Os 895; antidepressant Paroxetine, Median 56 days 0·5 mg (paroxetine); 71% able to cease N/A Included patients who had
(2018)14 use median 2–5 years venlafaxine (IQR 28–84 days) 1·0 mg (venlafaxine) had severe withdrawal
syndrome previously
Tint and colleagues 28 SSRI, 3 days; 14 days Unknown 46% (3 days); 46% N/A No difference between 3 day
(2008)16 venlafaxine (14 days) and 14 day taper
Baldwin and 249 Paroxetine 7 days; 14 days 10 mg (paroxetine); DESS 5·4 (SD 8·3) for N/A No difference between 7 day
colleagues (2006)30 (N=115) or 5 mg (escitalopram) paroxetine; DESS 3·2 and 14 day taper (but both
escitalopram (SD 4·8) for escitalopram; slightly better than AD when
(N=134) no difference between 7 compared with other studies)
and 14 days
Himei and Okamura 385 Paroxetine AD (N=80); taper, 10 mg 33·8% (AD); 4·6% (taper) 7·4 36 patients with withdrawal
(2006)33 reducing by 10 mg syndrome were recommenced
every 2 weeks on paroxetine and tapered at
(N=305) 5 mg every 2–4 weeks with no
re-emergence of symptoms
van Geffen (2005)34 74 Fluvoxamine, AD (N=14); taper, Unknown 86% (AD); 52% (taper) 1·65 Significant reduction in
fluoxetine, 2 weeks–4 months withdrawal symptoms with
paroxetine, (N=52) tapering compared with AD
citalopram
Murata and 56 Paroxetine AD (N=23); taper, 10 mg 78·2% (AD); 6·1% (taper) 12 Odds ratio of 55·8 by
colleagues (2010)35 average univariate logistic regression
38·6 weeks, range of tapering compared with AD
2–197 weeks
(N=33)
DESS=Discontinuation-Emergent Signs and Symptoms. AD=abrupt discontinuation. N/A=not applicable.

Table 1: Studies that measured withdrawal symptoms in patients tapered off antidepressants

Withdrawal guidelines for benzodiazepines recom­mend Pharmacological characteristics of SSRI

dose reductions that are proportional to the present dose withdrawal
(most commonly 10% reductions), yielding expo­nentially Withdrawal or discontinuation syndrome from SSRIs
decreasing regimens, as opposed to linear reductions.45,49,52 has the same determinants as described previously.
For example, tapering from 20 mg of diazepam at a rate of Withdrawal symptoms are more common when SSRIs
10% a week would entail a 2 mg reduction in the first week. are given in high doses,53,54 or for long periods.53
The second week’s cumulative reduction would be 3·8 mg Medications with shorter half-lives, such as paroxetine,
(a further 1·8 mg reduction), the third week’s cumulative produce withdrawal symptoms with greater incidence,6,15–18
reduction would be 5·42 mg (a further 1·62 mg), and so on quicker onset,6,15–18 and greater severity6,15–18 than medi­
(figure 2B). These expo­ nentially decreasing regimens cations with longer half-lives, such as fluoxetine.6,15,17,18
produce approximately linear reductions of effect at the Paroxetine produces withdrawal symptoms within
target receptor. Reductions are continued to doses well 2 days,55 whereas symptoms of fluoxetine withdrawal can
under the minimum therapeutic dose (that might appear be delayed by 2–6 weeks.9,56
miniscule) before complete cessation. This process is done As with withdrawal from other medications, the
to avoid a step down in action at the target receptor that is appearance of these withdrawal effects correlates with
substantially greater than the size of steps previously percentage reductions in plasma concentration.55 Higher
tolerated. For example, the final dose of diazepam SSRI plasma levels before cessation57 and just after
recommended by tapering guidelines is 1 mg45 (equivalent cessation58 predict increased withdrawal symptoms.
to 4% GABA-A receptor occupancy).52 Reintroduction of the dis­continued SSRI generally resolves
As withdrawal symptoms are thought to abate because of symptoms within 24 h.3 Approaches have been trialled to
homoeostatic adaptations to reduced medication levels, a diminish withdrawal symptoms by tapering of SSRIs,9,12 or
pause is recommended between dose reductions.45,48,49 substitution for the longest acting SSRI, fluoxetine,3,12
As the exact timing of these adaptations is not fully under­ according to the approaches used for with­drawal from
stood, most guidelines for withdrawal have been developed other agents. Individual factors, including genetics,35 are
on the basis of clinical experience; a consensus suggests thought to play a role in determining withdrawal effects.
waiting 1–4 weeks between dose reductions, to allow
withdrawal symptoms to resolve.45,48 Most guide­ lines Neurobiology of SSRI withdrawal
recommend individualisation of this process, given the SSRIs are thought to produce their effect through an
variation in adaptation to changes in drug levels, and con­ initiating step of inhibition of the serotonin transporter,
sequent severity and duration of with­drawal symptoms.45,48 leading to an increase in synaptic levels of serotonin,

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 Personal View

of the withdrawal syndrome.47 Dysregulation of somato­

A
100
sensory functions could result in paraesthesia, whereas
movement disorders (eg, dystonia) could be due to
80 altered dopaminergic function.47
GABA occupancy (%)

Aspects of SSRI withdrawal syndrome might also be

60 attributed to neuronal changes in tissues outside the
brain, given the presence of serotonergic receptors in
40
sites such as the vasculature and gut.67
20
Pharmacological principles of tapering SSRIs
0 As with other withdrawal syndromes, a rational tapering
0 1 2 3 4 5 regimen for SSRIs will entail step-wise reductions in their
Diazepam dose (mg/kg)
action at serotonin transporters, their principal receptor
B targets.59 PET studies in which a radioligand was bound to
25 serotonin transporters have shown that the dose-response
curve between SSRIs and serotonin transporters conforms
Cumulative dose reduction (mg)

20 to the typical hyperbolic relationship, which arises as a

consequence of the law of mass action (figure 3). The line
15
of best fit for the dose-response curve, which corresponds
10
to a Michaelis-Menten equation,68 can be used to derive
values for the percentage inhibition of SERT at different
5 doses of citalopram (figure 3, table 2).60 Notably, serotonin
transporter inhibition drops off sharply for doses lower
0 than the minimum therapeutic dose for SSRIs.
0 10 20 30 40 50
Time (week)
It is therefore likely that tapering regimens with linear
dose reductions will cause increasingly severe withdrawal
Figure 2: Recommended tapering regimen for diazepam based on its reactions, as the reductions in serotonin transporter
dose-response relationship
inhibition become increasingly large (figure 4A). For
(A) Relationship between dose of diazepam and action at GABA-A receptors in
non-human primates. Adapted from Brouillet and colleagues.51 (B) Reductions in example, reducing the dose of citalopram in 5 mg
diazepam dose recommended by tapering guidelines for 20 mg diazepam increments from 20 mg will produce hyperbolically
(10% dose reduction per week).45,49 GABA=γ-aminobutyric-acid. enlarging decreases in serotonin transporter inhibition:
an absolute decrease in serotonin transporter inhibition
thereby transducing increased responses at serotonergic of 3% from 20 mg to 15 mg, 6% from 15 mg to 10 mg,
receptors.59,60 Serotonergic neurons also modulate other 13% from 10 mg to 5 mg, and 58% from 5 mg to 0 mg.
neurotransmitter systems, including noradrenaline, Even reductions from 2·5 mg (a quarter of the smallest
dopamine, and GABA.47 Effects on neurogenesis, available tablet) to 0·0 mg will produce an absolute
inflammation, and the hypothalamic–pituitary–adrenal reduction in serotonin transporter inhibition of 42·9%,
axis, downstream of serotonergic actions, are also and reduction from 1·25 mg (an eighth of a tablet)
hypothesised in the antidepressant effects of SSRIs.59,61,62 to 0·00 mg will produce a 28% reduction (larger than
Although the details remain to be elucidated, SSRI the change from 40 mg to 5 mg, which produces a
withdrawal has been attributed to a relative deficiency of 27·3% reduction). These large reductions in inhibition
serotonin in the context of widespread adaptation of could account for the paucity of success of previous
serotonergic receptors.9,47,63 SSRI treatment has been tapering regimens,39,40 and particularly for the difficulties
shown to down-regulate the density of serotonergic recep­ with withdrawal symptoms that patients have towards
tors in rats.64 It has also been shown in humans that even the end of their taper, at low doses.14,36
short-term SSRI administration reduces the sensitivity To produce a linear reduction of pharmacological effect,
of cortical 5-hydroxytryptamine receptor 2A65 and a hyperbolically decreasing pattern of dose reduc­tion is
5-hydroxytryptamine receptor 4.66 The reversal of effects on required (figure 4B). Rather than decreasing the dose by
neurotransmitters that are indirectly affected by SSRIs, fixed amounts, the dose should be decreased according
including noradrenaline, glutamate, and GABA, among to fixed intervals of biological effect, for example,
other targets, could also play a role in SSRI withdrawal.9,47,63 10% reductions of serotonin transporter occupancy
The role of serotonin in coordinating sensory and auto­ (20% reductions are shown in figure 4B). A tapering
nomic function with motor activity has been implicated regimen that would produce approximately 10% reductions
in SSRI withdrawal syndrome.42 Reduced stimulation of in serotonin receptor occupancy with each citalopram
5-hydroxytryptamine receptor 1A in the raphe nucleus, dose reduction would be: 20 mg, 9·1 mg, 5·4 mg, 3·4 mg,
known to be involved in motion sickness,47 is thought to 2·3 mg, 1·5 mg, 0·8 mg, 0·4 mg, and 0·00 mg (table 2).
See Online for appendix be related to the dizziness, vertigo, nausea, and lethargy Further SSRI examples are shown in the appendix. These

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regimens allow pharmacologically informed application

A
of the withdrawing principles outlined above (“stop slow 100
as you go low”).1,49 The tapering regimen described above
uses doses that are close to those that have been used

Striatal SERT occupancy (%)

80
successfully in trials involving tapering strips,14 and in
case studies involving difficult withdrawal syndromes.36 60

Limitations 40

There are potential limitations to interpreting the dose- 20

response curve of the PET study presented.60 The number
of participants in each group is relatively small, perhaps 0
limiting the ability to capture individual variation. 0 10 20 30 40 50 60
Dose (mg/day)
However, the shape of the dose-response curve
(ie, hyperbolic) should be the same for each individual, B
suggesting hyperbolic dose reduction regimens should 100
be universally applicable.
Striatal SERT occupancy (%)

SSRIs might also exert neurotrophic, anti-inflammatory, 80

and neuroendocrine effects;61,62 however, these are thought

60
to be downstream of effects on serotonin transporters
and consequent to changes to the serotonergic system,59,61,62 40
indicating that serotonin transporter occupancy is likely
to be a key indicator of biological response to SSRIs. 20
It is difficult to determine whether serotonin trans­
porter inhibition will linearly correspond to withdrawal 0
0 20 40 60 80 100 120 140 160 180 200 220
effects. Serotonin transporter binding is related to the Plasma citalopram (µg/L)
anti­depressant effects of SSRIs; the ratio of serotonin
transporter binding between terminal regions and the Figure 3: Hyperbolic relationship between SERT and dose or plasma
median raphe nucleus has been shown to predict treat­ concentration of citalopram
(A) Relationship between dose of citalopram and SERT occupancy (%).
ment response to SSRIs.69 It is theoretically possible that (B) Relationship between plasma level of citalopram and SERT occupancy (%).
a minimum threshold of serotonin transporter inhibition SERT=serotonin transporter. Reproduced from Meyer and colleagues,60 by
is required before a clinical effect is seen, with levels permission of the American Journal of Psychiatry.
lower than this having minimal effects;60 this could also
correspond to withdrawal effects. However, with­drawal
Citalopram dose (mg) SERT occupancy (%)
effects from other medications do not observe threshold
effects,45,48 and withdrawal effects have been observed at 60·0 87·8%

many doses during tapering of SSRIs,9,35 suggesting that 40·0 85·9%

withdrawal is likely to be a continuous entity. Furthermore, 20·0 80·5%
a hyperbolic relation­ship exists between dose of SSRI and 19·0 80·0%
reduction in depressed mood, as shown in a mega- 9·1 70·0%
analysis;70 a hyperbolic relationship has also been shown 5·4 60·0%
between dose of SSRI and risk of withdrawal symptoms.55 3·4 50·0%
These findings indicate that the hyperbolic relationship 2·3 40·0%
between dose and serotonin transporter inhibition 1·5 30·0%
could also extend to withdrawal effects, suggesting that 0·8 20·0%
serotonin transporter inhibition could be approximately 0·37 10·0%
linearly related to withdrawal effects. SERT occupancy was calculated using the Michaelis-Menten equation of best fit
Another potential limitation to interpreting the dose- derived by Meyer and colleagues.60 Common clinical doses and doses
response curve from Meyer and colleagues60 is that corresponding to 10% decrements of SERT inhibition are displayed. These doses
could be produced by a combination of tablets and liquid formulations.
serotonin transporter occupancy was measured in the Approximations might be necessary. SERT=serotonin transporter.
striatum, which might not have direct relevance to
Table 2: Derivation of SERT occupancy from citalopram dose using the
antidepressant actions. However, this and a subsequent
Michaelis-Menten equation of best fit
PET study71 showed that SSRIs cause similar serotonin
transporter inhibition in brain regions relevant to SSRI
action (eg, subgenual cingulate, amygdala, and raphe conclude that SSRIs, like most pharma­cological agents,
nuclei), with a similar hyperbolic relationship between have a hyperbolic relationship between dose and biological
dose of SSRI and serotonin transporter occupancy at all effects, and that this could be relevant in generating
regions examined.71 Therefore, it seems reasonable to rational discontinuation regimens.

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However, studies have reported tapering regimens that

A
100
have been successful only when they taper to similar
doses of SSRIs.14,36 The use of liquid formulations of
SSRIs might be necessary to achieve these small doses.
Striatal SERT occupancy (%)

80
It is difficult to establish the optimal time interval
60 between dose reductions. In the absence of studies
evaluating the rate at which neuroadaptation can occur,
40
several aspects can provide guidance. For all SSRIs except
20
fluoxetine, pharmacokinetic properties predict that they
will achieve steady state between 5 days and 14 days after
0 dose reduction (table 3).72 As outlined above, discon­
tinuation symptoms have been detected in patients for
B
100
varying periods of time, from a number of days,9 to weeks
and months,18,21–23,73,74 and, in some cases, for more than a
year.21,22,73,74 These records have generally been derived from
Striatal SERT occupancy (%)

80
patients who abruptly cease their medication; it is possible
60 that with more cautious reductions, the discontinuation
symptoms will last for shorter periods. The clinical effects
40
of SSRIs can be delayed by weeks following their
20
commencement,59,70 whereas side-effects arise in days.75 It
is unclear whether withdrawal symptoms are likely to
0 follow the temporal pattern of antidepressant effects, or
0 10 20 30 40 50 60 70 side-effects. It might be prudent to allow 4 weeks after a
Dose (mg/day)
reduction in SSRI to observe for delayed withdrawal
Figure 4: Effect of linear and hyperbolic citalopram dose reductions on SERT effects. This would also allow for observation of recurrence
occupancy of underlying symptoms as a result of the decrease in
(A) Linear dose decrements of citalopram (eg, intervals of 5 mg) produce SSRI dose. However, the best guide might be the interval
exponentially increasing changes in SERT occupancy. (B) Hyperbolic dose
decreases of citalopram produce linear changes in SERT occupancy (eg, intervals required for the patient’s Discontinuation-Emergent Signs
of 20% SERT occupancy). SERT=serotonin transporter. Reproduced from Meyer and Symptoms score to return to baseline after a test
and colleagues,60 by permission of the American Journal of Psychiatry. reduction.

Practical application of hyperbolic dose Other determinants of withdrawal symptoms

reduction from SSRIs
There are likely to be individual differences in experiences Other drug and patient characteristics are likely to affect
of SSRI withdrawal effects.3 We suggest that a personalised the severity of withdrawal syndromes from SSRIs.
rate for withdrawal could be established by an initial trial Paroxetine and fluoxetine are both metabolised by
reduction of SSRI dose, equivalent to a reduction of cytochrome P450 2D6 and inhibit their own metabolism,
10% serotonin transporter occupancy (or 5% if being resulting in non-linear kinetics.76 This predicts dis­
cautious), with subsequent monitoring of the severity and proportionate declines in plasma concentrations during
duration of withdrawal symptoms. An initial 10% reduc­ drug withdrawal. Although this effect might not be
tion in serotonin transporter occupancy is suggested clinically significant for fluoxetine because of its long half-
because this would result in approximately halving the life, it is likely to be significant for paroxetine.47 Paroxetine
dose from the therapeutic minimum dose (eg, from 20 mg might produce a more severe withdrawal syndrome than
to 10 mg of citalopram), which is tolerated well by most other SSRIs because it has pronounced muscarinic
patients. If the patient’s Discontinuation-Emergent Signs antagonist effects and moderate nor­ epinephrine trans­
and Symptom score were to have returned to baseline porter inhibiting effects.47,63 It is also likely that patient
1 month after the initial reduction, then a rate equivalent to factors, such as presence of different cytochrome
10% reduction of serotonin transporter occupancy per enzymes, serotonin transporter sensitivity to inhibition,
month could be prescribed. This process should be subject and psychological factors, could contribute to the risk of
to ongoing monitoring, with the rate titrated to patient withdrawal symptoms. Further understanding of these
tolerance. factors, and testing of plasma levels of SSRIs, might be
The SSRI should be tapered such that the final instructive in designing personalised tapering regimens.
reduction to zero is equal to (or less than) the size of
reduction previously tolerated by the patient. This should Practical consequences of hyperbolic dose
be when the dose is equivalent to approximately reduction
10% serotonin transporter occupancy. Notably, this will The model above resolves an uncertainty often raised by
be a very small dose—eg, 0·4 mg for citalopram. patients and treating physicians, which is whether to use

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 Personal View

a micro-taper or mini-taper strategy. Micro-tapering

Daily dose Half-life Time to reach Linear kinetics Cytochrome
involves miniscule decrements in SSRI medication every (mg) steady state P450 inhibition
day or week. Mini-tapering involves larger, step-wise
Fluoxetine 20–80 1–4 days 5–11 weeks No 2D6
decrements, with longer intervals between decrements
Norfluoxetine ·· 7–15 days ·· ·· 2D6, 3A4
(generally intervals of weeks). Mini-tapering appears
Fluvoxamine 50–300 15 h 10 days No 1A2, 2C19
more sensible than micro-tapering. Withdrawal symp­
Paroxetine 20–50 20 h 7–14 days No 2D6
toms are reported to last for several weeks (or longer)
Sertraline 50–150 26 h 5–7 days Yes Minimal
after medication discontinuation in a large proportion
Citalopram 10–60 36 h 6–10 days Yes Not relevant
of patients.9,13 Consequently, micro-tapering presents the
Escitalopram 5–30 27–33 h 7–10 days Yes 2C19, 2D6, 3A4
possibility of cumulative withdrawal effects being super­
imposed on one another. This process would make it Adapted from Hiemke and colleagues. 72

difficult to establish which reduction (or set of reductions) Table 3: Pharmacokinetic characteristics of SSRIs and their clinically active metabolites
was responsible for the symptoms experienced. It there­
fore seems prudent to decrease the dose of medication,
then allow a substantial period of time to elapse while 40·00
withdrawal effects resolve, before making the next
20·00
decrement.
10·00
Fluoxetine
Substitution of short-acting SSRIs with fluoxetine has 5·00
been suggested as a way to avoid intolerable withdrawal
Dose (mg)

symptoms.3,77 Fluoxetine has been routinely identified to 2·50

cause less severe withdrawal effects than other SSRIs,

1·25
which has been attributed to its longer half-life.3,29,77
Fluoxetine takes 35–75 days to reach steady state,47 which 0·60
is likely to be responsible for observations that its 90th
withdrawal symptoms can arise weeks after cessation.9,56 0·30 percentile
10th 30th 50th 70th
Therefore, it would be prudent to wait 3 months percentile percentile percentile percentile
0
(35–75 days plus 4 weeks) to observe for late-arising 0 4 8 12 16 20 24 28 32
withdrawal symptoms. Given this property of fluoxetine, Time (weeks)
which is similar to an in-built tapering system, it could
Figure 5: Hypothetical nomogram for determining withdrawal rates for citalopram
be reasonable to reduce doses by the equivalent of An example tapering regimen from 20 mg citalopram is indicated (semi-log scale for dose). The patient’s results
approximately 30% serotonin transporter occupancy in initially follows the trajectory for the 50th percentile, with dose reductions equivalent to 10% serotonin transporter
each iteration, titrated to patient tolerance. occupancy every 4 weeks (20·0 mg, 9·1 mg, and 5·4 mg). She then experiences unpleasant side-effects (eg,
Nevertheless, we should be wary of the idea that Discontinuation-Emergent Signs and Symptoms score of >3). Her tapering shifts to the slower trajectory for the
70th percentile and she experiences no periods of intolerable withdrawal symptoms as she completes the taper.
fluoxetine is self-tapering, and can therefore be abruptly
or rapidly ceased, as guidelines suggest.29,78 Although its
pharmacokinetic profile predicts a gradual decline in approaches, have been found to reduce the risk of
plasma level, a short reduction (eg, 2 weeks)27 could still relapse in patients with recurrent depression and those
represent a rapid withdrawal schedule that exceeds a tapering their antidepressants.39,40
10% decrease in biological effect per month. We suggest that, in the absence of more robust evidence
to guide tapering (especially where guidelines advise to
Future directions for research taper gradually without specific instructions), the tapering
We have proposed a pharmacologically informed regimen described here should be considered for adop­
method for tapering SSRI treatment, the validity of tion into clinical practice. There are few disadvantages of
which should be evaluated by randomised controlled recommending slower tapers.29 It should at least be
trials. Withdrawal nomograms aggregating variation in recognised that tapering periods of 2–4 weeks are likely
responses to withdrawal could guide taper rates to be inadequate for reducing withdrawal symptoms
(figure 5). Risk determinants, such as plasma SSRI for many patients, with longer periods of tapering, and
level, cytochrome enzyme status, PET measurement of regimens that include lower doses of medication, more
serotonin transporter occupancy, and other genetic, likely to be effective. Further empirical study of tapering
metabolic, and psychological factors, could be in­ regimens, including the one proposed here, is urgently
corporated into the nomogram as their effects are required, with a consequent update of formal guidelines.
clarified. Pharmacological and non-pharmacological Contributors
means to improve the tolerability of SSRI withdrawal MAH conceived the manuscript idea, wrote the manuscript, and drew
also warrant research. Psychological interventions, the figures. DT helped to develop the idea, and revised and edited the
manuscript.
such as preventive cognitive therapy, and other CBT

www.thelancet.com/psychiatry Published online March 5, 2019 http://dx.doi.org/10.1016/S2215-0366(19)30032-X 7

 Personal View

Declaration of interests 22 Fava GA, Bernardi M, Tomba E, Rafanelli C. Effects of gradual

MAH declares no competing interests. DT reports personal fees from discontinuation of selective serotonin reuptake inhibitors in panic
Lundbeck, and grants and personal fees from Janssen, outside the disorder with agoraphobia. Int J Neuropsychopharmacol 2007;
submitted work. 10: 835–38.
23 Bhanji NH, Chouinard G, Kolivakis T, Margolese HC.
References Persistent tardive rebound panic disorder, rebound anxiety and
1 Bain KT, Holmes HM, Beers MH, Maio V, Handler SM, Pauker SG. insomnia following paroxetine withdrawal: a review of rebound-
Discontinuing medications: a novel approach for revising the withdrawal phenomena. Can J Clin Pharmacol 2006; 13: e69–74.
prescribing stage of the medication-use process. J Am Geriatr Soc 24 Johnson CF, Macdonald HJ, Atkinson P, Buchanan AI, Downes N,
2008; 56: 1946–52. Dougall N. Reviewing long-term antidepressants can reduce drug
2 Howland RH. Potential adverse effects of discontinuing psychotropic burden: a prospective observational cohort study. Br J Gen Pract 2012;
drugs: part 2: antidepressant drugs. J Psychosoc Nurs Ment Health Serv 62: 773–79.
2010; 48: 9–12. 25 Eveleigh R, Muskens E, Lucassen P, et al. Withdrawal of unnecessary
3 Haddad PM, Anderson IM. Recognising and managing antidepressant medication: a randomised controlled trial in primary
antidepressant discontinuation symptoms. Adv Psychiatr Treat 2007; care. BJGP Open 2017; 34: bjgpopen17X101265.
13: 447–57. 26 NICE. Depression in adults: recognition and management (CG90).
4 Schatzberg AF, Haddad P, Kaplan EM, et al. Serotonin reuptake London: National Institute for Health and Care Excellence, 2009.
inhibitor discontinuation syndrome: a hypothetical definition. 27 MIMS. Antidepressants, a guide to switching and withdrawing.
Discontinuation Consensus panel. J Clin Psychiatry 1997; http://www.mims.co.uk/Tables/882430/Switching-Antidepressants/
58 (suppl 7): 5–10. (accessed Nov 1, 2018).
5 American Psychiatric Association. The diagnostic and statistical 28 Hirsch M, Birnbaum RJ. Antidepressant medication in adults:
manual of mental disorders, 5th edn. Arlington, VA: American switching and discontinuing medication. https://www.uptodate.
Psychiatric Publishing, 2013. com/contents/discontinuing-antidepressant-medications-in-adults
6 Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. (accessed Feb 11, 2019).
Selective serotonin reuptake inhibitor discontinuation syndrome: 29 Ogle NR, Akkerman SR. Guidance for the discontinuation or
a randomized clinical trial. Biol Psychiatry 1998; 44: 77–87. switching of antidepressant therapies in adults. J Pharm Pract 2013;
7 Warner CH, Bobo W, Warner C, Reid S, Rachal J. 26: 389–96.
Antidepressant discontinuation syndrome. Am Fam Physician 2006; 30 Baldwin DS, Cooper JA, Huusom AKT, Hindmarch I. A double-blind,
74: 449–56. randomized, parallel-group, flexible-dose study to evaluate the
8 Shelton RC. Steps following attainment of remission: tolerability, efficacy and effects of treatment discontinuation with
discontinuation of antidepressant therapy. escitalopram and paroxetine in patients with major depressive
Prim Care Companion J Clin Psychiatry 2001; 3: 168–74. disorder. Int Clin Psychopharmacol 2006; 21: 159–69.
9 Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. 31 Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M,
Withdrawal symptoms after selective serotonin reuptake inhibitor Hindmarch I. Absence of discontinuation symptoms with
discontinuation: a systematic review. Psychother Psychosom 2015; agomelatine and occurrence of discontinuation symptoms with
84: 72–81. paroxetine: a randomized, double-blind, placebo-controlled
10 Black K, Shea C, Dursun S, Kutcher S. Selective serotonin reuptake discontinuation study. Int Clin Psychopharmacol 2004; 19: 271–80.
inhibitor discontinuation syndrome: proposed diagnostic criteria. 32 Phelps J. Tapering antidepressants: is 3 months slow enough?
J Psychiatry Neurosci 2000; 25: 255–61. Med Hypotheses 2011; 77: 1006–08.
11 Young A, Haddad P. Discontinuation symptoms and psychotropic 33 Himei A, Okamura T. Discontinuation syndrome associated with
drugs. Lancet 2000; 355: 1184. paroxetine in depressed patients: a retrospective analysis of factors
12 Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines involved in the occurrence of the syndrome. CNS Drugs 2006;
for treating depressive disorders with antidepressants: a revision of 20: 665–72.
the 2008 British Association for Psychopharmacology guidelines. 34 van Geffen EC, Hugtenburg JG, Heerdink ER, van Hulten RP,
J Psychopharmacol 2015; 29: 459–525. Egberts AC. Discontinuation symptoms in users of selective
13 Davies J, Read J. A systematic review into the incidence, severity serotonin reuptake inhibitors in clinical practice: tapering versus
and duration of antidepressant withdrawal effects: are guidelines abrupt discontinuation. Eur J Clin Pharmacol 2005; 61: 303–07.
evidence-based? Addict Behav 2018; published online Sept 4. 35 Murata Y, Kobayashi D, Imuta N, et al. Effects of the serotonin 1A,
DOI:10.1016/j.addbeh.2018.08.027 (preprint). 2A, 2C, 3A, and 3B and serotonin transporter gene polymorphisms
14 Groot PC, van Os J. Antidepressant tapering strips to help people on the occurrence of paroxetine discontinuation syndrome.
come off medication more safely. Psychosis 2018; 10: 142–45. J Clin Psychopharmacol 2010; 30: 11–17.
15 Bogetto F, Bellino S, Revello RB, Patria L. Discontinuation syndrome 36 Amsden GW, Georgian F. Orthostatic hypotension induced by
in dysthymic patients treated with selective serotonin reuptake sertraline withdrawal. Pharmacotherapy 1996; 16: 684–86.
inhibitors: a clinical investigation. CNS Drugs 2002; 16: 273–83. 37 Dominguez RA, Goodnick PJ. Adverse events after the abrupt
16 Tint A, Haddad PM, Anderson IM. The effect of rate of discontinuation of paroxetine. Pharmacotherapy 1995; 15: 778–80.
antidepressant tapering on the incidence of discontinuation 38 Benazzi F. Venlafaxine withdrawal symptoms. Can J Psychiatry 1996;
symptoms: a randomised study. J Psychopharmacol 2008; 22: 330–32. 41: 487.
17 Hindmarch I, Kimber S, Cockle SM. Abrupt and brief 39 Bockting CLH, Klein NS, Elgersma HJ, et al. Effectiveness of
discontinuation of antidepressant treatment: effects on cognitive preventive cognitive therapy while tapering antidepressants versus
function and psychomotor performance. Int Clin Psychopharmacol maintenance antidepressant treatment versus their combination in
2000; 15: 305–18. prevention of depressive relapse or recurrence (DRD study):
18 Royal College of Psychiatrists. Coming off antidepressants. 2012. a three-group, multicentre, randomised controlled trial.
www.rcpsych.ac.uk/healthadvice/treatmentswellbeing/anti Lancet Psychiatry 2018; 5: 401–10.
depressants/comingoffantidepressants.aspx (accessed March 1, 2018). 40 Scholten WD, Batelaan NM, van Oppen P, et al. The efficacy of a
19 Bosman RC, Huijbregts KM, Verhaak PF, et al. Long-term group CBT relapse prevention program for remitted anxiety disorder
antidepressant use: a qualitative study on perspectives of patients patients who discontinue antidepressant medication: a randomized
and GPs in primary care. Br J Gen Pract 2016; 66: e708–19. controlled trial. Psychother Psychosom 2018; 87: 240–42.
20 Valuck RJ, Orton HD, Libby AM. Antidepressant discontinuation 41 Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following
and risk of suicide attempt. J Clin Psychiatry 2009; 70: 1069–77. rapid versus gradual discontinuation of antidepressants.
21 Davies J, Regina P, Montagu L. Antidepressant withdrawal: a survey Am J Psychiatry 2010; 167: 934–41.
of patients’ experience by the All-Party Parliamentary Group for 42 Maixner SM, Greden JF. Extended antidepressant maintenance and
Prescribed Drug Dependence. 2018. http://prescribeddrug.org/wp- discontinuation syndromes. Depress Anxiety 1998; 8 (suppl 1): 43–53.
content/uploads/2018/10/APPG-PDD-Survey-of-antidepressant- 43 Turton S, Lingford-Hughes A. Neurobiology and principles of
withdrawal-experiences.pdf (accessed Nov 1, 2018). addiction and tolerance. Medicine (Baltimore) 2016; 44: 693–96.

8 www.thelancet.com/psychiatry Published online March 5, 2019 http://dx.doi.org/10.1016/S2215-0366(19)30032-X

 Personal View

44 Dilsaver SC. Withdrawal phenomena associated with antidepressant 63 Renoir T. Selective serotonin reuptake inhibitor antidepressant
and antipsychotic agents. Drug Saf 1994; 10: 103–14. treatment discontinuation syndrome: a review of the clinical
45 Ashton H. The diagnosis and management of benzodiazepine evidence and the possible mechanisms involved. Front Pharmacol
dependence. Curr Opin Psychiatry 2005; 18: 249–55. 2013; 4: 45.
46 Hodding GC, Jann M, Ackerman IP. Drug withdrawal syndromes: 64 Wamsley JK, Byerley WF, McCabe RT, McConnell EJ, Dawson TM,
a literature review. West J Med 1980; 133: 383–91. Grosser BI. Receptor alterations associated with serotonergic agents:
47 Olver JS, Burrows GD, Norman TR. Discontinuation syndromes an autoradiographic analysis. J Clin Psychiatry 1987; 48 (suppl): 19–25.
with selective serotonin reuptake inhibitors: are there clinically 65 Meyer J, Kapur S, Eisfeld B, et al. The effect of paroxetine on
relevant differences? CNS Drugs 1999; 12: 171–77. 5-HT(2A) receptors in depression: an [(18)F]setoperone PET
48 Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in imaging study. Am J Psychiatry 2001; 158: 78–85.
primary care. CNS Drugs 2009; 23: 19–34. 66 Haahr ME, Fisher PM, Jensen CG, et al. Central 5-HT4 receptor
49 Brett J, Murnion B. Management of benzodiazepine misuse and binding as biomarker of serotonergic tonus in humans:
dependence. Aust Prescr 2015; 38: 152–55. a [11C]SB207145 PET study. Mol Psychiatry 2014; 19: 427–32.
50 Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: 67 Mawe GM, Hoffman JM. Serotonin signalling in the gut: functions,
the combined effects of multiple drugs or enzyme inhibitors. dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol
Adv Enzyme Regul 1984; 22: 27–55. 2013; 10: 473–86.
51 Brouillet E, Chavoix C, Bottlaender M, et al. In vivo bidirectional 68 Atkins GL, Nimmo IA. A comparison of seven methods for fitting
modulatory effect of benzodiazepine receptor ligands on the Michaelis-Menten equation. Biochem J 1975; 149: 775–77.
GABAergic transmission evaluated by positron emission 69 Lanzenberger R, Kranz GS, Haeusler D, et al. Prediction of SSRI
tomography in non-human primates. Brain Res 1991; 557: 167–76. treatment response in major depression based on serotonin
52 Ashton H. The treatment of benzodiazepine dependence. Addiction transporter interplay between median raphe nucleus and projection
1994; 89: 1535–41. areas. Neuroimage 2012; 63: 874–81.
53 Weller IVD, Ashby D, Brook R, et al. Report of the CSM Expert 70 Hieronymus F, Nilsson S, Eriksson E. A mega-analysis of fixed-dose
Working Group on the safety of selective serotonin reuptake trials reveals dose-dependency and a rapid onset of action for the
inhibitors. London: Medicines and Healthcare Products Regulatory antidepressant effect of three selective serotonin reuptake inhibitors.
Agency, 2005. Transl Psychiatry 2016; 6: e834.
54 Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. 71 Baldinger P, Kranz GS, Haeusler D, et al. Regional differences in
Symptoms following abrupt discontinuation of duloxetine SERT occupancy after acute and prolonged SSRI intake investigated
treatment in patients with major depressive disorder. J Affect Disord by brain PET. Neuroimage 2014; 88: 252–62.
2005; 89: 207–12. 72 Hiemke C, Härtter S. Pharmacokinetics of selective serotonin
55 Michelson D, Fava M, Amsterdam J, et al. Interruption of selective reuptake inhibitors. Pharmacol Ther 2000; 85: 11–28.
serotonin reuptake inhibitor treatment. Double-blind, 73 Stockmann T, Odegbaro D, Timimi S, Moncrieff J. SSRI and SNRI
placebo-controlled trial. Br J Psychiatry 2000; 176: 363–68. withdrawal symptoms reported on an internet forum.
56 Zajecka J, Fawcett J, Amsterdam J, et al. Safety of abrupt Int J Risk Saf Med 2018; 29: 175–80.
discontinuation of fluoxetine: a randomized, placebo-controlled 74 Belaise C, Gatti A, Chouinard VA, Chouinard G. Patient online
study. J Clin Psychopharmacol 1998; 18: 193–97. report of selective serotonin reuptake inhibitor-induced persistent
57 Henry ME, Moore CM, Kaufman MJ, et al. Brain kinetics of postwithdrawal anxiety and mood disorders. Psychother Psychosom
paroxetine and fluoxetine on the third day of placebo substitution: 2012; 81: 386–88.
a fluorine MRS study. Am J Psychiatry 2000; 157: 1506–08. 75 Ferguson JM. SSRI antidepressant medications: adverse effects and
58 Yasui-Furukori N, Hashimoto K, Tsuchimine S, Tomita T. tolerability. Prim Care Companion J Clin Psychiatry 2001; 3: 22–27.
Characteristics of escitalopram discontinuation syndrome: 76 Preskorn SH. Clinically relevant pharmacology of selective
a preliminary study. Clin Neuropharmacol 2016; 39: 125–27. serotonin reuptake inhibitors. An overview with emphasis on
59 Stahl SM. Mechanism of action of serotonin selective reuptake pharmacokinetics and effects on oxidative drug metabolism.
inhibitors. Serotonin receptors and pathways mediate therapeutic Clin Pharmacokinet 1997; 32 (suppl 1): 1–21.
effects and side effects. J Affect Disord 1998; 51: 215–35. 77 Schatzberg AF, Blier P, Delgado PL, Fava M, Haddad PM,
60 Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter Shelton RC. Antidepressant discontinuation syndrome:
occupancy of five selective serotonin reuptake inhibitors at different consensus panel recommendations for clinical management and
doses: an [11C]DASB positron emission tomography study. additional research. J Clin Psychiatry 2006; 67 (suppl 4): 27–30.
Am J Psychiatry 2004; 161: 826–35. 78 Perahia DG, Quail D, Desaiah D, Corruble E, Fava M. Switching to
61 Malberg JE, Schechter LE. Increasing hippocampal neurogenesis: duloxetine from selective serotonin reuptake inhibitor
a novel mechanism for antidepressant drugs. Curr Pharm Des 2005; antidepressants: a multicenter trial comparing 2 switching
11: 145–55. techniques. J Clin Psychiatry 2008; 69: 95–105.
62 Janssen DG, Caniato RN, Verster JC, Baune BT. © 2019 Elsevier Ltd. All rights reserved.
A psychoneuroimmunological review on cytokines involved in
antidepressant treatment response. Hum Psychopharmacol 2010;
25: 201–15.

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