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Kotzalidis, 2007 The adult SSRI/SNRI withdrawal syndrome: A clinically heterogeneous entity.


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Clinical Neuropsychiatry Journal of Treatment Evaluation. 2007;4(42):61–75.
The adult SSRI/SNRI withdrawal syndrome: A clinically heterogeneous entity.
Kotzalidis G, Patrizi B, Koukopoulos A, Savoia V, Gaia R, et al.
Full text at http://www.clinicalneuropsychiatry.org/pdf/02_kotzalidis.pdf

Various reports and controlled studies show that, in some patients interrupting treatment with selective serotonin re- uptake inhibitors or serotonin and noradrenaline re-uptake inhibitors, symptoms develop which cannot be attributed to rebound of their underlying condition. These symptoms are variable and patient-specific, rather than drug specific, but occur more with some drugs than others. It has been claimed that the shorter the half-live, the more a drug is likely to induce a withdrawal syndrome; however, this is not supported by data. The drugs most often involved with withdrawal are paroxetine and venlafaxine, while it appears that withdrawal syndrome associated with discontinuation (or steep dose reduction) of fluoxetine is milder and occurs later. Acute lack of serotonin or its drug substitute on receptors or transporters is thought to be at the basis of the development of the syndrome. However, the fact that the symptoms described for withdrawal overlap to a great extent with those of the serotonin syndrome makes it possible that both serotonergic hypo- and hyperactivity, alternating and fluctuating, may be responsible for the syndrome and for the multitude of its expressions. There is no specific treatment other than reintroduction of the drug or substitution with a similar drug. The syndrome usually resolves in days or weeks, even if untreated. Current practice is to gradually withdraw drugs like paroxetine and venlafaxine, but even with extremely slow tapering, some patients will develop some symptoms or will be unable to completely discontinue the drug.
Treatment Considerations: The reticence to recognise the SSRI/SNRI withdrawal/discontinuation syndrome (Haddad and Qureshi 2000) may lead to underestimation and inappropriate management. Since many of the symptoms of the SSRI/SNRI withdrawal may constitute side effects of antidepressant medication, it is easy to find cases misattributed to the effects of another antidepressant during switches (Haddad and Qureshi 2000) or to rebound of underlying symptomatology (Haddad 2001). Similarly to other antidepressant drug classes, gradual tapering is needed with SSRIs and SNRIs (Haddad 1998); the patient should be informed and educated on the possible appearance of withdrawal symptoms. About one patient out of five abruptly suspends SSRI treatment; this results in increased withdrawal symptoms in these patients, as compared to those who taper-off their drug more gradually and according to a schedule prepared by their physician (Rosenbaum and Zajecka 1997, Anderson and Nutt 2000). The British National Formulary (BNF) recommends to taper-off in at least four weeks to obtain minimal SSRI/SNRI withdrawal symptoms (British National Formulary 2000); this rule must apply to venlafaxine, fluvoxamine, paroxetine, and sertraline, while fluoxetine might constitute an exception, as the time course and pattern and severity of withdrawal differs from those of other SSRIs and SNRIs (Rosenbaum and Zajecka 1997).

Tapering rate is affected by the type of antidepressant, treatment duration, past history of withdrawal symptoms, and the need to withdraw the drug (Haddad 2001). Since fluoxetine is less associated with withdrawal syndromes in the immediate aftermath of suspension, one possible strategy is to switch from other SSRI and SNRI antidepressants to fluoxetine, and then taper-off gradually (Haddad 2001), since the latter was shown to suppress withdrawal symptoms of both SSRIs and venlafaxine (Giakas and Davis 1997). Fluoxetine is more appropriate therapeutically in patients who tend to quit treatment abruptly or in those who miss doses, because it is associated with later onset of withdrawal symptoms, that tend to be milder and occur in less patients; this suggestion has been based on the longer half-life of this drug and the smoother, slower disappearance from blood (Zajecka et al. 1998), but a clear demonstration of this hypothesis is lacking.

In cases where fluoxetine administration is considered inappropriate, reintroduction of the same antidepressant as before suppresses the syndrome; withdrawal is then scheduled at a much slower rate and this was shown to prevent the reemergence of withdrawal symptoms (Dominguez and Goodnick 1995, Benazzi 1996).

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The above schedule is to be intended as the minimum requirement for avoiding the development of a withdrawal syndrome. It does not guarantee that the syndrome will not develop. Patient and doctor should closely collaborate in defining the exact timing for discontinuation.
Blier and Tremblay (2006) analysed much animal and human literature to conclude that serotonin receptor adaptation after protracted SSRI treatment were not important in generating discontinuation symptoms, but rather it appeared that following abrupt SSRI suspension there were changes in 5-HT transporter status and overall central serotonin function that could account for symptoms. They support that reduced serotonergic function is crucial for the expression of withdrawal symptoms, and that long-term NMDA receptor adaptations could mediate this effect. However, impaired glutamate transmission or glutamatergic hyperactivity could be secondary to serotonergic dysregulation and partially explain both some serotonin syndrome symptoms as well as SSRI/SNRI withdrawal. We propose that it is central serotonin system instability, through waxing and waning that could account for the symptoms arising from SSRI/SNRI discontinuation and overlap with those of the serotonin syndrome. Furthermore, to hypothesise the mere existence of reduced central serotonergic function as the cause for this complex and multifaceted syndrome would not fit with animal data showing down-regulated protein expression and binding of serotonin transporter in mice who were chronically treated with paroxetine (Hirano et al. 2005); the ensuing reduced serotonin reuptake activity would result in more serotonin in the synapse.

Blier and Tremblay (2006), despite providing fascinating evidence on long-term adaptations ensuing after protracted treatment with SSRIs, mention no animal study designed to study brain receptor modifications after abrupt cessation of SSRI treatment. They do not, simply because there exist no such studies.
Syndromes that develop after discontinuation of SSRIs or SNRIs are quite similar and differ in some respects from the one occurring with abrupt suspension of tricyclic antidepressants. Although not all patients who stop their SSRI/SNRI medication will develop a withdrawal syndrome, a high proportion will develop some symptoms upon discontinuation. Hence, it is recommended to discontinue such drugs with an extremely slow tapering schedule, especially if the patient had developed a withdrawal syndrome when he/she discontinued another drug, antidepressant, antipsychotic or if he/she is a substance user/abuser. SSRI/SNRI antidepressants should be avoided in the latter population, due to the likelihood of manifesting craving for the drug and improper intake. Despite all precautions, some patients will eventually develop symptoms when completely off-medication and will be prompted to resume intake of an at least minimal dose (for example, 5 mg/day paroxetine). In such cases, substitution with another drug of the same class, but less likely to yield withdrawal problems, like fluoxetine, with successive gradual tapering-off of the new drug, may prove useful. Alternatively, informing the patient that the syndrome will resolve without leaving any long- term sequela, might induce him/her to quit the drug and tolerate the withdrawal symptoms.


The claims that the term withdrawal syndrome should not be used, but rather substituted with the term discontinuation syndrome, as some of its symptoms could refer to rebound of the underlying condition and because it is possible that patients associate it with drug abuse and severe problems of dependence, are unwarranted, since patients should always be precisely informed in their interest on which problems they are facing and the emergence of symptoms which never occurred before in a patient may not be the uncovering of the underlying disorder.


Withdrawal syndromes are variable in the syndrome and patient-specific, rather than drug specific, but some symptoms may be associated more with some of these drugs. For example, electric shock-like sensations are more usual with paroxetine and venlafaxine rather than with sertraline or fluoxetine. Furthermore, the likelihood of a drug to elicit a withdrawal syndrome at abrupt discontinuation or dose reduction is different among these drugs. Venlafaxine and paroxetine are the drugs that have been associated with the emergence of withdrawal syndromes more often, even if we correct for factors like total prescriptions/intake, market diffusion and share or the duration of availability in the market. It has also been claimed that the shorter the half-live, the more a drug is likely to induce a withdrawal syndrome; however, this could only be a marginal factor, as only after combining it with the aforementioned factors some trend toward correlation with syndrome induction frequency may emerge.


The partial overlap of the SSRI/SNRI withdrawal syndrome with the serotonin syndrome, although symptom intensity is stronger in the latter, raises the question that central serotonergic systems may oscilla- te during withdrawal and alternate between hypo- and hyperactivity. The pathophysiology of the syndrome is unclear.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

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