Antidepressants

The information below is intended as a reference only, and should not be taken as medical advice. If you have questions about your medications, consult your pharmacist, doctor, nurse, or other healthcare professional.

Taper Approach

Some people can stop antidepressants without problems even after being on treatment for months. Others can have problems after being on treatment for as little as two weeks. Some can never stop. Drugs active on the serotonin system, including SSRIs, SNRIs, most tricyclic antidepressants and others like mirtazapine appear more likely to cause withdrawal problems than antidepressants with no effect on serotonin systems. Based on the effect of missing doses while on treatment, people will often know before starting to withdraw whether there is likely to be a problem – but fluoxetine’s long half-life may falsely reassure prescribers and those taking it into thinking there will be no problem.

Abrupt stopping of antidepressants carries a higher risk of discontinuation symptoms. Until recently guidelines recommended tapering over 2-4 weeks, however data indicates this is little better than abrupt stopping and is often not tolerated by patients. Because antidepressants, especially SSRIs, have well-documented withdrawal syndrome symptoms, tapering that is guided by a patient’s symptoms is the most rational course to deprescribe. This rule of thumb even applies to those antidepressants that have a longer half-life (e.g. fluoxetine). There is currently no high-quality data to support the amount, or rate of taper, and the best clinical approach is to be guided by the patient. Starting with a taper amount, such as a 10% dose reduction, can help determine the required rate of taper. Patients who have experienced previous withdrawal symptoms when they have missed a dose are at increased risk of withdrawal symptoms while tapering. Therefore, ensure an inquiry about past experience, and providing appropriate education, can be helpful. If patients do not experience withdrawal or other distressing symptoms, and have not had previous problems, dropping the dose initially in a 25% step could be an appropriate suggestion. If symptoms do occur, discuss a smaller taper increment with the patient. As shorter half-life antidepressants such as paroxetine are associated with greater withdrawal symptoms, some suggest switching to longer half-life antidepressants, mimicking the approach taken with benzodiazepine withdrawal. There is no evidence that this is more helpful, and the potency of serotonin reuptake inhibition differs between SSRIs, which may explain why some antidepressants are more likely to cause withdrawal symptoms.

It is important to remember that there is no rule stating that tapering steps and intervals should be regular. In fact, recent analyses of the relationship between serotonin receptor occupancy and dose suggests the need to plan for a non-linear hyperbolic approach with a slower rate of taper at the end in patients having difficulty discontinuing after 4-8 weeks. Dose reduction can hit a “shelf” where it becomes very difficult to drop further for a time, but after which reducing can become easier again. This is in line with approaches to tapering other medications such as benzodiazepines and though it takes longer, may ultimately give a greater chance of success. It is important to recognize that some patients may not be able to discontinue a medication completely. In this situation, the lowest dose required to control discontinuation symptoms will minimize harms.

Tablet, capsule size, and the limited availability of liquid preparations can make the amount by which a dose is tapered a challenge. Consulting a pharmacy regarding options such as tablet splitting, conversion to available liquid preparations or other compounding options is recommended. Note that these approaches often cannot be used with extended-release formulations. If the patient cannot afford compounding, many tablet form, non extended- release SSRIs can be dissolved into a liquid; a proportion of the resultant (well-shaken) solution can be calculated and administered. Pharmacists can offer important advice on the water solubility of tablet preparations, but it is important to note that such solutions have no guarantee of stability and the required portion must be taken immediately, and the remainder discarded. Alternate day dosing has also been suggested but this can be unhelpful with shorter half-life drugs than fluoxetine as it can lead to on-off discontinuation symptoms. An alternate option can be to switch to a tricyclic antidepressant available in your jurisdiction, that is a weaker serotonin reuptake inhibitor and to reduce this slowly over time. Local pharmacists can provide advice on these. We know less about antidepressant withdrawal than about opiate or alcohol withdrawal.

Monitoring the Taper: Potential Harms of Deprescribing

When embarking on a trial of deprescribing, discussions with the patient is important. In these discussions, clearly reach a shared understanding of the three key deprescribing monitoring process aspects (i.e.: what to monitor; who will monitor; and the agreed upon criteria for considering a restarting of the medication). Regarding this third aspect, patients and family will feel more reassured about deprescribing trials if it is framed as ‘pause and monitor’ with the potential to reinitiate the medication at any time. It is vital that clinicians, patients and caregivers have a shared understanding that the need to restart a medication does not constitute a failure on either the patient’s or clinician’s part; restarting a medication simply reflects good monitoring.

It is important to acknowledge that while reducing treatment burden, ADRs, and ensuring appropriate prescribing is the ideal, there are some real potential risks that come with deprescribing. These fall into three broad categories: 1) Adverse drug withdrawal events, both acute and protracted; 2) Recurrence of the original indication; and 3) Unmasked interactions.

Symptoms of the acute antidepressant discontinuation syndrome (e.g. flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal, emotional lability etc). The risk and/or severity of the discontinuation syndrome can be mitigated in most people with an appropriate tapering and monitoring schedule. Typically, discontinuation symptoms abate within one to two weeks of a dose reduction; some patients may be willing to persevere through these initial weeks. An important minority of patients can experience protracted withdrawal symptoms, typically somatic and psychological, which have been reported to last months to years after discontinuing antidepressants. In some, the reinstatement of the drug (often at a much lower dose) is necessary to control these symptoms. However while acute withdrawal problems can be suppressed by increasing the dose to the original drug, protracted withdrawal problems may not respond as clearly to the original agent.

For some patients that experienced the sexual dysfunction brought on by SSRIs, this side-effect could also persist beyond stopping the drug. Recent antidepressants product monographs have been updated to reflect these potential risks. There are no clear effective management options and acknowledgement, and support are important aspects of care.

Second, there is a real potential for depressive symptoms to re-emerge as the antidepressant is discontinued. If the reinstatement of the previous dose results in rapid symptom resolution, especially for psychological withdrawal symptoms, this would suggest that the symptoms experienced are much more likely related to withdrawal versus a recurrence of depression. This is why the “pause and monitor” approach during the tapering phase of the deprescribing is so crucial.

Lastly, while we classically think of drug interactions as being additive (i.e. interactions occur because a new medication was added), sometimes they can be unmasked because antidepressants may serve to inhibit the metabolism of other medications as outlined in the previous article in this series. In particular, SSRIs are CYP2D6 inhibitors; dosages of medications (e.g. some beta blockers and calcium channel blockers) that are metabolized by this pathway could be too high after SSRIs are discontinued.

Initial Withdrawal Symptoms

Nausea, diarrhea, abdominal pains, sweating, headache, dizziness, cold and flu-like symptoms, anxiety, irritability, trouble sleeping, electric shock-like feelings, visual after images, sounds and light sensitivity, muscle aches and pains, chills, confusion, pounding heart (palpitations), sexual dysfunction, twitching or other unusual movements, depression, agitation, and suicidal ideation.

Protracted Withdrawal Symptoms

After the initial withdrawal features wear off, there may be enduring food intolerance, altered taste or smell sensations, cardiac disturbances, pain or burning or other stranger sensory sensations, stress intolerance, temperature dysregulation, anxiety and depression, enduring sexual dysfunction.

References
  • Antimisiaris D, McHolan B, Moga D, et al. Depression Part 3: Drug Related Problems. The Senior Care Pharmacist 2021;36(2)
  • Maund E, Stuart B, Moore M, et al. Managing Antidepressant Discontinuation: A Systematic Review. Ann Fam Med 2019;17(1):52-60. doi: 10.1370/afm.2336 [published Online First: 2019/01/24]
  • Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. The Lancet Psychiatry 2019 doi: 10.1016/s2215-0366(19)30032-x [published Online First: 2019/03/10]
  • Hengartner MP, Schulthess L, Sorensen A, et al. Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum. Therapeutic Advances in Psychopharmacology 2020;10:2045125320980573.
  • Healy D, Le Noury J, Mangin D. Enduring sexual dysfunction after treatment with antidepressants, 5alpha-reductase inhibitors and isotretinoin: 300 cases. Int J Risk Saf Med 2018

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