Higher Risk of Withdrawal Symptoms With Antidepressants

A new study published in November 2022 in Drug Safety[1] found that antidepressants caused more reports of withdrawal symptoms than other classes of drugs in the study. The researchers also found that the risk of suffering from more severe withdrawal symptoms was higher for several patient groups.

What is antidepressant withdrawal?

Antidepressant withdrawal or antidepressant discontinuation syndrome can affect patients when they stop taking their antidepressant medications.[2] This can cause a range of symptoms, such as dizziness, nausea, paresthesia (tingling sensation), headaches, anxiety, feeling abnormal, suicidal thoughts, insomnia and depression.[3]

These symptoms are more common when the antidepressant treatment is longer than four to six weeks, particularly when patients stop taking their medication abruptly or do not slowly decrease their dosage.[4] For most patients, symptoms usually last only a few weeks and resolve without intervention, but for some they can be so severe that they impact their quality of life and even lead to hospitalization.

The results of the new study

The new study is based on an analysis of individual case safety reports from the WHO global database, VigiBase, the largest drug safety database worldwide.[5] Out of the 28 million individual case safety reports on possible adverse drug reactions from 140 countries, the researchers identified 31,688 reports of antidepressant withdrawal syndrome in patients 12 years or older. These reports involved 28 antidepressants, which the researchers divided into three groups: tricyclics, selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

A comparison of antidepressant-withdrawal reports with reports of withdrawal symptoms for all other drugs in the database showed that antidepressants overall, and particularly those classified as “other” and SSRIs, were more likely to cause withdrawal symptoms than all other classes of drugs. The same was true, although to a much lower extent, when the researchers compared antidepressants with the partial opioid agonist buprenorphine (BELBUCA, BUTRANS, SUBOXONE, ZUBSOLV). Although buprenorphine is known to cause withdrawal symptoms, reports of withdrawal were again more likely for antidepressants, though only for those classified as “other” and SSRIs.

The researchers also looked at which antidepressants in each group were associated with disproportionately more reports than others. Across all comparisons, four antidepressants stood out: the SSRI paroxetine (PAXIL, PEXEVA) and the selective serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine (CYMBALTA, DRIZALMA SPRINKLE), venlafaxine (EFFEXOR XR) and desvenlafaxine (PRISTIQ).

SNRIs were classified as “other” antidepressants in this study.[6] Public Citizen’s Health Research Group has designated venlafaxine and desvenlafaxine as Limited Use for depression treatment and duloxetine as Do Not Use due to the serious safety concerns, as discussed in more detail below.[7] Paroxetine has been designated as Limited Use.

The new VigiBase study also found that men, adolescents and young adults were at a higher risk of severe withdrawal symptoms.[8] The same was true for patients who had taken antidepressants for more than two years and those who were taking several psychotropic medications concomitantly (at the same time). For example, patients who were prescribed an antipsychotic medication in addition to an antidepressant were more than three times as likely to report withdrawal symptoms, and for those who were also taking benzodiazepines (tranquilizers) and mood stabilizers, the risk was almost doubled. The risk of serious reactions was also higher the more medications patients were taking concomitantly.

However, it is important to keep in mind that the adverse drug event reports included in this study do not provide information on whether patients slowly decreased or abruptly stopped their medication or whether the reported symptoms were due to a relapse of the underlying condition rather than withdrawal.[9]

Implications of this study

The risk of severe antidepressant withdrawal symptoms, especially for some patient groups, comes in addition to the other serious adverse events associated with antidepressants. For instance, all antidepressants carry an FDA-required black-box warning — the agency’s most prominent warning— because they can increase the risk of suicidal behaviors in children and young adults.[10]

SNRIs and SSRIs also can increase the risk of certain cardiovascular problems and abnormal bleeding, cause sexual dysfunction or lead to a life-threatening condition called serotonin syndrome (which is characterized by agitation, confusion, hallucinations, rapid heartbeat, high blood pressure, high fever, shivering, sweating, nausea, vomiting, diarrhea and muscle rigidity). Duloxetine also can cause serious liver damage, falls and fainting.

Because antidepressants are not only prescribed to treat depression but for several other conditions as well, the results of this study are of importance for many different patient groups. For example, duloxetine is approved for certain types of chronic pain and venlafaxine for three different anxiety disorders.[11]

What You Can Do

Do not discontinue any medication discussed above without consulting your health care provider. If you are planning to discontinue any antidepressant drug, it is important not to do so abruptly, but to gradually reduce the dosage under medical supervision to minimize antidepressant discontinuation syndrome.

However, withdrawal symptoms can occur even if patients gradually decrease their dosage. Seek immediate treatment if you develop unremitting withdrawal signs or any severe adverse events associated with SSRIs and SNRIs described above.
 

References

[1] Gastaldon C, Schoretsanitis G, Arzenton E, et al. Withdrawal syndrome following discontinuation of 28 antidepressants: Pharmacovigilance analysis of 31,688 reports from the WHO spontaneous reporting database. Drug Saf. 2022. 45(12):1539-1549.

[2] Hirsch, M, Birnbaum, R. Discontinuing antidepressant medications in adults. UpToDate. Updated October 21, 2022.

[3] Gastaldon C, Schoretsanitis G, Arzenton E, et al. Withdrawal syndrome following discontinuation of 28 antidepressants: Pharmacovigilance analysis of 31,688 reports from the WHO spontaneous reporting database. Drug Saf. 2022. 45(12):1539-1549.

[4] Mayo Clinic. Antidepressant withdrawal: Is there such a thing? January 2019. https://www.mayoclinic.org/diseases-conditions/depression/expert-answers/antidepressant-withdrawal/faq-20058133. Accessed on February 23, 2023.

[5] Gastaldon C, Schoretsanitis G, Arzenton E, et al. Withdrawal syndrome following discontinuation of 28 antidepressants: Pharmacovigilance analysis of 31,688 reports from the WHO spontaneous reporting database. Drug Saf. 2022. 45(12):1539-1549.

[6] Drug-Induced Sexual Dysfunction in Women. Worst Pills, Best Pills News. July 2022. https://www.worstpills.org/newsletters/view/1473. Accessed March 9, 2023.

[7] Some SNRIs Useful for Depression; Avoid Others. Worst Pills, Best Pills News. March 2016. https://www.worstpills.org/newsletters/view/1023. Accessed March 9, 2023.

[8] Gastaldon C, Schoretsanitis G, Arzenton E, et al. Withdrawal syndrome following discontinuation of 28 antidepressants: Pharmacovigilance analysis of 31,688 reports from the WHO spontaneous reporting database. Drug Saf. 2022. 45(12):1539-1549.

[9] Ibid.

[10] Some SNRIs Useful for Depression; Avoid Others. Worst Pills, Best Pills News. March 2016. https://www.worstpills.org/newsletters/view/1023. Accessed March 9, 2022.

[11] Drug-Induced Sexual Dysfunction in Women. Worst Pills, Best Pills News. July 2022. https://www.worstpills.org/newsletters/view/1473. Accessed March 9, 2023.