Article topic: Antidepressant discontinuation syndrome
Author: Serena Semaan
Editors: Nancy Zrara, Christie Dib
Reviewer: Lobana Mahdawi
Introduction
Antidepressant drugs are commonly prescribed for depression and anxiety, as well as for obsessive-compulsive disorder (OCD), insomnia, chronic pain, erectile dysfunction (ED), smoking cessation, migraine, and Attention-deficit/hyperactivity disorder (ADHD). However, these drugs can lead to unpleasant effects during the discontinuation process, known as antidepressant discontinuation syndrome (ADS). ADS may occur following treatment with all types of antidepressants, although most literature focuses on selective serotonin reuptake inhibitors (SSRIs). DSM-5-TR enlists ADS among the “medication-induced movement disorders and adverse effects of medication”.The signs of ADS may also consist of flu-like signs, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal (anxiety/agitation) which can last for months or more for some patients.
Discontinuation of antidepressants may occur due to remission of the condition requiring pharmacotherapy, unsatisfactory response despite “adequate” trailing, loss of response, severe adverse reactions, change in the therapeutic schema due to the introduction of new drugs having relevant clinical interactions, or changes in the insurance plan coverage. Gradual discontinuation is recommended, particularly upon reaching low SSRI doses, following a hyperbolic decrease rather than a fixed decrement.
Rational pharmacotherapy consisting of brief augmentation techniques with benzodiazepines, anticholinergic, antihistamines, beta-blockers, or the non-selective α-2 agonist clonidine must be considered, especially in the case of sudden discontinuation poorly responsive to the proper reintroduction of the discontinued drug.
Gradual tapering of the antidepressant is warranted for patients who’ve already proved to be liable to antidepressant discontinuation symptoms, depressed patients presenting hints of sub-threshold bipolarity, panic disorder, or those subjects who already experienced jitteriness/anxiety syndrome upon commencing an antidepressant drug. Patients with major depressive disorder (MDD) who already achieved remission would have lower odds of relapse in case of slow tapering over six months compared to abruptly discontinued controls. However, there is very low certainty of evidence that abrupt discontinuation without psychological support may inflate the risk of relapse.
Insufficient evidence exists about the effect of abrupt discontinuation of the antidepressant on adverse events compared to the continuation of the antidepressant, without specific assessment of withdrawal symptoms, according to the same piece of evidence, concluding that effects of abrupt discontinuation on withdrawal symptoms are very uncertain. It has been considered that withdrawal reactions to antidepressant drugs would happen with both abrupt and gradual discontinuation of the SSRIs and (SNRIs), with no obvious advantage of the latter strategy.
The non-SSRI antidepressant could also cause antidepressant discontinuation symptoms or related symptoms such as rebound, discontinuation-induced refractoriness, and tolerance treatment-emergent loss of efficacy. Integrative management with concurrent pharmacotherapy and psychotherapy may decrease the effects happening within the discontinuation process.
Etiology
The exact pathophysiology of ADS is not fully comprehended despite multiple hypotheses. When first reported, many used the term “withdrawal” to describe the discontinuation symptoms, but antidepressant medications are not associated with drug-seeking behavior. (3)
Through inhibition of the serotonin reuptake pump, long-term SSRI use raises synaptic levels of serotonin, which causes the down-regulation of postsynaptic receptors. (4)Some people think that abruptly stopping using an SSRI could cause a temporary shortage of synaptic serotonin .(5) Down-regulated receptors will continue to function in their relatively inactive form for days to weeks, which exacerbates this shortage. This is considered to cause antidepressant discontinuation syndrome either directly or indirectly through effects on downstream neurotransmitter systems, such as norepinephrine, dopamine, and g-amino-butyric acid, which are linked to depressive and anxiety disorders. (5,7)
Tricyclic antidepressants also affect the cholinergic system, so quick withdrawal may result in symptoms of Parkinsonism and balance issues. However, tricyclic antidepressants also affect the serotonergic system, so rapid discontinuation may also result in these symptoms. Since MAOIs modify alpha2-adrenergic and dopaminergic receptors, stopping them may result in agitation and psychosis. (7)
Presentation
The DSM-5-TR considered that ADS may occur after treatment with all types of antidepressants and that the incidence depends on the dosage and half-life of the medication the patient takes and the rate at which the medication is tapered.
The most common presentation of ADS can be resumed by the classical mnemonic “FINISH” (Berber, 1998): Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, and Hyperarousal (anxiety/agitation).
Other symptoms can also be described and are resumed in this table (12,13).
| SSRI | Atypical antidepressant | TCA | MAOI | |
| Flu-like symptoms | + | + | + | – |
| Headache | + | + | + | + |
| Lethargy | + | + | + | – |
| Abdominal cramping | + | – | + | – |
| Abdominal pain | + | – | + | – |
| Appetite disturbance | + | + | + | – |
| Diarrhea | + | + | – | |
| Nausea/vomiting | + | + | + | – |
| Insomnia | + | + | + | + |
| Nightmares | + | + | + | + |
| Ataxia | + | – | + | – |
| Dizziness | + | + | + | – |
| Lightheadedness | + | + | + | – |
| Vertigo | + | + | + | – |
| Blurred vision | + | – | – | – |
| Electric shock sensations | + | + | – | – |
| Numbness | + | – | – | – |
| Paresthesia | + | + | – | – |
| Akathisia | + | + | + | – |
| Myoclonic jerks | – | – | – | + |
| Parkinsonism | + | – | + | – |
| Tremor | + | – | + | – |
| Aggression/irritability | + | – | – | + |
| Agitation | + | – | + | + |
| Anxiety | + | + | + | – |
| Low mood | + | + | + | + |
| Catatonia | – | – | – | + |
| Delirium | – | – | – | + |
| Delusions | – | – | – | + |
| Hallucinations | – | – | – | + |
Diagnosis
Antidepressant syndrome, also known as selective serotonin reuptake inhibitor (SSRI) discontinuation syndrome, is a collection of symptoms that can occur when a person abruptly stops taking antidepressants, such as SSRIs .(17)
The diagnosis of antidepressant syndrome is based on a patient’s reported symptoms and medical history (2).
Common symptoms of the antidepressant syndrome include flu-like symptoms, such as headache, dizziness, and fatigue, as well as gastrointestinal symptoms, such as nausea and diarrhea.(17)
Other symptoms can include anxiety, agitation, insomnia, and tremors. (2) In some cases, a person may experience vivid or intense dreams or even hallucinations. (17)
It is important to note that the onset of antidepressant syndrome symptoms can vary from person to person and may take several days or even weeks to develop.(2) The severity of the symptoms can also vary, from mild to severe, and can last from a few days to several weeks. (17)
In conclusion, the diagnosis of antidepressant syndrome is based on a patient’s reported symptoms and medical history and can include a variety of symptoms such as flu-like symptoms, gastrointestinal symptoms, anxiety, agitation, and vivid or intense dreams.
Risk factors
Antidepressant syndrome, also known as SSRI (selective serotonin reuptake inhibitor) discontinuation syndrome, is a potentially serious condition that can occur after stopping or reducing the use of certain types of antidepressants. This condition is characterized by symptoms such as flu-like symptoms, dizziness, headache, fatigue, and agitation, the risk of developing antidepressant syndrome varies depending on several factors, including the type of antidepressant used, the dose, and the length of time it has been taken. (20)
A study published in the Journal of Clinical Psychopharmacology found that up to 50% of people who discontinued the use of an SSRI antidepressant experienced symptoms of antidepressant discontinuation syndrome. (21)
Another study published in the Journal of Affective Disorders found that the risk of developing antidepressant syndrome increased with the use of high-potency antidepressants, such as paroxetine and venlafaxine, and was highest in people who stopped using these drugs abruptly. (22)
In conclusion, the risk of developing antidepressant syndrome is significant and should be taken into consideration by individuals taking these medications and their healthcare providers. Gradual tapering of the dose under the supervision of a healthcare professional is required to minimize the risk of experiencing symptoms of antidepressant syndrome (20).
Treatment
If ADS occurs, the first step is reassuring the patient that the condition is reversible, not serious or life-threatening, and will resolve within one to two weeks. (7)
The second step is restarting the same antidepressant medication with a slow dose taper or with the original dose and taper at a slower rate if ADS occurs during the tapering of the AD .(7)
In clinical practice, temporary augmentation strategies with benzodiazepines, anticholinergics, antihistamines, beta-blockers, or the non-selective alpha-2 agonist clonidine should be taken into consideration, especially in cases of abrupt discontinuation that is not well-responding to the prompt reintroduction of the discontinued antidepressant.(14)
This is especially true for antidepressants with “sedative” pharmacodynamic profiles: for example, supplementation with anticholinergic or antihistamine drugs should be suggested for the most sedative tricyclic antidepressants, or TCAs, or, to a lesser extent, for the SSRIs paroxetine and citalopram .(15)
Prevention
One way to prevent antidepressant syndrome is to slowly decrease the dose of the antidepressant when discontinuing the medication, as recommended by the American Psychiatric Association. This gradual reduction can help the body adjust and minimize withdrawal symptoms. (18)
Another preventative measure is to closely monitor patients taking antidepressants for signs of antidepressant syndrome and adjust their treatment as necessary, according to the National Institute of Mental Health. (19)
Additionally, avoiding the use of multiple antidepressants or combining them with other psychotropic drugs, as this can increase the risk of antidepressant syndrome. (18)
Prognosis
The prognosis of antidepressant syndrome is generally considered to be good with appropriate treatment. Antidepressant syndrome, also known as Antidepressant Discontinuation Syndrome, is a condition that occurs when a person stops taking their antidepressant medication abruptly. This can result in various symptoms, such as dizziness, headache, nausea, fatigue, and sleep disturbances. (2)
However, the symptoms of antidepressant syndrome are typically mild and self-limiting and resolve within a few days to two weeks. In severe cases, the symptoms may persist for a longer period and may require medical intervention.(1)
Treatment for antidepressant syndrome typically involves the gradual tapering of the antidepressant medication and the use of supportive measures, such as rest, and hydration, and in some cases, a temporary switch to a different antidepressant may be necessary. (2)
It is important to note that the severity and duration of antidepressant syndrome can vary from person to person and depends on several factors, such as the type of antidepressant being used, the dose, and the individual’s medical history. (1)
In conclusion, the prognosis of antidepressant syndrome is generally considered to be good with appropriate treatment. The symptoms are typically mild and self-limiting and resolve within a few days to two weeks. Gradual tapering of the antidepressant medication and supportive measures are often effective in managing the symptoms.
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