Tips to manage and prevent discontinuation syndromes

Abruptly stopping common psychotropics—particularly antidepressants, benzodiazepines, or atypical antipsychotics—can trigger a discontinuation syndrome, with:

• rebound or relapse of original symptoms
• uncomfortable new physical and psychological symptoms
• physiologic withdrawal at times.

To increase health professionals’ awareness of the risk of these adverse effects,¹ this article describes discontinuation syndromes associated with various psychotropics and offers strategies to anticipate, recognize, and manage them.

Antidepressant Discontinuation Syndromes

Discontinuation syndromes can occur with tricyclic and tetracyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and other newer antidepressants. Symptoms usually start within a few days of stopping a drug—or less commonly, reducing its dosage—and are usually mild and self-limited. Serious outcomes have been reported.

Distinguishing antidepressant discontinuation symptoms from depression recurrence is important. Discontinuation symptoms emerge within 1 to 3 days, whereas depressive symptoms usually occur 2 to 3 weeks after an antidepressant is stopped. Discontinuation reactions remit within a few days, especially if the antidepressant is re-instituted.

TCAs block serotonin and norepinephrine reuptake, increasing the availability of these biogenic amines at receptor sites in the brain and other tissues. Abrupt discontinuation can cause physical symptoms—such as lethargy, headache, and tremor—and psychological symptoms including irritability, anxiety, agitation, and low mood (Table 1).²

Long-term use of TCAs with potent anticholinergic properties leads to upregulation of postsynaptic muscarinic receptors, creating a “supersensitive” state. Abrupt discontinuation can cause cholinergic rebound, with symptoms emerging as soon as 12 hours—but typically 24 to 48 hours—after the last dose.

Table 1

Discontinuation symptoms seen with TCAs

MAOIs such as phenelzine and tranylcypromine inhibit the enzyme monoamine oxidase, which is responsible for monoamine degradation and increases synaptic monoamine concentrations. Discontinuation syndromes may include acute confusional states, paranoid delusions, hallucinations, or worsening of depressive symptoms.³ These problems rarely occur in clinical practice, however, because MAOIs’ serious side effects discourage doctors from prescribing them.

SSRIs and other agents. SSRIs block synaptic reuptake of serotonin. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine inhibit both serotonin and norepinephrine reuptake. Mirtazapine—an alpha2-adrenergic and heteroreceptor antagonist—increases serotonin and norepinephrine at the synapse. Bupropion increases dopamine and norepinephrine turnover in the CNS and also blocks serotonin.

Up to 30% of patients who stop taking SSRIs develop discontinuation symptoms.⁴ Six symptom clusters—disequilibrium, sensory symptoms, general somatic symptoms, sleep disturbance, GI symptoms, and affective symptoms—characterize the SSRI discontinuation syndrome (Table 2).⁵ The four most common symptoms—in decreasing order of frequency—are dizziness, nausea, lethargy, and headache.⁶ Ataxia, sensory abnormalities, and possibly aggressive and impulsive behavior differentiate this discontinuation syndrome from that of the TCAs.

Table 2

Discontinuation symptoms seen with SSRIs

Risk factors. Risk factors for SSRI discontinuation syndrome have been identified (Table 3).⁷ Symptoms usually begin 1 to 3 days after an SSRI is abruptly stopped and are usually mild. However, some patients report falls, inability to work, and difficulty walking and driving. Untreated symptoms are short-lived and remit within 1 to 2 weeks. They also remit if the original antidepressant is reintroduced or a pharmacologically similar agent is substituted.

Discontinuation syndrome risk among SSRIs is highest for paroxetine, intermediate for sertraline and fluvoxamine, and lowest for fluoxetine.⁴ Citalopram may cause a mild and transient discontinuation syndrome.⁸ Citalopram’s long elimination half-life (30 to 35 hours) and fewer and much less-potent active metabolites⁹ may explain its relatively low risk of discontinuation symptoms.

Discontinuation reactions have been reported to occur 100 times more frequently with paroxetine than with fluoxetine.¹⁰ Fluoxetine’s lower rate could be explained by its 2- to 3-day half-life, compared with half-lives of 33 hours or less for paroxetine, sertraline, citalopram, and fluvoxamine. A longer half-life might protect against a discontinuation syndrome.

Among other newer antidepressants:

• venlafaxine’s discontinuation syndrome is similar to the SSRI syndrome¹¹
• no discontinuation symptoms have been reported with mirtazapine, bupropion, or duloxetine.

Table 3

SSRI discontinuation syndrome: The patient at risk…

Causes. Theories to explain SSRI discontinuation syndrome include cholinergic rebound,¹² as described with TCAs, or a decrease in available synaptic serotonin coinciding with down-regulated serotonin receptors.¹³ Paroxetine’s pharmacologic properties—cholinergic effects, short halflife, and high potency of serotonin reuptake blockade—may explain its relatively high frequency of discontinuation symptoms.