Current p SYCHIATRY N ew Investigators Tips to manage and prevent discontinuation syndromes Informed tapering can protect patients when you stop a medication Sriram Ramaswamy, MD Shruti Malik, MBBS, MHSA Vijay Dewan, MD Instructor, department of psychiatry Foreign medical graduate Assistant professor Creighton University Department of psychiatry Omaha, NE University of Nebraska Medical Center Omaha, NE bruptly stopping common psychotropics New insights on psychotropic A —particularly antidepressants, benzodi- drug safety and side effects azepines, or atypical antipsychotics—can trigger a discontinuation syndrome, with: This paper was among those entered in the 2005 • rebound or relapse of original symptoms Promising New Investigators competition sponsored • uncomfortable new physical and psycho- by the Neuroleptic Malignant Syndrome Information Service (NMSIS). The theme of this year’s competition logical symptoms was “New insights on psychotropic drug safety and • physiologic withdrawal at times. side effects.” To increase health professionals’ awareness of URRENT SYCHIATRY 1 C P is honored to publish this peer- the risk of these adverse effects, this article reviewed, evidence-based article on a clinically describes discontinuation syndromes associated important topic for practicing psychiatrists. with various psychotropics and offers strategies to NMSIS is dedicated to reducing morbidity and anticipate, recognize, and manage them. mortality of NMS by improving medical and psychiatric care of patients with heat-related disorders; providing ANTIDEPRESSANTS support information for medical professionals, patients Discontinuation syndromes can occur with tricyclic and families; and improving scientific understanding of and tetracyclic antidepressants (TCAs), monoamine these conditions through research. oxidase inhibitors (MAOIs), selective serotonin VOL. 4, NO. 9 / SEPTEMBER 2005 29 N ew Investigators Discontinuation syndromes Table 1 TCAs block serotonin and norepineph- Discontinuation symptoms seen with TCAs rine reuptake, increasing the availabil- Physical Lethargy, headache, tremor, sweating, ity of these biogenic amines at receptor symptoms anorexia, insomnia, nausea, vomiting, sites in the brain and other tissues. diarrhea, akathisia (rare), parkinsonism (rare) Abrupt discontinuation can cause physical symptoms—such as lethargy, Psychological Irritability, anxiety/agitation, low mood, headache, and tremor—and psycho- symptoms excessive dreaming, nightmares, paradoxical activation resulting in logical symptoms including irritability, manic/hypomanic symptoms (rare) anxiety, agitation, and low mood (Table 1).2 TCA: Tricyclic antidepressants Long-term use of TCAs with potent Source: Reference 2 anticholinergic properties leads to up- regulation of postsynaptic muscarinic Table 2 receptors, creating a “supersensitive” Discontinuation symptoms seen with SSRIs state. Abrupt discontinuation can cause cholinergic rebound, with symp- Type Symptoms toms emerging as soon as 12 hours— Disequilibrium Lightheadedness/dizziness, vertigo, ataxia but typically 24 to 48 hours—after the last dose. Sensory symptoms Paraesthesia, numbness, MAOIs such as phenelzine and tranyl- electric shock-like sensations cypromine inhibit the enzyme mono- General somatic Lethargy, headache, tremor, sweating, amine oxidase, which is responsible for symptoms anorexia monoamine degradation and increases synaptic monoamine concentrations. Sleep disturbance Insomnia, nightmares, excessive dreaming Discontinuation syndromes may GI symptoms Nausea, vomiting, diarrhea include acute confusional states, para- Affective symptoms Irritability, anxiety/agitation, low mood noid delusions, hallucinations, or worsening of depressive symptoms.3 SSRIs: Selective serotonin reuptake inhibitors These problems rarely occur in clinical Source: Reference 5 practice, however, because MAOIs’ serious side effects discourage doctors reuptake inhibitors (SSRIs), and other newer anti- from prescribing them. depressants. Symptoms usually start within a few SSRIs and other agents. SSRIs block synaptic reup- days of stopping a drug—or less commonly, reduc- take of serotonin. Serotonin-norepinephrine reup- ing its dosage—and are usually mild and self-lim- take inhibitors (SNRIs) such as venlafaxine and ited. Serious outcomes have been reported. duloxetine inhibit both serotonin and norepineph- Distinguishing antidepressant discontinuation rine reuptake. Mirtazapine—an alpha2-adrener- symptoms from depression recurrence is important. gic and heteroreceptor antagonist—increases sero- Discontinuation symptoms emerge within 1 to 3 tonin and norepinephrine at the synapse. Bu- days, whereas depressive symptoms usually occur 2 propion increases dopamine and norepinephrine to 3 weeks after an antidepressant is stopped. turnover in the CNS and also blocks serotonin. Discontinuation reactions remit within a few days, Up to 30% of patients who stop taking SSRIs especially if the antidepressant is re-instituted. develop discontinuation symptoms.4 Six symptom continued on page 37 30 Current VOL. 4, NO. 9 / SEPTEMBER 2005 p SYCHIATRY Current p SYCHIATRY continued from page 30 clusters—disequilibrium, sensory symptoms, Table 3 general somatic symptoms, sleep disturbance, GI SSRI discontinuation syndrome: symptoms, and affective symptoms—characterize The patient at risk. the SSRI discontinuation syndrome (Table 2, page 30).5 The four most common symptoms—in Is taking an SSRI with a relatively short half-life decreasing order of frequency—are dizziness, Has received antidepressant treatment > 4 weeks nausea, lethargy, and headache.6 Ataxia, sensory abnormalities, and possibly aggressive and Has history of treatment-emergent anxiety, discontinuation symptoms, nonadherence impulsive behavior differentiate this discontinua- SSRI: Selective serotonin reuptake inhibitor tion syndrome from that of the TCAs. Source: Reference 7 Risk factors. Risk factors for SSRI discontinuation syndrome have been identified (Table 3).7 Symp- toms usually begin 1 to 3 days after an SSRI is Causes. Theories to explain SSRI discontinuation abruptly stopped and are usually mild. However, syndrome include cholinergic rebound,12 as some patients report falls, inability to work, and described with TCAs, or a decrease in available difficulty walking and driving. Untreated symp- synaptic serotonin coinciding with down-regulat- toms are short-lived and remit within 1 to 2 ed serotonin receptors.13 Paroxetine’s pharmaco- weeks. They also remit if the original antidepres- logic properties—cholinergic effects, short half- sant is reintroduced or a pharmacologically sim- life, and high potency of serotonin reuptake ilar agent is substituted. blockade—may explain its relatively high fre- Discontinuation syndrome risk among SSRIs quency of discontinuation symptoms. is highest for paroxetine, intermediate for sertra- line and fluvoxamine, and lowest for fluoxetine.4 ATYPICAL ANTIPSYCHOTICS Citalopram may cause a mild and transient dis- Except for aripiprazole—which is a partial continuation syndrome.8 Citalopram’s long elimi- dopamine receptor agonist—most atypical anti- nation half-life (30 to 35 hours) and fewer and psychotics are serotonin-dopamine antagonists. much less-potent active metabolites9 may explain Discontinuation syndrome occurs most com- its relatively low risk of discontinuation symptoms. monly with clozapine. Discontinuation reactions have been reported Clozapine. Abruptly stopping clozapine can exacer- to occur 100 times more frequently with paroxe- bate psychosis or cause delirium, agitation, confu- tine than with fluoxetine.10 Fluoxetine’s lower sion, and diaphoresis. Less-common symptoms rate could be explained by its 2- to 3-day half-life, may include extrapyramidal effects, nausea, diar- compared with half-lives of 33 hours or less for rhea, headache, or restlessness.14 Clozapine is a paroxetine, sertraline, citalopram, and fluvoxam- weak dopamine D2 antagonist and a potent antag- ine. A longer half-life might protect against a dis- onist at the serotonin 5HT2, alpha adrenergic, his- continuation syndrome. taminergic, and anticholinergic receptors. Thus, Among other newer antidepressants: rebound from cholinergic, serotonin, dopamine • venlafaxine’s discontinuation syndrome and/or adrenergic receptor supersensitivity is is similar to the SSRI syndrome11 thought to cause its discontinuation syndrome.15 • no discontinuation symptoms have been Other atypicals. Case reports describe tics and with- reported with mirtazapine, bupropion, or drawal-emergent dyskinesia with risperidone16 and duloxetine. supersensitivity psychosis and a cholinergic/sero- VOL. 4, NO. 9 / SEPTEMBER 2005 37 N ew Investigators Discontinuation syndromes tonergic syndrome with olanzapine.17,18 Anecdotal when physical dependence also can develop. reports suggest that abruptly discontinuing queti- More-severe benzodiazepine discontinuation syn- apine can cause nausea, emesis, lightheadedness, drome is associated with higher dosages, longer diaphoresis, orthostasis, tachycardia, and nervous- duration of therapy, shorter half-lives, and rapid ness.19,20 Although discontinuation syndromes have tapers. Patient factors associated with withdrawal not been reported with ziprasidone or aripiprazole, symptoms include: tapering any atypical antipsychotic during discon- • personality traits such as dependency and tinuation is prudent. neuroticism • high pretreatment anxious and depressive BENZODIAZEPINES symptoms Benzodiazepines modulate the neurotransmitter