Antidepressant withdrawal reactions
Robert M. Wolfe
Family physicians encounter a wide variety of complications associated with antidepressant medications. Various symptoms that occur when antidepressants are gradually or suddenly withdrawn have been described in the literature for more than 35 years. Family physicians should be familiar with these symptoms. This article describes some withdrawal syndromes and discusses their management.
The patient, a 43-year-old man, had been treated for depression with sertraline for about six months and was taking a maintenance dosage of 25 mg per day. Because the patient experienced drowsiness, the dosage was tapered to 12.5 mg per day for a week and then stopped. The patient began taking venlafaxine, 37.5 mg, one-half tablet twice daily Within 48 hours of discontinuing the sertraline, he noticed the onset of severe dizziness and lightheadedness, aggravated by sudden changes in position but without a sensation of spinning or nausea. Venlafaxine was discontinued after five days without relief of symptoms. When the dizziness persisted for another week, sertraline was restarted at a dosage of 12.5 mg at bedtime, and the dizziness and lightheadedness ceased by the following morning. He was subsequently tapered slowly from the sertraline with no further symptoms.
The patient was a 37-year-old woman with a history of severe refractory migraine headache that was unresponsive to multiple-drug therapies, including most antidepressants. She was given a therapeutic trial of venlafaxine, in a dosage of 37.5 mg twice daily, which was increased gradually to 75 mg these times daily, with the addition of lithium carbonate, 600 mg twice daily. Initially the therapy produced a noticeable improvement in the headaches, but within a few weeks the benefit began to fade and, because of insomnia and anorexia, the patient, without contacting her physician, decided to abruptly discontinue all medications. Within 48 hours she developed severe stomach cramps, nausea and vomiting, anxiety and panic attacks. She also began to experience severe restlessness (akathisia), will a compulsive need to pace back and forth in her home, and an inability to sit still for more than a few moments. The venlafaxine was restarted, and the symptoms completely abated within three to four hours. Venlafaxine was subsequently tapered gradually with no further problems.
This patient was a 20-year-old male student who was very anxious because he had been unable to regain weight lost several years earlier following a motor vehicle accident. After consultation with a gastroenterologist failed to find any organic cause, he was given amitriptyline, and the dosage was gradually increased to 50 mg daily in an attempt to stimulate weight gain. After two months, this treatment was discontinued because of lack of effect. Three days after discontinuing the amitriptyline, he began to have nausea and vomiting, lethargy, dizziness and lightheadedness. When symptoms persisted, he was suspected of having a withdrawal reaction, and the amitriptyhne was restarted at a dosage of 25 mg per day All symptoms disappeared within 30 minutes. Subsequently, the amitriptyline was gradually tapered and discontinued with no recurrence of symptoms.
Antidepressant Withdrawal Syndromes
A number of syndromes are known to be associated with withdrawal from antidepressants, with onset ranging from 24 to 48 hours to several weeks after discontinuation or tapering of the medicine and persisting from days to weeks. Two possible types of symptoms may occur when a medication dosage is lowered or discontinued: those directly caused by removal of the drug, and those related to relapse of the underlying illness the drug was used to treat. Withdrawal symptoms tend to be stereotypic, to appear in proportion to the daily dosage and length of treatment, and to disappear over time. Relapse, on the other hand, follows a characteristic illness pattern and does not resolve spontaneously. This article exclusively addresses withdrawal symptoms.
Symptoms related to tricyclic antidepressant withdrawal have been reported to begin immediately or up to 48 hours after withdrawal, and to continue for as long as 14 days. Dilsaver discussed four main syndromes associated with withdrawal of tricyclic medications: (1) gastrointestinal or somatic distress, with or without anxiety and agitation, (2) sleep disturbances, (3) movement disorders and (4) paradoxic activation or mania[2,3] (Table 1). These syndromes are not restricted to adults; many of the same findings have occurred in children withdrawing from tricyclic antidepressants,[4,5] and mental irritability and tachypnea have even occurred in a few infants born to mothers taking tricyclic antidepressants during pregnancy.[6, 7]
A useful mnemonic that aids in remembering this bewildering assortment of symptoms is “AMINES” — adrenergic excess (i.e., symptoms of adrenaline excess), mania (or mood fluctuations), intestinal flu illness, extrapyramidal symptoms and sleep disturbances.
Withdrawal Reactions with Tricyclic Antidepressants
Incidence 21 to 80 percent Onset Days Duration Days to two weeks Symptoms Medical
Gastrointestinal: abdominal pain, anorexia, diarrhea, dry mouth, nausea,salivation, vomiting
Somatic: chills, coryza, fatigue, flu-like syndrome, headache, malaise, myalgia, sweating, weakness
Cardiovascular: bigeminy, palpitations, PVCs, tachycardia
Autonomic dysfunction: increased body temperature, piloerection Neurologic
Akathisia, delirium, disorientation, dizziness or vertigo, dyskinesia, jitteriness/tremor, impaired memory or thinking, paresthesias
Sleep disorders: excessive, vivid and early-onset dreaming, insomnia, nightmares, sleep apnea Psychiatric Anxiety, apathy, depersonalization, depression, irritability, hypomania,
PVCs = premature ventricular contractions. Information from Lawrence JM. Reactions to withdrawal of antidepressants, antiparkinsonian drugs, and lithium. Psychosomatics 1985;26:869-74,877.
TRAZODONE AND SSRIS
Recent literature has called attention to a number of withdrawal syndromes associated with trazodone (Desyrel) and selective serotonin reuptake inhibitors (SSRIs) that are similar in many ways to those described after tricyclic withdrawal[8-42] (Tables 2 and 3). SSRIs include fluoxetine (Prozac), fluvoxamine Luvox), paroxetine (Paxil) and sertraline Zoloft). Although venlafaxine (Effexor) and clomipramine (Anafranil) are nonselective serotonin reuptake inhibitors, for the sake of simplicity they will be included with the SSRIs in this article. Trazodone, although primarily serotonergic in action, has withdrawal effects very similar to those of tricyclic antidepressants.
Withdrawal Reactions with Trazodone (Desyrel)
Incidence Unknown Onset One to two days Duration Four to five days Symptoms Medical
Gastrointestinal: abdominal pain, anorexia, diarrhea, nausea, vomiting
Somatic: fatigue, flu-like syndrome, headache, malaise, myalgia, weakness,
Cardiovascular: palpitations, tachycardia Neurologic
Jitteriness/tremor, paresthesias, restless legs(*)
Sleep disorders: excessive, vivid and early-onset dreaming, insomnia,
Anxiety, auditory distortions, depersonalization, hypomania, mania, panic
(*)Single case report. Information from Lawrence JM. Reactions to withdrawal of antidepressants, antiparkinsonian drugs, and lithium. Psychosomatics 1985;26:869-74,877.
Withdrawal Reactions with SSRIS, Clomipramine (Anafranil) and Venlafagne (Effexor)
Incidence Variable(*) Onset
Days (onset of withdrawal symptoms may be delayed one to three weeks
after fluoxetine discontinuation)[dagger] Duration One to two weeks Symptoms Medical
Gastrointestinal: abdominal pain, anorexia, diarrhea, dry mouth,
increased appetite, nausea, vomiting Somatic: blurry or double vision, chest discomfort, chills, coryza, fatigue,
flu-like syndrome, headache, malaise, myalgia, sweating, weakness Cardiovascular: palpitations, postural hypotension[double dagger] Neurologic
Akathisia, [sections] disorientation, dizziness or vertigo, dyskinesia and dystonia, \
imbalance, jitteriness / tremor, impaired memory or thinking, paresthesias
(burning, tingling or electric shock sensations in spine or perioral area),
Lhermitte’s sign (electric shock sensation in spine or limbs, elicited by
neck flexion), // transient “rushing” or “buzzing” in head,
scotomas, tinnitus Sleep disorders: excessive, vivid and early-onset dreaming,
insomnia, nightmares Psychiatric
Anxiety, apathy, aggressiveness, confusion, depersonalization, hallucinations, lowered mood or depression, hypomania, irritability, panic
SSRIs = selective serotonin reuptake inhibitors.
(*) — A recent retrospective study4o of 171 patients revealed 21 cases of withdrawal reactions (12.3 percent) with the following incidence rate: clomipramine: 30.8 percent; paroxetine: 20 percent, fluvoxamine: 14 percent; sertraline: 2.2 percent, and fluoxetine: zero percent. In a review of adverse drug reactions(42) the incidence of withdrawal reactions was higher with paroxetine (0.3 reports per 1000 prescriptions) than with sertraline and fluvoxamine (0.03), and least with fluoxetine (0.002), for a ratio of 150:15:1. Based on two studies(19,23) that showed withdrawal reaction rates of approximately 35 percent with paroxetine, an estimate of SSRI withdrawal reactions has been calculated to be 35 percent with paroxetine, 3 to 4 percent with sertraline and fluvoxamine, and 0.5 percent with fluoxetine (this estimate may be too for for fluvoxamine; other studies(13,14) have reported withdrawal rates from 28 to 86 percent with fluvoxamine). [dagger] — In rare cases, mild symptoms have persisted up to 13 weeks. [double dagger] — Single case report on sertraline.(32) [sections] — Single case report on venlafaxine.(37) \ — Single case report on fluoxetine.(9) [Paragraph] — Single case report on paroxetine.(25) Information from Lawrence JM. Reactions to withdrawal of antidepressants, antiparkinsonian drugs, and lithium. Psychosomatics 1985,26:869-74,877.
The most frequent withdrawal symptoms in two large studies[40,42] involving SSRIs, were dizziness, paresthesias, anxiety, nausea and sleep disturbances insomnia, nightmares). Reports of incidence vary widely; withdrawal effects are more common with prolonged antidepressant administration (withdrawal is uncommon if the medicine has been used for less than five weeks) and more common with drugs having shorter half-lives. The lowest incidence of withdrawal symptoms is related to fluoxetine (Table 3), which has a half-life of seven to nine days for the active metabolite norfluoxetine.
The highest number of reported cases of withdrawal syndrome is related to paroxetine, whose half-life is 24 hours. Paroxetine also inhibits its own clearance by suppressing the hepatic P450IID enzyme, So that when the drug is stopped or tapered, the clearance rate accelerates as the plasma level falls because of decreased P450IID inhibition; this would tend to cause a higher rate of withdrawal reactions. Fluvoxamine (with a half-life of 15 hours) would be expected to have an incidence of withdrawal reactions close to that of paroxetine; the rate for sertraline (with a half-life of one to four days) falls between that of fluoxetine and paroxetine.
MAOIS AND OTHER ANTIDEPRESSANTS
Abrupt discontinuation of monoamine oxidase inhibitors (MAOIs) has been reported to cause a variety of symptoms, including anxiety, headaches, muscle weakness, paresthesias and shivering (Table 4). Psychosis, delirium and hallucinations have also been described. MAOI withdrawal has been likened to both opiate withdrawal and amphetamine withdrawal.[3,44]
Withdrawal Reactions with MAOIs
Incidence Unknown Onset Days Duration Days to weeks Symptoms Medical
Headache, orthostatic hypotension, muscle
weakness, shivering Neurologic
Ataxia, athetosis, catatonia, delirium,
drowsiness, paresthesias, sleep
Anxiety, agitation, hallucinations, irritability,
paranoia, pressured speech, psychosis
MAOIs = monoamine oxidase inhibitors. Information from Lawrence JM. Reactions to withdrawal of antidepressants, antiparkinsonian drugs, and lithium. Psychosomatics 1985;26:869-74,877.
Withdrawal reactions have not yet been reported in patients discontinuing bupropion (Wellbutrin).
Biologic Basis of Antidepressant
PATHOPHYSIOLOGY OF TRICYCLIC
Two main theories attempt to explain the mechanism of the tricyclic withdrawal syndrome: the cholinergic overdrive theory and the adrenergic overdrive theory. Both theories are based on the concept that blockade of a receptor site tends to cause that receptor to become supersensitive, or “up-regulated.” This situation, for example, is familiar to physicians who use beta blockers: prolonged beta blockade causes the beta-adrenergic receptor to become supersensitive, so after the beta blocker is discontinued abruptly, a period of rebound occurs when the up-regulated receptor produces symptoms of “adrenergic overdrive” such as tachycardia, arrhythmias and potential coronary insufficiency.
CHOLINERGIC OVERDRIVE THEORY
A similar mechanism is believed to cause antidepressant withdrawal reactions. Tricyclic-antidepressants bind to muscarinic receptors, one of the two major classes of cholinergic receptors. The vast majority of cholinergic receptors in the brain are muscarinic; elsewhere, muscarinic receptors are present in many organs (such as the intestine), where they are responsible for functions such as sweat gland secretion and smooth muscle contraction. The degree of cholinergic blockade is believed to be proportional to the muscarinic, receptor affinity of the tricyclic antidepressants.
The cholinergic overdrive theory postulates that persistent cholinergic blockade leads to receptor up-regulation, thus explaining the tolerance to tricyclic antidepressant side effects (such as constipation and dry mouth) that develops over time as the system tries to counteract the blockade and restore normal cholinergic tone. With sudden tricyclic-antidepressant withdrawal, the receptor takes time to return to normal, leading to a period of cholinergic overactivity, or overdrive. This theory accounts for symptoms such as vomiting, diarrhea, abdominal cramps, sweating and delirium, all of which are symptoms of cholinergic poisoning (such as occur after organophosphate poisoning) and are relieved by anticholinergic agents such as atropine.
ADRENERGIC OVERDRIVE THEORY
The adrenergic theory of tricyclic antidepressant withdrawal suggests that, as a result of norepinephrine reuptake inhibition causing increased norepinephrine in the synapse between neurons, the alpha autoreceptor (which gives negative feedback) is stimulated, causing a decrease in adrenergic firing. Prolonged presence of norepinephrine in the synapse causes blunting of this heightened receptor sensitivity (much as the carbon dioxide receptors desensitize in persons with chronic obstructive pulmonary disease), so that after the tricyclic antidepressant is withdrawn, the autoreceptor fails to provide normal inhibition, resulting in adrenergic overdrive and symptoms of adrenaline excess such as shakes, anxiety and arrhythmias.
PATHOPHYSIOLOGY OF SSRI
AND TRAZODONE WITHDRAWAL
The exact mechanism behind SSRI and trazodone withdrawal symptoms is unknown. It has been suggested[16,40,41] that some withdrawal symptoms may result from a mechanism involving 5-hydroxytryptophan (5-HT) receptor down-regulation (i.e., desensitizing to create a deficiency of serotonin after SSRI withdrawal), since some of the withdrawal effects, such as vertigo and emesis, also occur in persons with motion sickness and migraine headaches, both of which are believed to be related to fluctuations in central serotonin levels.
Trazodone has been postulated to cause withdrawal reactions similar to the symptoms of tricyclic antidepressant withdrawal through the following adrenergic rebound mechanisms: serotonin /5-[HT.sub.2] neurons, which are stimulated by the drug, also inhibit adrenergic neurons, and when the trazodone is stopped, lifting of this inhibition produces adrenergic rebound.
Extrapyramidal symptoms are relatively rare in SSRI withdrawal, although such one case has been reported after fluoxetine withdrawal. The second illustrative case, in which akathisia resulted from venlafaxine withdrawal, is the first incidence reported in the literature of such a withdrawal side effect with a serotonin reuptake inhibitor. A possible explanation of its cause is that it might have resulted from noradrenergic rebound overdrive in the ventral tegmental nucleus (VTN), causing suppression of dopaminergic tone, since dopamine deficiency in the VTN is believed to be the cause of akathisia. This theory is supported by the fact that venlafaxine has the highest norepinephrine/serotonin reuptake blockade of the serotonin reuptake inhibitors, and that beta blockers are effective in the treatment of antidepressant-induced akathisia.
Three options for patients who develop withdrawal symptoms from tricyclic antidepressants have been described. The principles are equally applicable to all antidepressants withdrawal reactions (Figure 1). The first choice is to withhold treatment if symptoms are mild, since they often run their course in a few days to a week. A second option to reinstitute the antidepressant treatment, then slowly taper the dosage. A low dosage may be used, but if withdrawal symptoms are severe or occur during the tapering process, the original dosage should be used, followed by a more gradual tapering.
A third choice is to withhold the antidepressant and add other medications to control withdrawal symptoms. In the case of tricyclic antidepressant or trazodone withdrawal, an anticholinergic agent can be administered to control symptoms of cholinergic rebound. Atropine sulfate, benztropine mesylate (Cogentin) and trihexyphenidyl (Artane), in divided doses, tapered over five to 10 days, are all effective (Table 5).[9,18,-,35,39,47-50] Success has been reported 34 with a mixture of belladonna extracts and phenobarbitol (Donnatal), and intramuscular and oral atropine for gastrointestinal symptoms related to trazodone withdrawal. Centrally acting anticholinergic agents are preferred; in one report, propantheline, a peripherally acting anticholinergic, was effective in the treatment of intestinal symptoms but did not alleviate insomnia; a change to benztropine, which crosses the blood-brain barrier, also relieved the insomnia.
Medical Treatment of Antidepressant Withdrawal Symptoms
Symptoms Treatment examples(*)
Cholinergic rebound Centrally acting anticholinergic symptoms (nausea, Atropine sulfate, 0.8 mg orally, three vomiting, diarrhea, or four times daily sweating) related or to tricyclic Benztropine mesylate (Cogentin), antidepressant or 0.5 to 4 mg orally, as needed trazodone (Desyrel) (often effective used only once daily) withdrawal or
Trihexyphenidyl (Artane), 1 to 4 mg orally,
three or four times daily
2 tablets orally, three or four
times daily Anxiety Benzodiazepine
Lorazepam (Ativan), 0.5 to 1 mg orally,
as needed Dizziness Meclizine (Antivert), 12.5 to 25 mg orally
every six hours, as needed
Dimenhydrinate (Draminime), 50 mg orally
every six hours, as needed Extrapyramidal symptoms
Akathisia Beta blocker
Propranolol (Inderal), 10 to 20 mg
orally, three or four times daily
Lorazepam, 0.5 to 2 mg orally, as
Clonazepam (Klonopin), 0.5 to 2 mg
orally, as needed
Benztropine or trihexyphenidyl, as above
Diphenhydramine (Benadryl), 12.5 to
50 mg orally, three or four times
Hydroxyzine, 25 to 50 mg orally, three
or four times daily
Acute dystonia Diphenhydramine, 50 mg intramuscularly
or 25 to 50 mg in a slow intravenous push
Benztropine, 2 mg intramuscularly or
1 to 2 mg in a slow intravenous push
NOTE: Three options are available for the treatment of all antidepressant drug withdrawal syndromes: (1) discontinue the antidepressant with no additional therapy and allow withdrawal symptoms, if they are mild, to run their course for a few days to a week, (2) reintroduce the same antidepressant or increase dosage if withdrawal reactions occur during tapering, then taper more slowly, (3) discontinue the antidepressant and introduce other medications to control specific withdrawal symptoms. (*) — Adult dosages; appropriate adjustments must be made in pediatric patients. Information from references 9,18,34,35,39,47-50.
Hyoscyamine sulfate in sublingual tablets (Levin/SL) is an anticholinergic agent that may be used as an alternative to parenteral atropine or benztropine for treatment of severe vomiting.
Treatment of SSRI or MAOI withdrawal reaction is similar: either no treatment at all or reinstitution of the drug at the original dosage level, followed by more gradual tapering. Inconsistent results have been reported with substitution of a different antidepressant. Two cases have been reported in which this treatment helped; in one case, nightmares after discontinuation of clomipramine were relieved by venlafaxine and, in another case, switching to fluoxetine relieved withdrawal symptoms resulting from discontinuation of paroxetine.
The patient in the first illustrative case, however, continued to have withdrawal symptoms from sertraline discontinuation despite the substitution of venlafaxine; in another reported case, administration of sertraline did not abate withdrawal symptoms resulting from discontinuation of paroxetine. In other cases, use of haloperidol and desipramine[26,28] had no effect on withdrawal symptoms resulting from paroxetine discontinuation. In general, substituting a different antidepressant should be considered an unreliable treatment for SSRI withdrawal symptoms and should only be done to treat the underlying psychiatric illness.
Various therapies have been used to treat movement disorders that present in withdrawal syndromes. If akathisia develops and the antidepressant cannot be reinstituted, small dosages of a beta blocker may be tried. One report described success with propranolol, 30 to 80 mg a day, in the treatment of akathisia caused by direct administration (not withdrawal) of a variety of antidepressants, including trazodone, desipramine, imipramine and tranylcypromine. Benzodiazepines, including diazepam (Valium) and alprazolam (Xanax), have also been used to control symptoms of akathisia or anxiety, and clonazepam (Klonopin) was effective in relieving neonatal withdrawal symptoms (hypertonia, and hyperreflexia) related to maternal clomipramine use. A case of severe extrapyramidal symptoms resulting from fluoxteine withdrawal was successfully treated in an emergency department setting with diphenhydramine, 50 mg given intramuscularly.
Prevention of Withdrawal Reactions
To prevent withdrawal reactions, it is probably prudent to taper most antidepressants over a week or more. The exception to this is fluoxetine, which has such a long half-life that it “self-tapers” on discontinuation. Patients should also be advised not to abruptly discontinue their medication and should be reassured that having a withdrawal reaction does not mean that the medicine is “bad.”
Even with tapering, withdrawal reactions may still occur with any antidepressant; fortunately, most symptoms are self-limited and are usually not serious. Psychiatric consultation should be obtained if significant mood fluctuations, such as mania, appear. If a severe reaction such as delirium, dehydration, severe mania or cardiac arrhythmia requires hospital admission, the patient should also be treated with standard modalities for the medical symptoms (e.g, intravenous fluid for dehydration, lithium and neuroleptics for mania).
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ROBERT M. WOLFE, m.d. has a family practice in the Chicago suburbs. He is also a clinical assistant professor or family medicine at the University of Illinois College of Medicine and a clinical instructor in the Department of Family Medicine at thee University of Health Sciences/Chicago Medical School, North Chicago. Dr. Wolfe graduated from the University of Chicago Pritzker School of Medicine. After two years of pathology training at Nortwestern University Medical Center, Chicago, he completed a family practice residency at West Suburban Hospital Medical Center, Oak Park, Ill.
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