Psychiatric Annals

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GRAND ROUNDS 

Intractable Withdrawal From Venlafaxine Treated With Fluoxetine

William J Giakas, MD; John M Davis, MD

Abstract

Venlafaxine is a high-potency serotonin and norepinephrine reuptake inhibitor with a high antidepressant efficacy.1,2 Receptor binding studies also indicate a favorable profile with little activity at histamine Hl, muscarinic, alpha 1-adrenergic, and alpha 2-adrenergic, dopamine D2, serotonin 5 HT1A, and serotonin 5 HT2 receptors.3 These features make venlafaxine an attractive antidepressant choice in the treatment of major depression.

Although antidepressant efficacy and adverse effect profiles are essential considerations in the proper management of major depression, withdrawal syndromes associated with antidepressant discontinuation may be an often-ignored clinical problem that could jeopardize future acceptance of treatment recommendations. Withdrawal syndromes can occur during discontinuation of tricyclic agents and are believed to be cholinergically mediated.4 Discontinuation of paroxetine, a serotonin reuptake inhibitor with anticholinergic activity, has precipitated a variety of symptoms, including gastrointestinal disturbances, insomnia, fatigue, and visual phenomena.5,6 A recent report describes one patient with possible venlafaxine withdrawal that was characterized by nausea, headache, sinus congestion, feelings of abdominal distention, fatigue, and tinnitus.7 Repeated attempts at discontinuing the medication failed because of recurrent withdrawal symptoms, and the patient was maintained on a regimen of venlafaxine.

We report three consecutive patients who experienced severe physical symptoms of withdrawal during venlafaxine discontinuation. Repeated attempts at gradually tapering the dosage were unsuccessful and led to intolerable withdrawal sensations. The lowest dose of venlafaxine, which did not produce withdrawal symptoms, was continued while fluoxetine was added. Fluoxetine, a serotonin reuptake inhibitor, has a long elimination half-life and is generally believed to have no associated withdrawal syndrome during abrupt discontinuation. After 4 weeks of combined treatment, venlafaxine was discontinued. While receiving fluoxetine, these three patients were able to tolerate venlafaxine discontinuation with no recurrence of withdrawal symptoms. Serotonergic mechanisms may have a central role in the withdrawal syndrome precipitated by venlafaxine withdrawal.

CASE REPORTS

Case 1

Ms. A is a 26-year-old woman with no prior history of psychiatric illness or substance abuse who presented with symptoms of major depression characterized by depressed mood, anhedonia, decreased motivation, diminished libido, middle insomnia, and fatigue. Seven months of treatment with sertraline in dosages of up to 100 mg/day, conducted by her primary care physician, yielded no benefit. At the time of consultation, the patient tolerated a 2-day tapering of sertraline without symptoms of withdrawal. Venlafaxine was initiated at 37.5 mg twice daily 5 days after discontinuing sertraline. The dosage of venlafaxine was titrated to 75 mg twice daily with no adverse effects and resulted in complete depressive remission. The patient was taking no concomitant medications.

After 4 months' remission, the dosage of venlafaxine was decreased to 75 mg once a day, and the patient complained of dizziness, headache, and hot flashes. The dosage was changed to 37.5 mg twice daily, and the patient still complained of these symptoms, but at reduced intensity. The patient was encouraged to continue the dose for another week to adjust to the withdrawal, and then venlafaxine was decreased to 18.75 mg three times daily. Gradually, over 3 weeks, the regimen was decreased to 9.375 mg once a day (one fourth of the 37.5-mg tablet).

The patient phoned, quite distressed, reporting that each attempt at finally discontinuing venlafaxine produced hot flashes, malaise, nausea, headaches, and dizziness. These symptoms developed within 2 to 3 hours of missing a scheduled dose (ie, 26 to 28 hours after the last dose). Her mood remained euthymic, and she reported no anxiety, panic, nausea, or vomiting. Each time she restarted the 9.375-mg dose of venlafaxine, the physical symptoms resolved within 3 to 4 hours. The discontinuation was attempted three times, but the patient found the withdrawal symptoms too intolerable, and venlafaxine was…

Venlafaxine is a high-potency serotonin and norepinephrine reuptake inhibitor with a high antidepressant efficacy.1,2 Receptor binding studies also indicate a favorable profile with little activity at histamine Hl, muscarinic, alpha 1-adrenergic, and alpha 2-adrenergic, dopamine D2, serotonin 5 HT1A, and serotonin 5 HT2 receptors.3 These features make venlafaxine an attractive antidepressant choice in the treatment of major depression.

Although antidepressant efficacy and adverse effect profiles are essential considerations in the proper management of major depression, withdrawal syndromes associated with antidepressant discontinuation may be an often-ignored clinical problem that could jeopardize future acceptance of treatment recommendations. Withdrawal syndromes can occur during discontinuation of tricyclic agents and are believed to be cholinergically mediated.4 Discontinuation of paroxetine, a serotonin reuptake inhibitor with anticholinergic activity, has precipitated a variety of symptoms, including gastrointestinal disturbances, insomnia, fatigue, and visual phenomena.5,6 A recent report describes one patient with possible venlafaxine withdrawal that was characterized by nausea, headache, sinus congestion, feelings of abdominal distention, fatigue, and tinnitus.7 Repeated attempts at discontinuing the medication failed because of recurrent withdrawal symptoms, and the patient was maintained on a regimen of venlafaxine.

We report three consecutive patients who experienced severe physical symptoms of withdrawal during venlafaxine discontinuation. Repeated attempts at gradually tapering the dosage were unsuccessful and led to intolerable withdrawal sensations. The lowest dose of venlafaxine, which did not produce withdrawal symptoms, was continued while fluoxetine was added. Fluoxetine, a serotonin reuptake inhibitor, has a long elimination half-life and is generally believed to have no associated withdrawal syndrome during abrupt discontinuation. After 4 weeks of combined treatment, venlafaxine was discontinued. While receiving fluoxetine, these three patients were able to tolerate venlafaxine discontinuation with no recurrence of withdrawal symptoms. Serotonergic mechanisms may have a central role in the withdrawal syndrome precipitated by venlafaxine withdrawal.

CASE REPORTS

Case 1

Ms. A is a 26-year-old woman with no prior history of psychiatric illness or substance abuse who presented with symptoms of major depression characterized by depressed mood, anhedonia, decreased motivation, diminished libido, middle insomnia, and fatigue. Seven months of treatment with sertraline in dosages of up to 100 mg/day, conducted by her primary care physician, yielded no benefit. At the time of consultation, the patient tolerated a 2-day tapering of sertraline without symptoms of withdrawal. Venlafaxine was initiated at 37.5 mg twice daily 5 days after discontinuing sertraline. The dosage of venlafaxine was titrated to 75 mg twice daily with no adverse effects and resulted in complete depressive remission. The patient was taking no concomitant medications.

After 4 months' remission, the dosage of venlafaxine was decreased to 75 mg once a day, and the patient complained of dizziness, headache, and hot flashes. The dosage was changed to 37.5 mg twice daily, and the patient still complained of these symptoms, but at reduced intensity. The patient was encouraged to continue the dose for another week to adjust to the withdrawal, and then venlafaxine was decreased to 18.75 mg three times daily. Gradually, over 3 weeks, the regimen was decreased to 9.375 mg once a day (one fourth of the 37.5-mg tablet).

The patient phoned, quite distressed, reporting that each attempt at finally discontinuing venlafaxine produced hot flashes, malaise, nausea, headaches, and dizziness. These symptoms developed within 2 to 3 hours of missing a scheduled dose (ie, 26 to 28 hours after the last dose). Her mood remained euthymic, and she reported no anxiety, panic, nausea, or vomiting. Each time she restarted the 9.375-mg dose of venlafaxine, the physical symptoms resolved within 3 to 4 hours. The discontinuation was attempted three times, but the patient found the withdrawal symptoms too intolerable, and venlafaxine was begun again at 9.375 mg once a day.

Fluoxetine, in a dosage of 10 mgJday, was added to the regimen in an attempt to avoid the withdrawal symptoms on the presumption that they might be serotonergic in origin. After 4 weeks of treatment with fluoxetine, the patient was able to discontinue venlafaxine without recurrence of the abstinence syndrome. Two weeks later, fluoxetine was also discontinued. No withdrawal was produced, and the patient remained stable and euthymic.

Case 2

Ms. B is a 33-year-old woman with a history of Crohn's disease and major depression who had received a trial of alprazolam and later a 6month trial of bupropion under the care of her primary care physician. At consultation, the patient reported depressed mood, irritability, anxiety, diminished interest, decreased libido, passive suicidal ideation, excessive fatigue, impaired concentration, and frequent tension headaches. A subsequent trial of paroxetine proved ineffective. Venlafaxine was initiated at a dosage of 18.75 mg twice daily and titrated to 37.5 mg twice daily. The patient also received 0.5 mg of lorazepam three times daily.

Because of complaints of increased headache and nausea, the dosage was decreased to 18.75 mg twice daily. The patient tried to discontinue the medication 1 week later and experienced severe feelings of unsteadiness, dizziness, electric sensations in her head, headaches, nausea, and vomiting. These symptoms emerged approximately 12 hours after missing the next scheduled dose (ie, 24 hours after the last dose). The patient took 18.75 mg of venlafaxine, and the majority of her withdrawal symptoms resolved within 6 to 8 hours. The patient was maintained on 18.75 mg of venlafaxine once daily and begun on 10 mg of fluoxetine once daily. After 2 weeks, the dosage was increased to 20 mg once daily because of persistent depressive symptoms. None of the withdrawal symptoms were present. Two weeks later, the venlafaxine was discontinued without further tapering, and no withdrawal occurred.

Case 3

Ms. C is a 35-year-old woman with a history of migraine headaches, dysmenorrhea, and weight gain associated with amitriptyline prescribed by her primary care physician for treatment of major depression characterized by depressed mood, loss of interest, agitation, nervousness, early-morning awakening, low energy, and impaired concentration. The patient responded to amitriptyhne but asked her internist to initiate a different antidepressant because of a 45-lb weight gain. The patient subsequently suffered a relapse. Trials of 20 mg/day of fluoxetine for 4 months, 100 mg/day of sertraline for 3 months, and 20 mg/day of paroxetine for 6 weeks produced no significant improvement.

The paroxetine dosage was decreased to 10 mg/day for 3 days, then discontinued with only a mild increase in her level of anxiety. Venlafaxine was initiated and titrated to a dosage of 75 mg twice daily. Although the patient achieved a depressive remission, her headaches continued, and 25 mg of desiprarnine every night was added, and the headaches resolved. During the course of treatment, alcohol dependence was disclosed, and treatment with naltrexone was begun. The patient remained abstinent but soon suffered a severe depressive relapse. The dosage of desiprarnine was slowly increased to achieve serum levels of more than 120 ng/mL, and her depressive symptoms resolved.

Because venlafaxine did not appear to be contributing to her antidepressant regimen, it was tapered to a dosage of 37.5 mg three times daily. One week later, the patient reported severe withdrawal symptoms characterized by tingling up her back, numbness in the hands, fatigue, dizziness, a feeling of being "off balance," throbbing in her head, nausea, and increased mood lability. These symptoms developed within 2 to 3 hours of missing her next scheduled venlafaxine dose (ie, 8 to 9 hours after her last dose). The patient increased the dosage to 75 mg twice daily on her own with complete resolution of the withdrawal symptoms, which she reported at a later visit. The withdrawal symptoms began to resolve within 1 hour of taking the 7 5 -mg dose. Fluoxetine, in a dosage of 10 mg once daily, was initiated while continuing 150 mg/day of venlafaxine. The desiprarnine dosage was decreased 50% to prevent toxicity resulting from expected fluoxetine effects on the desiprarnine serum level.

After 1 week of fluoxetine at a dosage of 10 nag/day, the dosage was increased to 20 mg/day for 3 additional weeks before another taper of venlafaxine was attempted. The venlafaxine was then tapered rapidly over 5 days without the emergence of irritability, dysphoria, anxiety, or any of the previously reported withdrawal symptoms. The patient continued 20 mg of fluoxetine every morning, 50 mg of desiprarnine every night, 50 mg of naltrexone every morning, and 10 mg of lorazepam every night, and has maintained a 4-month depressive remission.

DISCUSSION

Venlafaxine withdrawal is characterized by nausea, headache, fatigue, and dizziness. These symptoms may be intense and intractable, even with very slow tapering regimens, and appear to occur approximately 8 to 28 hours after the last dosage taken and 2 to 12 hours after missing the next scheduled dosage. These emergent symptoms subside markedly within 1 to 8 hours of raising the net dosage of venlafaxine. The addition of fluoxetine, a potent serotonin reuptake inhibitor with a long half-life, can effectively prevent an intolerable venlafaxine withdrawal syndrome and suggests a serotonergic basis for the withdrawal symptoms. When fluoxetine is continued long enough to achieve steady-state or nearsteady-state serum concentrations, venlafaxine can then be abruptly discontinued or rapidly tapered with little or no patient discomfort. Presumably, fluoxetine maintains substantial synaptic levels of serotonin, thereby permitting rapid withdrawal of venlafaxine. In patients for whom complete antidepressant discontinuation is clinically indicated, the longer elimination halflife of fluoxetine may confer a slower rate of reduction of synaptic serotonin during discontinuation, and this appears to be better tolerated in these venlafaxine withdrawal-sensitive patients.

We have observed withdrawal symptoms from venlafaxine in other patients who miss a dose or two. This observation further supports the association between these symptoms and drug withdrawal. Similar symptoms have been seen with almost all high-potency serotonin uptake inhibitors, which includes paroxetine, 6,9,13,16"18 fluvoxamine,11,12 sertraline,10,14,16,17 and trazodone.15,16 Our finding that fluoxetine administration essentially abolished these withdrawal symptoms suggests that these symptoms are hyposerotonergic in mechanism. Furthermore, because fluoxetine and its active metabolite both have a very long half-life and produce a very slow drug taper, serotonin mechanisms are further implicated.

Clinical similarity exists between this withdrawal syndrome, characterized by both central symptoms (electric sensations for example and vascular headaches) and intestinal symptoms (nausea and vomiting), and other clinical phenomena also believed to have a serotonergic basis. We note that central psychomimetic agents such as LSD and methylated tryptamine may have a serotonergic action and are known to produce unusual perceptual changes. Serotonin is also involved in migraine and other vascular headaches, and serotonergic drugs are used in the treatment of this type of headache. Serotonin and its receptors are also plentiful in the gastrointestinal tract and are believed to have a significant regulatory role there. Although the observed venlafaxine withdrawal symptoms are not identical to a full-fledged psychedelic experience or a true migraine headache, similarity is evident, so it is plausible that a serotonergic mechanism is involved. More important, the symptoms disappear when the original selective serotonin reuptake inhibitor is reinstated or, as in these cases, when fluoxetine is added.

We have had extensive experience with nefazodone and not seen withdrawal symptoms. We did a literature search and read many clinical studies for reports of this syndrome with nefazodone and failed to find any similar ones. The absence of a reported nefazodone withdrawal syndrome does not prove that this syndrome does not occur clinically. This absence may represent a failure to publish clinical observations that occurred. Nonetheless, because nefazodone does not seem to produce a withdrawal syndrome and is both a serotonin reuptake inhibitor and serotonina (5HT2) receptor antagonist, we would speculate that the venlafaxine withdrawal symptoms are not mediated by 5HT2. Because multiple types of receptors and serotonergic systems exist, the exact mechanism of withdrawal remains to be determined. Also important, we did not see, nor did others report, drug-seeking behavior during treatment with venlafaxine, so this withdrawal effect appears to be only that and not an addiction phenomenon in which drug craving and dose escalation are typical.

On a practical level, we note that although the exact mechanisms involved in venlafaxine withdrawal are unclear, the distress patients experience may be great and eminently treatable. The addition of fluoxetine for 4 weeks in these circumstances is a safe and effective procedure, which permits rapid discontinuation of venlafaxine with no reemergence of the serotonin withdrawal symptoms.

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10.3928/0048-5713-19970201-05

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