Posted by ed_uk on November 10, 2004, at 11:57:38
In reply to Re:To Bethesdabob, posted by bethesdabob on November 10, 2004, at 11:26:47
Hello BB,
I was very sorry to hear that your wife died last December. I will try to give you some information, but Im not sure how useful it will be. I feel bad because Im not sure that Im really helping. Please don't be overwhelmed by all the studies I've posted.
Before I start, I need to say that I cant be sure what was responsible for your wifes death, I can only make suggestions about what might have been the cause. The main thing which concerned me about your wifes medication was the very high dose of Effexor, particularly for someone with epilepsy. The high dose of Remeron also stood out. The possibility of a drug interaction is always a worry when someone is on so many medications.
Restlessness, sweating, chills/shivering, nausea/vomiting and confusion could all have been symptoms of the Serotonin Syndrome (SS). I would expect that there are also many other medical conditions which might cause these symptoms. How did the pathologist explain these symptoms?
Seizures may also occur in severe cases of the SS. I also found a report stating that one of the symptoms which occurred in a woman diagnosed with SS was chest pain, a symptom that your wife experienced. Here it is....
'OBJECTIVE: To report a possible case of serotonin syndrome associated with coadministration of tramadol hydrochloride and sertraline hydrochloride. CASE SUMMARY: A 42-year-old woman developed **atypical chest pain**, sinus tachycardia, confusion, psychosis, sundowning, agitation, diaphoresis, and tremor......'
...............................................
There have been numerous reports of the SS in patients taking venlafaxine(Effexor) and mirtazapine(Remeron). SS has occurred in people taking venlafaxine alone, venlafaxine combined with mirtazapine, venlafaxine in overdose, and venlafaxine combined with amphetamines (Adderall contains amphetamines).Here are the abstracts of some relevent articles....
ABSTRACT 1
Ann Pharmacother. 2003 Feb;37(2):209-11. Related Articles, Links
Serotonin syndrome induced by low-dose venlafaxine.
Pan JJ, Shen WW.
Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
OBJECTIVE: To report the case of a patient with serotonin syndrome induced by low-dose venlafaxine. CASE SUMMARY: A 29-year-old Taiwanese woman with major depressive disorder abruptly developed serotonin syndrome during low-dose (37.5 mg/d) venlafaxine monotherapy, with symptoms of restlessness, tremor, shivering, diarrhea, vomiting, ataxia, tachycardia, and myoclonus. The patient recovered in 2 hours after receiving prochlorperazine and lorazepam in the emergency department. Venlafaxine was discontinued, and she was discharged home. Two weeks later, the patient started to receive fluoxetine 20 mg/d and reported no adverse adverse effects during follow-up clinic visits. DISCUSSION: The clinical manifestations of this case meet Sternbach's criteria of serotonin syndrome. Its possible etiologic factors include panic attack, adverse drug reaction, pharmacodynamic interaction, and congenital absence of CYP2D6 enzyme activity. The Naranjo probability scale suggested a probable causality of venlafaxine treatment and serotonin syndrome. CONCLUSIONS: Clinicians should be aware of the risk of serotonin syndrome when the patient receives not only a combination of 2 antidepressants, but also the single potent serotonergic agent venlafaxine.ABSTRACT 2
J Emerg Med. 1997 Jul-Aug;15(4):491-3. Related Articles, Links
Isolated venlafaxine-induced serotonin syndrome.
Kolecki P.
Department of Medical Toxicology, Good Samaritan Regional Medical Center, Phoenix, Arizona 85006, USA.
Serotonin syndrome is a potentially fatal complication of serotonergic drug therapy. Usually, serotonin syndrome occurs with the concomitant use of two serotonergic drugs; this case report describes a patient with a classic presentation of serotonin syndrome induced solely by a venlafaxine overdose. Emergency physicians need to be aware that the serotonin syndrome may occur not only with serotonergic drug combinations but also with overdoses of a single potent serotonergic agent such as venlafaxine.ABSTRACT 3
Ann Pharmacother. 2002 Apr;36(4):641-3. Related Articles, Links
Severe serotonin syndrome induced by mirtazapine monotherapy.
Hernandez JL, Ramos FJ, Infante J, Rebollo M, Gonzalez-Macias J.
Department of Internal Medicine, Hospital Marques de Valdecilla, Santander, Spain. joselhh@teleline.es
OBJECTIVE: To document a case of serotonin syndrome (SS) associated with mirtazapine monotherapy, review the previously reported cases of SS associated with this tetracyclic antidepressant, and discuss the possible pathogenic mechanisms leading to this serious adverse drug reaction. CASE SUMMARY: A 75-year-old man developed agitation, confusion, incoordination, and gait disturbance because of progressive rigidity. Mirtazapine had been started 8 days earlier to control major depression. Physical examination revealed diaphoresis, low-grade fever, hypertension, tachycardia, bilateral cogwheel rigidity, hyperreflexia, tremor, and myoclonus, symptoms and signs that are consistent with severe SS. DISCUSSION: A review of the cases of SS with implication of mirtazapine as the cause was performed. The possible pathogenic mechanisms leading to this adverse reaction in this patient are also discussed, and pathophysiologic hypotheses are formulated. CONCLUSIONS: Although mirtazapine offers clinicians a combination of strong efficacy and good safety, we suggest bearing SS in mind when prescribing this drug, especially in frail, elderly patients with underlying chronic conditions. In these patients, it might be more adequate to start mirtazapine therapy at a lower dose (<15 mg/d).ABSTRACT 4
Clin Neuropharmacol. 2003 Mar-Apr;26(2):54-7. Related Articles, Links
Comment in:
Clin Neuropharmacol. 2003 Nov-Dec;26(6):287-8; author reply 289-90.
Clin Neuropharmacol. 2003 Nov-Dec;26(6):288-9; author reply 289-90.Mirtazapine-induced serotonin syndrome.
Ubogu EE, Katirji B.
Division of Neuromuscular Diseases, Department of Neurology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Hanna House 5th Floor, 11000 Euclid Avenue, Cleveland, OH 44106-5040, USA. eeubogu@excite.com
An 85-year-old woman developed sudden confusion and dysarthria progressing to mutism, orobuccal dyskinesias, generalized tremors worse with activity, ataxia, and rigidity with cog wheeling without high-grade fevers or dysautonomia. These findings were related temporally to the institution of mirtazapine as monotherapy for a major depressive illness with superimposed anxiety disorder. Withdrawal of the agent resulted in early notable clinical resolution with only residual hypertonia after 2 weeks. This is a rare report of serotonin syndrome induced by mirtazapine monotherapy. The hypothesized pathophysiologic mechanism in this case is overstimulation of serotonin (5-hydroxytryptamine or 5-HT) type 1A receptors (5-HT(1A)) in the brainstem and spinal cord in an individual with risk factors for hyperserotoninemia resulting from reduced, acquired endogenous serotonin metabolism.
A LETTER TO THE MEDICAL JOURNAL OF AUSTRALIATO THE EDITOR: We report two episodes of serotonin toxicity (or serotonin syndrome) caused by drug interaction in one individual chronically treated with dexamphetamine. The interacting drugs were venlafaxine, then later citalopram. We are not aware of any previous reports of serotonin toxicity caused by dexamphetamine in combination with either venlafaxine or any selective serotonin reuptake inhibitor (SSRI).
A 32-year-old man presented after two days of marked agitation, anxiety, shivering and tremor. He was being treated with dexamphetamine, 5 mg three times daily, for adult attention deficit hyperactivity disorder. He had started venlafaxine (75 mg daily) two weeks previously, and this had been increased to 150 mg daily after a week. On examination, he was alert and oriented, but diaphoretic, shivering and had fine motor tremor. His heart rate was 140 bpm, blood pressure was 142/93 mmHg and temperature 37.3°C. Pupils were 3 mm diameter and reactive, with no nystagmus or ocular clonus. There was generalised hypertonia, hyperreflexia, 12 beats of inducible ankle clonus, frequent myoclonic jerking and tonic spasm of the right side of his orbicularis oris muscle. His abdomen was tense, but non-tender, with normal bowel sounds. An electrocardiogram showed sinus tachycardia with a baseline tremor, but no other abnormality.
Therapy with dexamphetamine and venlafaxine was ceased, and cyproheptadine (8 mg doses up to a total of 32 mg over three hours) was given. The patient had a stepwise reduction in heart rate, with complete resolution of his symptoms, and was discharged the next morning. Dexamphetamine therapy was restarted three days later and citalopram therapy was commenced one week after discharge. Two weeks after discharge, he reported similar symptoms, and ceased citalopram. Three days later he was still agitated, with nausea, diarrhoea and teeth clenching. There was no rigidity, tremor or diaphoresis, and his heart rate was 76 bpm. He was given two 8 mg doses of cyproheptadine and was asymptomatic two days later.
Some of this patient's symptoms could be attributed to noradrenaline excess. However, the combination of neuromuscular and autonomic features is more consistent with serotonin toxicity. The fact the symptoms resolved after administration of cyproheptadine (a 5-HT2-receptor antagonist) supports this hypothesis. There is no theoretical reason why the interaction of citalopram (a pure SSRI) and dexamphetamine should cause catecholamine excess, and again the more likely explanation is serotonin toxicity.
Dexamphetamine causes psychostimulation and increased peripheral sympathomimetic activity. Centrally it causes presynaptic release of serotonin,1 and dopamine and catecholamine release.2 Venlafaxine and its metabolite, O-desmethylvenlafaxine, inhibit both neuronal 5-HT reuptake and noradrenaline reuptake,3 whereas citalopram, an SSRI, has little effect on noradrenaline reuptake.4 The combination of serotonin reuptake blockade and either presynaptic release of serotonin or monoamine oxidase inhibition by dexamphetamine will cause increased serotonin levels in the central nervous system, and is the likely mechanism of toxicity in this patient. This is consistent with the mechanism for other reports of serotonin toxicity.5
Increased awareness and cautious monitoring is advised when using a combination of dexamphetamine and either venlafaxine or an SSRI. This is particularly important in people using amphetamines recreationally and in children taking dexamphetamine for attention deficit hyperactivity disorder.
I also found this reference to a report of SS due to a combination of venlafaxine and mirtazapine but could not get access to the article........
World J Biol Psychiatry. 2002 Jul;3(3):167. Related Articles, LinksSerotonin syndrome produced by a combination of venlafaxine and mirtazapine.
Dimellis D.
.............RISPERIDONE .
There is also a small amount of evidence that some patients treated with risperidone plus a serotonin reuptake inhibitor may experience neurotoxicity. Venlafaxine inhibits the reuptake of serotonin. Here are a couple of reports...........
ABSTRACT 1
Ann Pharmacother. 2003 Mar;37(3):388-91. Related Articles, Links
Comment in:
Ann Pharmacother. 2003 Oct;37(10):1531-2; author reply 1532-3.Combination risperidone and SSRI-induced serotonin syndrome.
Karki SD, Masood GR.
School of Pharmacy, State University of New York at Buffalo, Buffalo, NY, USA. skarki@moroehosp.org
OBJECTIVE: To report 2 cases of serotonin syndrome associated with combined therapy of risperidone and selective serotonin-reuptake inhibitors (SSRIs) in elderly patients. CASE SUMMARIES: An 86-year-old white man was admitted to the emergency department because of increased confusion and generalized weakness over the past several days. His medication history indicated paroxetine 10 mg/d and risperidone 0.25 mg/d. The patient's confusion worsened and underwent acute changes that resembled delirium. He was placed in a geri chair and he became extremely agitated. He was then treated with escalating doses of risperidone. The patient died on day 5 of admission, at which time he was being treated with risperidone 2-3 mg/d. A 78-year-old white female nursing home resident was admitted to the emergency department because of increased confusion and generalized weakness. She was being treated with paroxetine for depression and risperidone for agitation. Her risperidone dose was increased to manage agitation. The patient's agitation worsened with increasing doses of risperidone; she developed tremor, dizziness, and muscle incoordination. After psychopharmacologic consultation, the risperidone and paroxetine were discontinued and she was treated with lorazepam. The patient recovered, returned to baseline status in 2 days, and was later transferred back to the nursing home. DISCUSSION: We believe that in both cases, serotonin syndrome was precipitated by risperidone in combination with SSRI antidepressants. A literature search indicated one report of serotonin syndrome with a combination of risperidone and paroxetine. CONCLUSIONS: An objective causality assessment revealed that the adverse drug event was probable in the first patient and definite in the second patient. We caution clinicians treating elderly patients with combined risperidone and SSRIs to include serotonin syndrome in differential diagnosis if the patient is showing signs of increasing agitation with escalating doses of risperidone.ABSTRACT 2
Ann Pharmacother. 2002 Mar;36(3):440-3. Related Articles, Links
Comment in:
Ann Pharmacother. 2002 Jul-Aug;36(7-8):1293; author reply 1294.Neurotoxic syndrome associated with risperidone and fluvoxamine (an SSRI)
Reeves RR, Mack JE, Beddingfield JJ.
GV (Sonny) Montgomery Veterans Administration Medical Center, Department of Psychiatry, Jackson, MS 39216-5116, USA. roy.reeves2@med.va.gov
OBJECTIVE: To report a case of a neurotoxic syndrome in a patient undergoing concomitant treatment with risperidone and fluvoxamine. CASE REPORT: A 24-year-old African American woman hospitalized for psychosis was unresponsive to risperidone. Because of obsessive symptoms, low doses of fluvoxamine were added to her treatment regimen. Within 2 days, she developed confusion, diaphoresis, diarrhea, hyperreflexia, and myoclonus, which then progressed to rigidity, fever, and unresponsiveness, requiring endotracheal intubation. Symptoms resolved over 10 days with discontinuation of medication, hydration, and bromocriptine 5 mg 3 times daily. Ultimately, she was treated with olanzapine and fluvoxamine without adverse effects. DISCUSSION: This represents the first reported case of a neurotoxic syndrome secondary to treatment with risperidone and fluvoxamine. Differential diagnosis between neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) could not be accurately determined because of the overlap of signs and symptoms of both syndromes. NMS and SS may represent different aspects of a more generalized neurotoxic syndrome. This could be an important consideration in formulating treatment for neurotoxic syndromes. CONCLUSIONS: Clinicians should be aware of potentially serious adverse reactions that may occur during concomitant treatment with antipsychotics and selective serotonin-reuptake inhibitors............
Overall, the thing which stands out the most when looking at your wife's medication is the very high dose of venlafaxine. As I already said, venlafaxine can cause the SS. Severe SS may cause seizures. Venlafaxine has also been reported to cause SS in the absense of the SS, particularly in overdose.
The association between Remeron and SS is much less certain, whether Remeron can actually cause SS seems to be quite controversial. The link between Risperdal and the SS is also doubtful.
............
It is important to notice that SS usually occurs quite rapidly after a change in medication eg. the addition of an extra med or an increase in dose. It is important to find out whether there were any changes in your wife's medication shortly before she died. Had there been a recent increase in the dose of Effexor or Remeron? Any Effexor dose changes are especially important.
Effexor, Remeron, Risperdal, Stadol and Adderall all need to be used with caution in epilepsy. It is possible that these meds may cause seizures. The link between seizures and Effexor is probably the strongest, there is less information about the effect of the other medications on epilepsy. I did notice the dose of Remeron was very high though, perhaps this could have caused a seizure, I don't know. Some animal research has been done to examine the link between venlafaxine and seizures, the introduction to the study noted that.....
'Clinical seizures after venlafaxine treatment have occasionally been reported when the drug was used at very high doses or in combination with other medications.'
I was concerned when you mentioned that your wife may have had abnormal liver function resulting from hepatitis. Again, it was the very large dose of venlafaxine which was the problem. Here is what the BNF says about venlafaxine....
'Halve dose in moderate hepatic(liver) impairment; avoid if severe'.
The implication is that mild impairment of liver function may not be relevant. The BNF always mentions mild impairment if it is thought to be relevant. Did you wife have any liver function tests performed which showed persistent damage from the hepatitis? Or had the liver healed?
When you mentioned the clonazepam I wondered whether your wife had missed a dose by mistake (or maybe a few doses). Abruptly stopping clonazepam can induce severe withdrawal symptoms and convulsions. Seizures may also occur on stopping Trileptal suddenly but this is probably not so likely. The problem with using clonazepam as a long-term anti-epileptic is that its anticonvulsant effect decreases significantly after a few weeks or months of continuous treatment, increasing the dose is not always effective in restoring its efficacy. It is possible that some of your wifes symptoms may have been due to withdrawal.
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I think the your wifes psychiatrist had some very difficult decisions to make. In general, it is recommended that if anyone suffers seizures while taking meds which can cause seizures, the possible culprits should be stopped. Eg. Stop the effexor, adderall etc. This can be very difficult, however, because the medication may be necessary to control other conditions such as bipolar disorder.
A FINAL POINT ..
Trileptal (an anticonvulsant/anti-manic) and Effexor (an antidepressant) can both cause hyponatremia (low blood sodium concentration) as a side effect. Here is the official English warning on the risk of hyponatremia with antidepressants....
'Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants; however, it has been reported more frequently with SSRIs than with other antidepressants. The CSM has advised that hyponatraemia should be considered in all patients who develop **drowsiness, confusion, or convulsions** while taking an antidepressant.'
Hyponatremia would not explain your wife's other symptoms though, SS is probably a better explanation.I hope this information is helpful and not too upsetting.
Ed
poster:ed_uk
thread:413243
URL: http://www.dr-bob.org/babble/20041108/msgs/414245.html