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Serotonin syndrome and neuroleptic malignant syndrome

From: "Max Fink [Psychiatry]" <mfink@epo.som.sunysb.edu>
Date: Tue, 19 Dec 1995 08:37:50 EST
Subject: Toxic serotonin syndrome, NMS, and catatonia

The inquiry about the serotonin syndrome reminded me that we had posted a story about a patient with recurrent depressive mood disorder who had received l-dopa, trazodone, and a single dose of nortriptyline -- after which she developed an acute syndrome of agitation, mutism, and diarrhea, followed by rigidity. On admission to a psychiatric ER, she was diagnosed with NMS and treated with lorazepam with some relief. As she had not received neuroleptics in many months, the diagnosis was changed to TSS -- toxic serotonin syndrome. She eventually received ECT and recovered to her usual euthymic inter-episode state.

Two good recent references are:

Sternbach H. The serotonin syndrome. [Review] American Journal of Psychiatry. 148 (6): 705-13, 1991 Jun. Comments: 1992 Mar, 149 (3): 411-2; 1992 Aug, 149 (8): 1116-7; 1993 Mar, 150 (3): 522.

Braitberg G. Serotonin syndrome [letter]. Medical Journal of Australia. 160 (8): 527-8, 1994 Apr 18. Comment on: 1993 Nov 1, 159 (9): 624-6.

TSS has all the hallmarks of NMS except that GI symptoms are more prominent and that neuroleptics are not the offending agent.

Perhaps we should include TSS in the same package as NMS [and catatonia] for treatment purposes?

From: "Max Fink [Psychiatry]" <mfink@epo.som.sunysb.edu>
Date: Wed, 20 Dec 1995 08:04:25 EST
Subject: Toxic serotonin syndrome, NMS, and catatonia

I have only recognized one case of TSS. The literature cases are quite remarkably like NMS. The literature argues that NMS is responsive to benzodiazepines and to ECT. In the next number of Biological Psychiatry, I have laid out the argument that NMS should be viewed and treated like catatonia, of which it is a subtype:

Fink M. Neuroleptic malignant syndrome and catatonia: one entity or two? [editorial]. [Review] Biological Psychiatry. 39 (1): 1-4, 1996 Jan 1. Comment: 1996 Sep 1, 40 (5): 431-3.

If the signs and symptoms of TSS are what have been described by others, and if it is not responsive to:

1. medication withdrawal
2. benzodiazepines

Date: Mon, 25 Dec 1995 10:58:15 -0500 (EST)
From: Bill Boyer <wboyer@emory.edu>
Subject: Serotonin syndrome and NMS

I am not convinced that stiffness is a prominent part of the [serotonin] syndrome. In a series of 13 patients I helped publish, it was not a common feature.

I have been using the presence of marked stiffness with hyperthermia to distinguish NMS from the serotonin syndrome.

[perhaps: Feighner JP, Boyer WF, Tyler DL, Neborsky RJ. Adverse consequences of fluoxetine-MAOI combination therapy. Journal of Clinical Psychiatry. 51 (6): 222-5, 1990 Jun. Comment: 1991 Feb, 52 (2): 87-8.]

From: "Max Fink [Psychiatry]" <mfink@epo.som.sunysb.edu>
Date: Mon, 5 Feb 1996 16:04:42 EST
Subject: Serotonin syndrome from venlafaxine + sertraline and in general

The Feder inquiry about the safety of venlafaxine brought out a case of TSS from the combination of Effexor (venlafaxine) and sertraline (Zoloft). The patient died and the treatment noted in the abstract is that of dantrolene/bromocriptine.

• The efficacy of dantrolene/bromocriptine in NMS is unproven.

• There is no evidence of efficacy of these drugs for TSS.

• We now look upon NMS as a type of catatonia and the best treatment remains benzodiazepines (or barbiturates) in high doses and, when these fail, ECT.

• It seems to me that clinicians should expect to be called for such emergencies and, when TSS or NMS or catatonia is a possibility, to eschew dantrolene/bromocriptine and to use lorazepam/ECT.

Date: Wed, 6 Mar 1996 16:57:20 +0200 (EET)
From: Pekka Roponen <shrink@walrus.megabaud.fi>
Subject: Serotonin syndrome from moclobemide + clomipramine

On Fri, 1 Mar 1996, Dr. Raymond W. Lam wrote:

Deaths have been reported with the combination of moclobemide and clomipramine so tricyclics are contraindicated. I usually warn about meperidine (Demerol) and sympathomimetics as potential concerns, but there have been no reports yet as far as I am aware. Our equivalent of the PDR says that amphetamines should not be used with moclobemide (as with MAOIs).

Date: Tue, 28 May 1996 00:36:32 -0500
From: Stephen R Saklad <Saklad@uthscsa.edu>
Subject: Serotonin syndrome

At 18:18 5/27/96, George Davidson wrote:

Is there a minor form of serotonin syndrome that one could recognise and treat before the full-blown thing happens?

What are the situations where serotonin syndrome is a realistic possibility and should be closely watched for?

• All drugs with MAOI activity (including isoniazid, but I've not had a problem).

• Serotonin precursors (tryptophan is the obvious potential problem, but it remains unmarketed in the USA).

• Drugs that stimulate or mimic serotonin release (eg, d-fenfluramine or high doses of cyproheptadine).

Date: 01 Jul 96 23:28:07 EDT
From: Raymond Behr <71514.3051@compuserve.com>
Subject: Serotonin syndrome from moclobemide + SSRIs

This was found in a recent article in the Psychiatric Times written by by Russell T. Joffe, M.D.:

Furthermore, the combination of moclobemide and SSRIs has been shown to be effective and well-tolerated in selected cases of refractory depression (Joffe RT, Bakish D. Combined SSRI-moclobemide treatment in psychiatric illness. J Clin Psychiatry. 1994; 55: 24-25), although these data are preliminary and do not suggest that this combination is safe for general use. Furthermore, the current package insert guidelines for the drug in Canada specify that moclobemide should not be used in combination with selective serotonin reuptake inhibitors.

(Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses have been reported however. See: Neuvonen PJ, et al. Lancet. 1993; 342 (8884): 1419 --Ed. [of Psychiatric Times])

Date: 09 Aug 96 22:47:17 EDT
From: Troy Caldwell <75112.1676@compuserve.com>
Subject: Serotonin syndrome

I'd be very grateful if you could explain what to have patients look for to identify serotonin syndrome.

--Bonnie Spring

Date: Thu, 13 Mar 1997 20:46:34 -0330
From: jamie@nfld.com (Dr. James Karagianis)
Subject: NMS from clozapine

At 12:48 AM 3/13/97, Joze Darovec wrote:

Do you believe in clozapine (alone) induced NMS? I do not. I am working in a psychiatric hospital with 600 beds, we have been using clozapine from 1975 on, continously having about 30 patients daily on it, and we haven't seen a single NMS due to clozapine as the only drug.

From: "George Nasra" <nasdoc@netacc.net>
Date: Sat, 15 Mar 1997 18:49:35 +0000
Subject: NMS from clozapine

When clozapine was new, the thought was it shouldn't cause NMS. Since then several reports were published that refuted that belief. I am including two as an example, there are others.

Miller DD, Sharafuddin MJA, Kathol RG: A case of clozapine-induced neuroleptic malignant syndrome. Journal of Clinical Psychiatry 52: 99-101, 1991

Anderson ES, Powers PS: Neuroleptic malignant syndrome associated with clozapine use. Journal of Clinical Psychiatry 52: 102-104, 1991

Date: Tue, 18 Mar 1997 01:34:14 -0600
From: Larry Ereshefsky <Ereshefsky@uthscsa.edu>
Subject: NMS from clozapine

The following case report includes a summary of the research and clinical criteria proposed to diagnose NMS. (DSM-IV also has criteria.) If a patient meets criteria, it is NMS, even if the drug is not likely to do it (as in our case of clozapine monotherapy).

Thornberg SA, Ereshefsky L. Neuroleptic Malignant Syndrome Associated with Clozapine Monotherapy. Pharmacotherapy 1993; 13 (5): 510-514.

Date: Sat, 28 Dec 1996 02:10:21 -0800 (PST)
From: Mary Montgomery <marym@teleport.com>
Subject: Serotonin syndrome

I'm posting this note because I found a good reference article, albeit dated at this point, on the subject:

Mills KC. Serotonin syndrome. [Review] American Family Physician. 52 (5): 1475-82, 1995 Oct. Comments: 1263, 1266, 1271.

Summary of the article:

Serotonin syndrome is a potentially life-threatening complication of psychopharmacologic drug therapy. The syndrome is produced most often by the concurrent use of two or more drugs that increase brainstem serotonin activity and is often unrecognized because of the varied and nonspecific nature of its symptomatology. Serotonin syndrome is characterized by alterations in cognition, behavior, autonomic nerous system function and neuromuscular activity. Patients with serotonin syndrome usually respond to discontinuation of drug therapy and supportive care alone, but they may require treatment with a specific antiserotonergic drug such as cyproheptadine, methysergide, and/or propranolol.

High points of the article:

• Serotonin syndrome occurs only in the setting of drug therapy that has a net effect of augmenting brain serotonin neurotransmission and occurs more commonly when two or more serotonergic drugs are given concurrently, however, the sydrome has also been reported with single drug exposure in both therapeutic and overdose settings.

• The earliest symptoms of serotonin syndrome are commonly misinterpreted as an exacerbation of the patient's underlying psychiatric condition; this mistake may then lead to either inappropriate continuation of the drug therapy or even an increased dosage of the offending medication. In its most severe presentation, serotonin syndrome resembles neuroleptic malignant syndrome.

• Antidepressants (obviously) are the most common offending agents. Although SSRIs and MAOIs are equally likely to cause serotonin syndrome, it's interesting that among the TCAs, the medications clomipramine and imipramine are the most likely precipitating agents. [I found this intriguing because I often use imipramine in combination with an SSRI. --JMT]

• Serotonin syndrome usually develops shortly after either an increase in the dose of one or the addition of another serotonergic medication. In half of the published cases, symptoms began within two hours of a change in medication. In only 25% of the cases was the onset of symptoms more than 24 hours after a change.

• Signs and symptoms based on review of 100 cases:

  Cognitive behavioral
  51	confusion/disorientation
  34	agitation/irritability
  29	coma/unresponsiveness
  15	anxiety
  14	euphoria/hypomania
  < 13	headache
  	drowsiness
  	seizures
  	insomnia
  	hallucinations
  	dizziness
  Autonomic
  45	hyperthermia
  45	diaphoresis
  36	sinus tachycardia
  35	hypertension
  28	dilated pupils
  26	tachypnea
  23	nausea
  20	unreactive pupils
  16	flushing
  15	hypotension
  < 15	diarrhea
  	ventricular tachycardia
  	cyanosis
  	abdominal cramps
  	salivation
  Neuromuscular
  58	myoclonus
  52	hyper-reflexia
  51	muscle rigidity
  48	restlessness/hyperactivity
  43	tremor
  40	ataxia/incoordination
  23	clonus
  16	bilateral positive babinski
  < 15	trismus
  	teeth chattering
  	opisthotonus
  	paresthesias

• The diagnosis of serotonin syndrome is based entirely on a strong clinical suspicion and the exclusion of other medical and psychiatric conditions. The typical patient with serotonin syndrome demonstrates altered behavior and cognitive ability, autonomic nervous system dysfunction, and neuromuscular abnormalities. Some patients report recurrent mild symptoms days to weeks before symptoms become more severe. In a few cases, patients rapidly progress to multiple organ failure and death. Serotonin syndrome has been reported in pediatric patients.

• No specific tests are available for the diagnosis of serotonin syndrome. Elevated serotonergic drug levels are not required to produce serotonin syndrome, and in over 90 percent of cases in which drug levels were measured, levels were within accepted therapeutic limits.

• Noteworthy drug interactions:
  1. Meperidine (Demerol) and dextromethorphan are potent inhibitors of serotonin uptake and are notorious for precipitating acute serotonin syndrome, especially in patients taking MAOIs, including selegiline (Eldepryl).

  2. Drugs that increase central nervous system dopamine concentrations, such as levodopa (Sinemet), bromocriptine (Parlodel) and selegilene, have the potential to precipitate serotonin syndrome by means of their ability to cause indirect serotonin release.

  3. Many cases of serotonin syndrome have occurred when lithium was combined with another serotonergic agent.

• The majority of patients can be effectively managed using four basic principles:
  1. Provide necessary supportive care.

  2. Discontinue all serotonergic drugs.

  3. Consider use of antiserotonergic medications.

  4. Make necessary adjustments in the medication regimen before reinstituting serotonergic medications.

• Cyproheptadine is consistently the most effective agent in humans. The inital dose is usually 4 to 8 mg orally. This dose can be followed by repeat doses of 4 mg every two to four hours, up to a total of 0.5 mg/kg/day. Watch for anticholinergic symptoms (e.g., urinary retention) when using higher doses.

• The prognosis is good: 70 percent of cases show complete resolution within 24 hours of symptom onset.

I hope that some among us may find this helpful. Summarizing and typing it gave me a chance to review and digest the information, which I began to look for only after being prompted by some of the excellent discussion here on the list.

--John M. Talmadge, M.D.

Date: Fri, 01 Aug 1997 09:55:25 -0700
From: "Kathleen Schilli, PharmD." <DrRx@ix.netcom.com>
Subject: Serotonin syndrome

Here are some additional points:

• Tramadol (Ultram) is another potent inhibitors of serotonin uptake.

• Codeine products have also been reported to contribute to serotonin syndrome.

• L-tryptophan, fenfluramine (Pondimen), and dexfenfluramine (Redux) can add to the total amount of serotonin by releasing serotonin from nerve terminals.

• Sedation and increased fall risk, especially with elderly patients, are other side-effects of cyproheptadine.

And another reference is:

Sporer, KA. Serotonin Syndrome: Implicated Drugs, Pathophysiology & Management, Drug Safety 1995; 13 (2): 94-104.

Date: Fri, 15 Aug 1997 19:51:45 -0400
From: Whit Garberson <jwgg@world.std.com>
Subject: Serotonin syndrome from two SSRIs

I want to report a couple of surprising turnarounds I've witnessed in the last couple of weeks of my geropsychiatry rounds. In two cases, I was referred frail elderly patients who had somehow been placed on two SSRIs concurrently.

Case 1 was an 80-something woman with chronic obstructive pulmonary disease... She was terribly depressed, anergic, and unwilling to put any effort into respiratory therapy, for which she had been admitted. She was tried on paroxetine 20 mg qd with intolerable GI discomfort, so her pulmonologist decided to switch her to fluoxetine 20 qd. However, the paroxetine order was never discontinued, and the two medications were given concurrently for a week. Interestingly, her GI distress seemed to diminish during this week, but otherwise she complained of weakness, despondency, and suicidal fantasies, interrupted only by frank panic episodes and some previously-unseen confusion and agitation. We discontinued the paroxetine, and within 36 hours saw a dramatic lifting of depression and anxiety and a sudden enthusiasm for rehabilitation.

Case 2 was a 90-something woman with... cellulitis. She was extremely fussy, mildly demented, and moderately depressed and -- most strikingly -- had an obsessive compulsive personality disorder. She got a urinary tract infection and began to show some paranoia not seen before. We had good success with fluvoxamine; she looked and felt much better on a total of 75 mg/day. However, her cellulitis flared up, she was admitted to the hospital, and she came back still on the fluvoxamine, but with the addition of paroxetine 20 mg/day. She was agitated, confused, reclusive, and anorectic and "didn't feel like herself." Significantly increased word-retrieval problems. This was one week ago. We discontinued the paroxetine, and today I saw this woman out of bed, propelling her own wheelchair, interacting with staff and residents quite appropriately, and en route to her first Catholic mass in > 2 years.

These cases are hard to draw firm conclusions from because there are of course other medical and psychosocial variables, but I thought they were interesting.

Date: Sun, 25 Jan 1998 15:34:42 PST
From: Camilla Cracchiolo <camilla@PrimeNet.Com>
Subject: Serotonin syndrome from St. John's wort

The LI-160 fraction (the part of St. John's wort soluble in alcohol) has been shown not to inhibit MAO. However, the whole herb does contain an unknown compound which irreversibly inhibits both MAO-A and MAO-B. There is one report of a stroke in an elderly woman using a whole herb St. John's wort and a sympathomimetic drug for bladder spasms. Classic signs of MAOI related stroke: sudden hypertensive crisis 48 hours after beginning St. John's wort, blood pressure shooting up to 260/140, gross tremors, residual right hemiparesis.

The evidence seems to be that the LI-160 fraction is safe, but all bets are off for other St. John's wort preparations.

I strongly advise against combining St. John's wort with stimulants unless you know for sure that you have the LI-160 fraction or a similar alcohol extract.

I also am now advising people not to use St. John's wort preparations made in the U.S. due to lack of manufacturing oversight. Some people here are just taking whole St. John's wort, chopping it up, and sticking it in capsules. Get German St. John's wort: there is some regulation of purity over there.

As to combining St. John's wort with SSRIs: I now have three anecdotal reports of what sounds like serotonin syndrome from St. John's wort. Two were in persons combining St. John's wort with SSRIs, and one (the most serious case) was in a person using St. John's wort alone. I would say that you should observe the same precautions as when combining any other serotonergic agents.

For more information, see my St. John's wort FAQ.

Date: Sun, 24 May 1998 16:41:52 PST
From: Camilla Cracchiolo <camilla@PrimeNet.Com>
Subject: Serotonin syndrome from St. John's wort

I received the following note and I thought I would pass this along. It confirms other reports I've received of side effects suggestive of serotonin syndrome.

I am a chemist (B.S.), and out here in North Dakota everyone seems to think a chemist automatically knows everything about drugs and chemicals. I had so many people bugging me about St. John's wort last year that I actually put together a one inch binder full of information.

I am passing on the URLs of some recent reports I have come across about the toxicity of St. John's wort. They deal with more reports of serotonin syndrome.

• St. John's Wort Tied to Serotonin Syndrome
  Clinical Psychiatry News, 3/98

• SSRIs and St. John's Wort: Possible Toxicity?
  American Family Physician [letter], 3/98

--Michael Froehlich

Date: Sun, 24 May 1998 20:17:18 PST
From: Camilla Cracchiolo <camilla@PrimeNet.Com>
Subject: Serotonin syndrome from St. John's wort

We don't know what's in most bottles of St. John's wort, given that there is no manufacturing regulation of herbal products in the US. There may be adulterates in St. John's wort products, but the symptoms listed are consistent with serotonergic agents and St. John's wort does appear to affect 5-HT1a and 5-HT2 receptors, at least in rats.

Several cases of serotonin syndrome-like effects occurred when mixing St. John's wort and SSRIs. This is again consistent with a serotonergic antidepressant. A few of the cases occurred in people who weren't taking any other antidepressant.

I don't know whether these were tablets or tinctures, but all the St. John's wort products I've seen are whole herb compounds.

The reports I looked up were not specific as to dosage, but other reports I've personally received were at the standard dose on the bottle and no one brand was represented more than another. However, in one case, the person switched from one brand to another; both were labelled to be the same strength and she took the same dose of each but had a much stronger reaction to the second brand. This fits with the Good Housekeeping Institute's recent finding that products labelled "Hypericin, 0.3%" have as much as a 17 fold difference in actual hypericin content. Hypericin is not the main antidepressant agent, but is an indicator of concentration. So much for labels.

Bottom line:

I still think St. John's wort is a potentially useful antidepressant; serious adverse reactions appear to be rare.

Avoid giving St. John's wort with other antidepressants, inform patients of the symptoms of serotonin syndrome, and tell them to check in immediately if they occur. Doctors should be alert to the signs of serotonin syndrome; any patient presenting with confusion or rapid heart rate should be asked (or their family asked) if they have taken St. John's wort or other herbs. In one case reported to me, the woman saw several doctors and wound up admitted to the hospital, but nobody had a clue as to what was going on with her because they didn't ask about herbal drugs!

The public needs to be educated about the risks of self treating depression with St. John's wort, and bottles need to be clearly labelled with the admonitions not to take it with other drugs without consulting a physician and to discontinue use and consult a doctor if certain symptoms occur.

Date: Thu, 22 Oct 1998 09:25:53 +0300
From: "Pekka V. Roponen, MD." <pekka.roponen@docpro.fimnet.fi>
Subject: Serotonin syndrome from moclobemide + clomipramine

On 22.10.1998 at 18:00, clgale@iconz.co.nz (c gale) wrote:

I have seen serotonin syndrome with moclobemide/clomipramine.

Date: Wed, 18 Nov 1998 10:27:42 -0200
From: Pekka Roponen <pekka.roponen@docpro.fimnet.fi>
Subject: Serotonin syndrome from molobemide + citalopram

Warning: we have had several fatalities when intoxicated with [citalopram and] molobemide (MAO-A inhibitor), so keep that in mind if you prescribe MAOIs before or after citalopram. The deaths resulted from serotonin syndrome, and somehow the SSRI always was citalopram (coindicence?).

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